Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators in Neuroprotection

Liliana Mititelu-Tartau, Maria Bogdan, Victor Gheorman, Liliana Foia, Ancuta Goriuc, Gabriela Rusu, Beatrice Buca, Liliana Pavel, Ana Cristofor, Cosmin-Gabriel Tartau and Gratiela Eliza Popa

#### Abstract

Due to brain plasticity, the nervous system is capable of manifesting behavioral variations, adapted to the influences from both external and internal environment. Multiple neurotransmitters are involved in the mediation of pathological processes at the molecular, cellular, regional, and interregional levels participating in cerebral plasticity, their intervention being responsible for various structural, functional, and behavioral disturbances. The current therapeutic strategies in neuroprotection aim at blocking on different levels, the molecular cascades of the pathophysiological mechanisms responsible for neuronal dysfunctions and ultimately for neuronal death. Different agents influencing these neurotransmitters have demonstrated beneficial effects in neurogenesis and neuroprotection, proved in experimental animal models of focal and global ischemic injuries. Serotonin, dopamine, glutamate, N-methyl-D-aspartate, and nitric oxide have been shown to play a significant role in modulating nervous system injuries. The imidazoline system is one of the important systems involved in human brain functioning. Experimental investigations have revealed the cytoprotective effects of imidazoline I2 receptor ligands against neuronal injury induced by hypoxia in experimental animals. The neuroprotective effects were also highlighted for kappa and delta receptors, whose agonists demonstrated the ability to reduce architectural lesions and to recover neuronal functions of animals with experimentally induced brain ischemia.

Keywords: neuroprotection, neurodegenerative diseases, ischemic stroke, imidazoline, opioids, nitric oxide

#### 1. Introduction

Increase in life expectancy has led to aging of the population and consequently to an expansion of the prevalence of neurodegenerative diseases (NDDs) [1].


NDDs (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia with Lewy bodies) determine cognitive and memory deterioration or alteration of the ability to move, speak, and breathe. These chronic and progressive disorders are an important cause of reduced quality of life, morbidity, caregiver burden and also, of the increase in total healthcare expenditure [3–5]. Table 1 lists

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators…

Neuroprotection can be defined as a "relative preservation of neuronal structure and/or function" or as an action that aims "to prevent neuronal damage over time (either acute or chronic)" [7]. Neuroprotective action is primary if it is exerted directly on the neuron, or secondary if it appears from an activity on an intermedi-

The mechanisms by which most agents with efficiency in NDDs act are not fully

Several experimental investigations highlight the multiple and various interrelations between adrenergic, serotoninergic, dopaminergic, glutamatergic, opioid, imidazoline systems, and the nitric oxide pathways, which may elucidate the effects of different compounds involved in the mediation of pathogenic mechanisms responsible for numerous structural, functional, and behavioral

This chapter presents a brief overview of the most studied mechanisms related

Imidazoline receptors are located not only in the mammalian central nervous system (CNS) cells but also in the peripheral nervous system [9], being involved in the mediation of various physiological processes in the body. It is currently known that there are four types of imidazoline receptors: I1, I2, I3, I4 (non I1-non I2), from

It has been emphasized that these receptors play an essential role in cell proliferation, regulation of adipose tissue formation, body temperature maintenance, mediation of gastrointestinal motility, neuroprotection, inflammation, nociceptive sensitivity, and some neurological or psychiatric disorders (such as depression) [11]. Moreover, it is known that these imidazoline receptor subtypes exert control over the activity of the hypothalamic-pituitary-adrenal and noradrenergic axis

A number of different endogenous ligands have been characterized: agmatine, the best known and largely studied, harmane and harmalane (derivatives of the beta-carboline group), and the newly discovered ribotide (acetic acid imidazole). Agmatine, the potent neurotransmitter of the imidazoline system, has an important role in the mediation of body's response to stress, analgesia, drug addiction, and

Endogenous agmatine is produced in response to stress (in conditions of ischemia, prolonged exposure to cold) and/or to inflammation [16]. It is assumed that agmatine is also an effective neurotransmitter, due to its concentration in the brain

Literature data have revealed that agmatine stimulates the activity of endothelial nitric oxide synthase [16], this effect being also proved by its level in the rat brain

abstinence syndrome, in modulation of seizures development, and in

to neuroprotection and details the possibilities to pharmacologically influence through the main known neurotransmitters the pathophysiological mechanisms

elucidated, requiring multiple and in-depth experimental and clinical studies.

the main clinical types of NDDs [6].

DOI: http://dx.doi.org/10.5772/intechopen.81951

ary that endangers neuronal function [8].

disturbances.

[12, 13].

15

neuroprotection [14, 15].

after cerebral ischemia [19, 20].

similar to classical neurotransmitters [17, 18].

linked to various NDDs.

2. The imidazoline system

which the first three have been mostly studied [10].

\*Adapted from Ropper A, Samuels M, Klein J. Adams and Victor's Principles of Neurology. 10th ed. McGraw-Hill Education; 2014.

#### Table 1.

Neurodegenerative diseases: main clinical types.

Neurodegeneration represents a loss of neurons and their structural components (dendrites, axons, and synapses) with a corresponding gradual atrophy in neuronal function [2].

#### Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators… DOI: http://dx.doi.org/10.5772/intechopen.81951

NDDs (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia with Lewy bodies) determine cognitive and memory deterioration or alteration of the ability to move, speak, and breathe. These chronic and progressive disorders are an important cause of reduced quality of life, morbidity, caregiver burden and also, of the increase in total healthcare expenditure [3–5]. Table 1 lists the main clinical types of NDDs [6].

Neuroprotection can be defined as a "relative preservation of neuronal structure and/or function" or as an action that aims "to prevent neuronal damage over time (either acute or chronic)" [7]. Neuroprotective action is primary if it is exerted directly on the neuron, or secondary if it appears from an activity on an intermediary that endangers neuronal function [8].

The mechanisms by which most agents with efficiency in NDDs act are not fully elucidated, requiring multiple and in-depth experimental and clinical studies.

Several experimental investigations highlight the multiple and various interrelations between adrenergic, serotoninergic, dopaminergic, glutamatergic, opioid, imidazoline systems, and the nitric oxide pathways, which may elucidate the effects of different compounds involved in the mediation of pathogenic mechanisms responsible for numerous structural, functional, and behavioral disturbances.

This chapter presents a brief overview of the most studied mechanisms related to neuroprotection and details the possibilities to pharmacologically influence through the main known neurotransmitters the pathophysiological mechanisms linked to various NDDs.

#### 2. The imidazoline system

Imidazoline receptors are located not only in the mammalian central nervous system (CNS) cells but also in the peripheral nervous system [9], being involved in the mediation of various physiological processes in the body. It is currently known that there are four types of imidazoline receptors: I1, I2, I3, I4 (non I1-non I2), from which the first three have been mostly studied [10].

It has been emphasized that these receptors play an essential role in cell proliferation, regulation of adipose tissue formation, body temperature maintenance, mediation of gastrointestinal motility, neuroprotection, inflammation, nociceptive sensitivity, and some neurological or psychiatric disorders (such as depression) [11]. Moreover, it is known that these imidazoline receptor subtypes exert control over the activity of the hypothalamic-pituitary-adrenal and noradrenergic axis [12, 13].

A number of different endogenous ligands have been characterized: agmatine, the best known and largely studied, harmane and harmalane (derivatives of the beta-carboline group), and the newly discovered ribotide (acetic acid imidazole). Agmatine, the potent neurotransmitter of the imidazoline system, has an important role in the mediation of body's response to stress, analgesia, drug addiction, and abstinence syndrome, in modulation of seizures development, and in neuroprotection [14, 15].

Endogenous agmatine is produced in response to stress (in conditions of ischemia, prolonged exposure to cold) and/or to inflammation [16]. It is assumed that agmatine is also an effective neurotransmitter, due to its concentration in the brain similar to classical neurotransmitters [17, 18].

Literature data have revealed that agmatine stimulates the activity of endothelial nitric oxide synthase [16], this effect being also proved by its level in the rat brain after cerebral ischemia [19, 20].

Neurodegeneration represents a loss of neurons and their structural components (dendrites, axons, and synapses) with a corresponding gradual atrophy in neuronal

\*Adapted from Ropper A, Samuels M, Klein J. Adams and Victor's Principles of Neurology. 10th ed. McGraw-Hill

Clinical type Disease/disorder

• Alzheimer's disease • Frontotemporal dementias • Some cases of Lewy-body disease

• Huntington's disease (chorea)

• Cerebrocerebellar degeneration

• Polyglucosan body disease

• Multiple system atrophy • Essential tremor

• Lewy-body disease • Restricted dystonia

• Spinocerebellar ataxias • Cerebellar cortical ataxias

muscular weakness and atrophy • Motor disorders with amyotrophy

disorders • Hereditary sensorimotor neuropathies

• Progressive supranuclear palsy • Dystonia musculorum deformans • Huntington's disease (chorea) • Acanthocytosis with chorea • Corticobasal ganglionic degeneration

myoclonus

• Posterior cortical atrophy (visuospatial dementia)

• Cortical-striatal-spinal degeneration (Jakob's disease) • Dementia-Parkinson-amyotrophic lateral sclerosis complex

• Frontotemporal dementia with parkinsonism or ALS

• Complicated hereditary and sporadic cerebellar ataxias

• Pure or predominantly sensory or motor neuropathic

• Spastic paraplegia without amyotrophy

• Riley-Day autonomic degeneration

• Pigmentary degeneration of retina

• Age-related macular degeneration

• Hereditary hearing loss with retinal diseases

• Hereditary hearing loss with system atrophies of the nervous

• Pure neurosensory deafness

• Stargardt's disease

system

• Familial dementia with spastic paraparesis, amyotrophy, or

• Lewy-body disease (Parkinsonian features) • Some cases of Parkinson's disease • Corticobasal ganglionic degeneration

Signs of progressive dementia with no other neurological signs (absent/inconspicuous)

Neuroprotection

Signs of progressive dementia accompanied by other neurological abnormalities

Signs of movement disorders or

Signs of progressive ataxia

Signs of slowly developing

Sensory and sensorimotor

Signs of progressive blindness with or without other neurological disorders

Neurodegenerative diseases: main clinical types.

Signs characterized by degenerative neurosensory

other posture abnormalities • Parkinson's disease

function [2].

deafness

Education; 2014.

Table 1.

14

expression of glial fibrillary acidic protein in astrocyte cultures and by inhibiting MAO activity [26, 27]. Moreover, the beneficial effects of agmatine have been observed on ischemic-hypoxic lesions, on glutamate-induced neurotoxicity by activating the imidazoline receptors [28, 29]. It was also demonstrated that agmatine administration improves learning activity and memory of rats in experimental models of Alzheimer's disease and streptozotocin-induced type two diabetes mellitus [22, 30]. Other experimental investigations highlight the neuroprotective effect of intranasal administration of agmatine in elderly female rats, with a significant improve-

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators…

DOI: http://dx.doi.org/10.5772/intechopen.81951

The neuroprotective effects of agmatine on the morphological changes determined by repeated induced stress on medial prefrontal cortex and hippocampus of the rat were also investigated [31]. It was emphasized that under constant stress conditions, morphological alterations of the brain are associated with the reduction of endogenous agmatine levels [measured by high-performance liquid chromatography (HPLC)] and with an increase of arginine-decarboxylase level in the pre-

The exogenous administration of agmatine lowers brain morphological impairment, suggesting thus its neuroprotective effects against structural changes in the rat brain, under recurrent stress circumstances [32]. Moreover, elevated levels of agmatine have been evidenced in the blood, cortex, hippocampus, and hypothalamus, immediately after brain hypoxic ischemia. Other studies emphasize the neuroprotective influences of agmatine, highlighted by the increase of its brain levels, in rats subjected to prolonged cold-exposure stress conditions [33].

The neuroprotective potential of agmatine was also highlighted in the experi-

Parkinson's disease in mice [29]. The use of agmatine attenuates the loss of cellular dopamine from the black substance and repeated treatment improves short-term memory impairment induced by MPTP in elderly mice. The behavioral benefits of agmatine are associated with the decrease in MPTP-induced glutamate capture in the hippocampal area, suggesting thus its involvement in modulation of glutamate recapture, the possible mechanisms responsible for lowering glutamate extracellular

It is known that alteration of spatial memory in Parkinson's disease and schizophrenia is attributed to several factors, including hypofunction of glutamate and reduction of hippocampal volume [34]. Literature data report that the administration of the N-methyl-D-aspartate (NMDA) receptor antagonists (phencyclidine, also coded MK801) frequently impairs the late alternation performance in a standardized behavioral model of cognitive functions alteration similar to schizophrenia in laboratory animals [34]. The use of the glutamate/NMDA receptor antagonist phencyclidine

manifested by locomotor hyperactivity, motor-negative deficits, and cognition alterations (with memory impairment and visual attention) in laboratory animals. This substance was used to induce the experimental schizophrenia in laboratory animals [35, 36]. Agmatine attenuates cognitive and behavioral deficiency in rats with exper-

The effects of agmatine on memory alterations similar to those found in Alzheimer's disease have been evaluated in rats; in the pathogenesis of this degenerative disorder (which causes cognitive deficits in rodents), the fragment beta amyloid Aβ2 25–35 plays an essential role. Studies have shown that agmatine significantly reduces the alterations in memory and spatial learning induced by the beta amyloid Aβ2 25–35 fragment (the neurotoxic component of beta amyloid Aβ 1–42) in various behavioral experimental models, such as: the swimming test, the radial

mental model of 1-methyl-4-phenyltetrahydropyridine (MPTP)-induced

induces a spectrum of behavioral, neurochemical, and anatomical changes,

imental phencyclidine-induced schizophrenic manifestations [37].

arm maze test, and the object recognition test [38].

17

levels, thereby alleviating its neurotoxicity [29].

ment of neurological status and increase of survival rate [28, 29].

frontal cortex, hippocampus, striatum, and hypothalamus [32].

#### Figure 1.

Neuroprotective effects of agmatine and their first discovery.

Along with evidence of its neuromodulatory and neuroprotective properties, there are numerous preclinical studies demonstrating the beneficial effects of exogenous administration of agmatine in depression, anxiety, hypoxic ischemia, pain, morphine tolerance, memory impairment, Parkinson's disease, Alzheimer's disease, epilepsy, and other related conditions with traumatic brain injuries (Figure 1) [21–23]. All these are arguments in favor of the potential of agmatine as a new pharmacological agent for the treatment of various neurological diseases and NDDs [24].

#### 3. The involvement of the imidazoline system in the mediation of cognitive functions

Electrophysiological studies involving various brain areas, performed on laboratory animals with experimentally induced cerebral alterations, have demonstrated the neurotropic effects of agmatine [25].

In vitro experimental researches have shown that activation of I2 receptors via the agmatine endogenous ligand exerts neuroprotective effects by increasing the

#### Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators… DOI: http://dx.doi.org/10.5772/intechopen.81951

expression of glial fibrillary acidic protein in astrocyte cultures and by inhibiting MAO activity [26, 27]. Moreover, the beneficial effects of agmatine have been observed on ischemic-hypoxic lesions, on glutamate-induced neurotoxicity by activating the imidazoline receptors [28, 29]. It was also demonstrated that agmatine administration improves learning activity and memory of rats in experimental models of Alzheimer's disease and streptozotocin-induced type two diabetes mellitus [22, 30].

Other experimental investigations highlight the neuroprotective effect of intranasal administration of agmatine in elderly female rats, with a significant improvement of neurological status and increase of survival rate [28, 29].

The neuroprotective effects of agmatine on the morphological changes determined by repeated induced stress on medial prefrontal cortex and hippocampus of the rat were also investigated [31]. It was emphasized that under constant stress conditions, morphological alterations of the brain are associated with the reduction of endogenous agmatine levels [measured by high-performance liquid chromatography (HPLC)] and with an increase of arginine-decarboxylase level in the prefrontal cortex, hippocampus, striatum, and hypothalamus [32].

The exogenous administration of agmatine lowers brain morphological impairment, suggesting thus its neuroprotective effects against structural changes in the rat brain, under recurrent stress circumstances [32]. Moreover, elevated levels of agmatine have been evidenced in the blood, cortex, hippocampus, and hypothalamus, immediately after brain hypoxic ischemia. Other studies emphasize the neuroprotective influences of agmatine, highlighted by the increase of its brain levels, in rats subjected to prolonged cold-exposure stress conditions [33].

The neuroprotective potential of agmatine was also highlighted in the experimental model of 1-methyl-4-phenyltetrahydropyridine (MPTP)-induced Parkinson's disease in mice [29]. The use of agmatine attenuates the loss of cellular dopamine from the black substance and repeated treatment improves short-term memory impairment induced by MPTP in elderly mice. The behavioral benefits of agmatine are associated with the decrease in MPTP-induced glutamate capture in the hippocampal area, suggesting thus its involvement in modulation of glutamate recapture, the possible mechanisms responsible for lowering glutamate extracellular levels, thereby alleviating its neurotoxicity [29].

It is known that alteration of spatial memory in Parkinson's disease and schizophrenia is attributed to several factors, including hypofunction of glutamate and reduction of hippocampal volume [34]. Literature data report that the administration of the N-methyl-D-aspartate (NMDA) receptor antagonists (phencyclidine, also coded MK801) frequently impairs the late alternation performance in a standardized behavioral model of cognitive functions alteration similar to schizophrenia in laboratory animals [34]. The use of the glutamate/NMDA receptor antagonist phencyclidine induces a spectrum of behavioral, neurochemical, and anatomical changes, manifested by locomotor hyperactivity, motor-negative deficits, and cognition alterations (with memory impairment and visual attention) in laboratory animals. This substance was used to induce the experimental schizophrenia in laboratory animals [35, 36]. Agmatine attenuates cognitive and behavioral deficiency in rats with experimental phencyclidine-induced schizophrenic manifestations [37].

The effects of agmatine on memory alterations similar to those found in Alzheimer's disease have been evaluated in rats; in the pathogenesis of this degenerative disorder (which causes cognitive deficits in rodents), the fragment beta amyloid Aβ2 25–35 plays an essential role. Studies have shown that agmatine significantly reduces the alterations in memory and spatial learning induced by the beta amyloid Aβ2 25–35 fragment (the neurotoxic component of beta amyloid Aβ 1–42) in various behavioral experimental models, such as: the swimming test, the radial arm maze test, and the object recognition test [38].

Along with evidence of its neuromodulatory and neuroprotective properties, there are numerous preclinical studies demonstrating the beneficial effects of exogenous administration of agmatine in depression, anxiety, hypoxic ischemia, pain, morphine tolerance, memory impairment, Parkinson's disease, Alzheimer's disease, epilepsy, and other related conditions with traumatic brain injuries (Figure 1) [21–23]. All these are arguments in favor of the potential of agmatine as a new pharmacological

Electrophysiological studies involving various brain areas, performed on laboratory animals with experimentally induced cerebral alterations, have demonstrated

In vitro experimental researches have shown that activation of I2 receptors via the

agent for the treatment of various neurological diseases and NDDs [24].

cognitive functions

Figure 1.

Neuroprotection

16

the neurotropic effects of agmatine [25].

Neuroprotective effects of agmatine and their first discovery.

3. The involvement of the imidazoline system in the mediation of

agmatine endogenous ligand exerts neuroprotective effects by increasing the

It has been revealed that agmatine diminishes the activation of hippocampal caspase-3 (the early indicator of neuronal apoptosis) and prevents the alteration of spatial memory induced by lipopolysaccharides, in the swimming test in rat [39], suggesting its neuroprotective effects.

in vitro studies, performed on human-derived dopaminergic neuroblastoma cell lines. It was postulated that the neuromodulatory properties of agmatine are related to the protective effects on the dopaminergic neurons, to NMDA receptor blocking, and to the decrease in oxidative stress, due to the inhibition of nitric oxide synthase

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators…

Other clinical trials highlighted that the treatment with agmatine was associated with cytoprotective actions, in patients with spinal cord injury, proved by lessening the glial weal construction, decreasing the collagen scar zone, relieving the neuronal alterations, and recovering remyelination [49]. Moreover, the beneficial effects of agmatine have been demonstrated in various CNS lesions such as: cerebrovascular accident, brain trauma, neuropathic pain, lumbar degenerative disc disease, and

The administration of dexmedetomidine has also shown neuroprotective effects

In patients with dementia due to brain frontal lesions, idazoxan alleviates attentional and executive dysfunctions evoked by classical cognitive function tests [54].

Clonidine, both a non-specific α2 adrenergic and imidazoline receptor agonist, decreases the cognitive function alterations induced by phencyclidine and MK801, facilitating spatial memory in the radial arm maze test in rats [35], but does not influence the behavioral and cognitive deficits in the experimental NMDA-induced excitotoxic dorsal hippocampal lesions [35]. Such findings indicate that clonidine improves memory alterations caused by glutamate hypofunction, but not by hippocampal injury, implying that multiple and distinct mechanisms are involved in

The administration of the α2 adrenergic receptor agonist clonidine or guanfacine prevents some of the behavioral effects of NMDA antagonists, proving that the monoaminergic system mediates a number of aspects of the cognitive deficit. Clonidine and guanfacine improve the lack of visual attention and spatial memory induced by phencyclidine in rats [34, 36]. It was demonstrated that low doses of clonidine recover the animal's ability to accurately choose the object and prevent the performance deficit induced by phencyclidine. At high doses, clonidine decreases the response time and induces a lack of the choice accuracy. These results indicate that clonidine treatment can alleviate phencyclidine-induced deficit of attention and of working memory, probably by preventing some of the neurochemical and

On the other hand, the use of only the selective α2 adrenergic receptor antagonist does not impair the animal's spatial memory, but dramatically aggravates the phencyclidine-induced memory deficit [36]. These data demonstrate that α2 adrenergic receptors mediate the inhibition of spatial memory disturbances, suggesting their important role in cognitive deficits associated to NMDA receptor

The role of moxonidine (an α2 adrenergic imidazoline I1 receptor agonist) on cognitive function in rats with Huntington's disease experimentally induced with 3 nitropropionic acid (3-NPA) was investigated in the Morris swimming test and in the elevated plus maze test. The administration of 3-NPA induces degenerative brain damage, progressive motor dysfunction, loss of grip force, emotional disturbances, weight loss, anxiety, and impairment of learning activity and memory. An increase in cerebral acetylcholinesterase level, enhancement of oxidative stress, and

4. The interrelation between the adrenergic and the imidazoline

systems in the mediation of cognitive functions

(NOS) activity [48, 23].

different other types of neuropathy [50–52].

DOI: http://dx.doi.org/10.5772/intechopen.81951

in humans with acute cerebral lesions [53].

the development of memory disorders.

hypofunction [34, 36].

19

anatomical effects of this psychotomimetic drug [34].

The neurotropic activity of agmatine has been also evidenced in the structural and cognitive alterations after the administration of NMDA (N-methyl-Daspartate) in rats [40]. The use of high performance liquid chromatography (HPLC) and electrochemical detection allowed highlighting that the treatment with NMDA is associated with low concentrations of monoamines (epinephrine, norepinephrine, dopamine, and serotonin) in rat PC12 cells [29, 40]. In this experimental model (swimming test), agmatine protects against NMDA-induced PC12 cell lesions, augmenting the levels of epinephrine, norepinephrine, and dopamine, but not influencing serotonin values, together with lowering intracellular Ca2+ overload. These results indicate that the neuroprotective action of agmatine may be related to NMDA-receptor modulation and/or to controlling the decrease in monoamine content and NMDA-induced intracellular Ca2+ overload [40].

Immunohistochemical studies and electrophysiological investigations performed on the brain have validated the neuroprotective actions of both imidazoline receptor antagonists idazoxan and efaroxan in rats with cerebral damages caused by the use of quinolinic acid [41], and also in mice with experimentally induced autoimmune encephalomyelitis, confirming the improvement of brain structural alterations and blood brain barrier lesions curtail [42].

A new (+)2-(ethyl-2,3-dihydrobenzofuranyl)-2-imidazoline derivative dexefaroxan—the (+) enantiomer of efaroxan has been characterized. It has a potent and selective α2 antagonist activity, with facultative effects on cognitive functions in the passive avoidance test in rats with memory-deficiency induced by scopolamine, diazepam, or by the 2-adrenergic agonist UK 14,304.

Dexefaroxan improves the cognitive performances in the passive avoidance test, facilitates spatial memory in the Morris swimming test in rats, and increases the object recognition ability in the specific behavioral test in mice [43, 44]. It has also proved to ameliorate the animal's memory deficits in these tests, particularly by attenuation of spontaneous memory loss, and to improve their spatial recognition ability, rather than through the acquisition skills or various other non-cognitive effects.

After subcutaneous administration of dexefaroxan, its pharmacodynamic effects persist for about 21–25 days, indicating that tolerance does not occur during prolonged treatment. Moreover, it was emphasized that dexefaroxan exerts protective effects on the spatial memory deficit caused by cortical devascularization in the Morris swimming test in rats [43].

Dexefaroxan has also been shown to exhibit neuroprotective effects on the devascularization-induced neurodegeneration, to ameliorate the structural changes in the hippocampus, and to remove the cognitive deficits induced by cerebral ischemia in rats [45, 46]. Its neuroprotective effects were present also in the excitotoxic lesions produced at the region of the basal magnocellular nucleus, increasing the olfactory discriminative capacity of rats, suggesting thus the possibility of its use in the treatment of memory disturbances in Alzheimer's disease [43].

Studies performed on genetically modified animals revealed that dexefaroxan improves cognitive performance in knockout mice with Alzheimer's disease [47].

Literature data regarding the neuroprotective action of imidazoline agonist and antagonist agents in human studies are only few, and the mechanisms involved in these effects are not completely deciphered.

Some investigations suggested that agmatine manifests protective activity against brain cell injury in different in vivo models of Parkinson's disease, as well as Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators… DOI: http://dx.doi.org/10.5772/intechopen.81951

in vitro studies, performed on human-derived dopaminergic neuroblastoma cell lines. It was postulated that the neuromodulatory properties of agmatine are related to the protective effects on the dopaminergic neurons, to NMDA receptor blocking, and to the decrease in oxidative stress, due to the inhibition of nitric oxide synthase (NOS) activity [48, 23].

Other clinical trials highlighted that the treatment with agmatine was associated with cytoprotective actions, in patients with spinal cord injury, proved by lessening the glial weal construction, decreasing the collagen scar zone, relieving the neuronal alterations, and recovering remyelination [49]. Moreover, the beneficial effects of agmatine have been demonstrated in various CNS lesions such as: cerebrovascular accident, brain trauma, neuropathic pain, lumbar degenerative disc disease, and different other types of neuropathy [50–52].

The administration of dexmedetomidine has also shown neuroprotective effects in humans with acute cerebral lesions [53].

In patients with dementia due to brain frontal lesions, idazoxan alleviates attentional and executive dysfunctions evoked by classical cognitive function tests [54].

#### 4. The interrelation between the adrenergic and the imidazoline systems in the mediation of cognitive functions

Clonidine, both a non-specific α2 adrenergic and imidazoline receptor agonist, decreases the cognitive function alterations induced by phencyclidine and MK801, facilitating spatial memory in the radial arm maze test in rats [35], but does not influence the behavioral and cognitive deficits in the experimental NMDA-induced excitotoxic dorsal hippocampal lesions [35]. Such findings indicate that clonidine improves memory alterations caused by glutamate hypofunction, but not by hippocampal injury, implying that multiple and distinct mechanisms are involved in the development of memory disorders.

The administration of the α2 adrenergic receptor agonist clonidine or guanfacine prevents some of the behavioral effects of NMDA antagonists, proving that the monoaminergic system mediates a number of aspects of the cognitive deficit. Clonidine and guanfacine improve the lack of visual attention and spatial memory induced by phencyclidine in rats [34, 36]. It was demonstrated that low doses of clonidine recover the animal's ability to accurately choose the object and prevent the performance deficit induced by phencyclidine. At high doses, clonidine decreases the response time and induces a lack of the choice accuracy. These results indicate that clonidine treatment can alleviate phencyclidine-induced deficit of attention and of working memory, probably by preventing some of the neurochemical and anatomical effects of this psychotomimetic drug [34].

On the other hand, the use of only the selective α2 adrenergic receptor antagonist does not impair the animal's spatial memory, but dramatically aggravates the phencyclidine-induced memory deficit [36]. These data demonstrate that α2 adrenergic receptors mediate the inhibition of spatial memory disturbances, suggesting their important role in cognitive deficits associated to NMDA receptor hypofunction [34, 36].

The role of moxonidine (an α2 adrenergic imidazoline I1 receptor agonist) on cognitive function in rats with Huntington's disease experimentally induced with 3 nitropropionic acid (3-NPA) was investigated in the Morris swimming test and in the elevated plus maze test. The administration of 3-NPA induces degenerative brain damage, progressive motor dysfunction, loss of grip force, emotional disturbances, weight loss, anxiety, and impairment of learning activity and memory. An increase in cerebral acetylcholinesterase level, enhancement of oxidative stress, and

It has been revealed that agmatine diminishes the activation of hippocampal caspase-3 (the early indicator of neuronal apoptosis) and prevents the alteration of spatial memory induced by lipopolysaccharides, in the swimming test in rat [39],

The neurotropic activity of agmatine has been also evidenced in the structural

(HPLC) and electrochemical detection allowed highlighting that the treatment with NMDA is associated with low concentrations of monoamines (epinephrine, norepinephrine, dopamine, and serotonin) in rat PC12 cells [29, 40]. In this experimental model (swimming test), agmatine protects against NMDA-induced PC12 cell lesions, augmenting the levels of epinephrine, norepinephrine, and dopamine, but not influencing serotonin values, together with lowering intracellular Ca2+ overload. These results indicate that the neuroprotective action of agmatine may be related to NMDA-receptor modulation and/or to controlling the decrease in monoamine con-

Immunohistochemical studies and electrophysiological investigations performed on the brain have validated the neuroprotective actions of both imidazoline receptor antagonists idazoxan and efaroxan in rats with cerebral damages caused by the use of quinolinic acid [41], and also in mice with experimentally induced autoimmune encephalomyelitis, confirming the improvement of brain structural alter-

Dexefaroxan improves the cognitive performances in the passive avoidance test, facilitates spatial memory in the Morris swimming test in rats, and increases the object recognition ability in the specific behavioral test in mice [43, 44]. It has also proved to ameliorate the animal's memory deficits in these tests, particularly by attenuation of spontaneous memory loss, and to improve their spatial recognition ability, rather than through the acquisition skills or various other non-cognitive

After subcutaneous administration of dexefaroxan, its pharmacodynamic effects

prolonged treatment. Moreover, it was emphasized that dexefaroxan exerts protective effects on the spatial memory deficit caused by cortical devascularization in the

Dexefaroxan has also been shown to exhibit neuroprotective effects on the devascularization-induced neurodegeneration, to ameliorate the structural changes in the hippocampus, and to remove the cognitive deficits induced by cerebral ischemia in rats [45, 46]. Its neuroprotective effects were present also in the excitotoxic lesions produced at the region of the basal magnocellular nucleus, increasing the olfactory discriminative capacity of rats, suggesting thus the possibility of its use in

Studies performed on genetically modified animals revealed that dexefaroxan improves cognitive performance in knockout mice with Alzheimer's disease [47]. Literature data regarding the neuroprotective action of imidazoline agonist and antagonist agents in human studies are only few, and the mechanisms involved in

Some investigations suggested that agmatine manifests protective activity against brain cell injury in different in vivo models of Parkinson's disease, as well as

persist for about 21–25 days, indicating that tolerance does not occur during

the treatment of memory disturbances in Alzheimer's disease [43].

A new (+)2-(ethyl-2,3-dihydrobenzofuranyl)-2-imidazoline derivative dexefaroxan—the (+) enantiomer of efaroxan has been characterized. It has a potent and selective α2 antagonist activity, with facultative effects on cognitive functions in the passive avoidance test in rats with memory-deficiency induced by

scopolamine, diazepam, or by the 2-adrenergic agonist UK 14,304.

and cognitive alterations after the administration of NMDA (N-methyl-Daspartate) in rats [40]. The use of high performance liquid chromatography

tent and NMDA-induced intracellular Ca2+ overload [40].

ations and blood brain barrier lesions curtail [42].

effects.

18

Morris swimming test in rats [43].

these effects are not completely deciphered.

suggesting its neuroprotective effects.

Neuroprotection

impairment of the activity of mitochondrial enzyme complexes I, II, and IV were also noted [28]. The treatment with moxonidine resulted in the alleviation of disturbances caused on animal weight, motor activity, gripping ability, anxiety, impairment of learning ability and memory, and biochemical disturbances, thus indicating that substances modifying the activity of I1 receptors may be potential pharmacological agents for the treatment of degenerative brain disorders [55].

Literature data have shown that agmatine eliminates neuroinflammation and lipopolysaccharide-induced memory impairment (which is known to stimulate iNOS activity and, implicitly, the NO production) in laboratory animals. It prevents cognitive alterations, probably as a result of inhibition of iNOS activity [39]. Other researchers have disproved these results by showing that agmatine can cause cognitive impairment due to the inhibition of NMDA receptors and of NO, important

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators…

On the other hand, it is known that the central cholinergic system plays a crucial role in the mediation of cognitive functions. Cognitive deficits have been induced in laboratory animals by using an anticholinergic agent, scopolamine, its administration producing a significant reduction in NOS activity, and an increase in arginase activity, of L-ornithine and putrescine levels in the hippocampus [51]. It has been observed that agmatine eliminates the scopolamine-induced alterations of memory

Although glutamatergic activity is required for cognitive processes, it is assumed that the increase of glutamate levels or of NMDA activity would also be responsible

Knowing that agmatine blocks NMDA receptors and also interferes with the

scopolamine-induced cognitive deficits can be attributed to its modulating effect on NO/NOS activity, on L-arginine, and also to the antagonization of NMDA receptors, with subsequent suppression of excessive glutamatergic activity [61, 65]. Abnormal release and disturbances of neuromodulatory activities due to variation in cerebral agmatine levels may be correlated to different CNS diseases (such as schizophrenia). Interactions of agmatine with other central neurotransmitter systems (such as glutamatergic and nitrergic) appear to be particularly important in the pathophysiological mechanisms of CNS disorders associated with brain damage

Neurodegeneration can be caused by chronic disease progression or by acute injury (cerebral ischemia—stroke or trauma) [67]. Ischemic stroke represents a vascular ailment with neurological consequences produced by the obstruction of the arteries in a part of the brain, therefore by blood supply privation [68]. Stroke can determine long-term neurological and psychiatric impairments, its therapy being

In a recent review article, Chamorro presented that ischemic stroke is "the first cause of permanent disability in adult people, the second single most frequent cause of death for people older than 60 years, the second most common cause of dementia, representing approximately 3% to 7% of the total health-care expenditure in

A superpose of pathologies in different neurological disorders was proposed

Opioids are substances with morphine-like action binding to specific opioid receptors (ORs). In the early 1990s, three important opioid receptor families [μ (MOR), κ (KOR), and δ (DOR)] were identified, and in 1994 another opioid receptor was discovered [nociceptin, orphanin FQ receptor (NOP), or the opioid receptor-like orphan receptor (ORL)]. ORs are found in the nervous system, lungs, heart, liver, and gastrointestinal and reproductive tracts. They have been inten-

since NDDs and ischemic stroke are frequently concomitant, hence the

sively studied and it was emphasized that they not only are related to

pathways of NO, NOS, and L-arginine, it was assumed that the removal of

elements in the modulation of learning and memory processes [62, 63].

for the scopolamine-induced cognitive disturbances [66].

focused on confining secondary injury processes [67].

neuroprotective therapy could be similar [70].

and learning capacity [64, 65].

DOI: http://dx.doi.org/10.5772/intechopen.81951

and cognitive functions deficit.

6. The opioid system

high income countries" [69].

21

The effects of clonidine have also been evaluated in mice with subacute brain ischemia obtained after permanent ligation of common carotid arteries. The subsequent brain damages consisted of expansion of cerebral infarction areas, assessed by computed tomography scans. This experimentally induced chronic cerebral hypoperfusion was associated with a significant impairment of animal's learning ability and memory in the Morris swimming test [25, 28]. Subacute treatment with clonidine for 7 days increases the expression of neuronal nuclei, glutamic aciddecarboxylase-67, and gamma-aminobutyric acid (GABA) B receptor (GABAB1) in hippocampal subregion cornu amonis (CA1) but does not influence the level of these elements in the hippocampal area CA3, nor in the dentate gyrus. These data support the idea that clonidine exerts neuroprotective effects on chronic cerebral ischemic lesions, by regulating GABAB1 receptors and the activity of glutamic aciddecarboxylase-67 [25].

Additionally, the decrease in superoxide dismutase (SOD), catalase (CAT), and glutathione levels as well as the increase of both malondialdehyde (MDA) level and cerebral acetylcholinesterase activity were noted in animals with brain ischemic lesions [28].

Both moxonidine and clonidine have shown a decrease in histopathological changes, oxidative stress, central cholinesterase activity, as well as a reduction in memory disturbances and learning deficits in mice with vascular dementia induced by subacute ischemia after permanent bilateral cerebral artery ligation [28, 40].

In vitro cell culture studies from the rat frontal cortex with glutamate-induced neurotoxicity revealed the partial neuroprotective effects of moxonidine, with a significant decrease in the number of dead cells [26]. Moxonidine has shown beneficial effects on cerebral spasm in an experimental rabbit model of subarachnoid hemorrhage [40, 56].

#### 5. The interrelations between the imidazoline system and the oxidative stress in the mediation of cognitive functions

Different pathological conditions of the body, as well as the physiological process of aging, can cause cognitive impairment and free oxygen radicals production, being responsible for abnormal functioning and cell death. Subsequently, a new idea has emerged claiming that nitric oxide (NO), along with the free radicals, plays a key role in the aging process, due to neurotoxic effects on the brain exerted by its excessive levels [57]. Nitric oxide is generated from L-arginine under the action of nitric oxide synthase (NOS). The three isoforms of NOS have different roles in the body: neuronal NOS (nNOS) is responsible for synaptic plasticity, learning and memory processes; endothelial NOS (eNOS) provides stabilization and regulation of vascular micro-environment and contributes to neuroplasticity [58]; and inducible NOS (iNOS) is involved in various pathophysiological conditions [57].

Numerous experimental researches reveal that NOS activity is significantly elevated in the brain of elderly rats, being associated with existing cognitive alterations [57, 59]. Mediated by the competitive inhibition of nNOS and iNOS, and correlated with the stimulation of NOS, agmatine contributes to the improvement of cognitive functions [19, 60, 61], while exhibiting neuroprotective effects [38, 39].

#### Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators… DOI: http://dx.doi.org/10.5772/intechopen.81951

Literature data have shown that agmatine eliminates neuroinflammation and lipopolysaccharide-induced memory impairment (which is known to stimulate iNOS activity and, implicitly, the NO production) in laboratory animals. It prevents cognitive alterations, probably as a result of inhibition of iNOS activity [39]. Other researchers have disproved these results by showing that agmatine can cause cognitive impairment due to the inhibition of NMDA receptors and of NO, important elements in the modulation of learning and memory processes [62, 63].

On the other hand, it is known that the central cholinergic system plays a crucial role in the mediation of cognitive functions. Cognitive deficits have been induced in laboratory animals by using an anticholinergic agent, scopolamine, its administration producing a significant reduction in NOS activity, and an increase in arginase activity, of L-ornithine and putrescine levels in the hippocampus [51]. It has been observed that agmatine eliminates the scopolamine-induced alterations of memory and learning capacity [64, 65].

Although glutamatergic activity is required for cognitive processes, it is assumed that the increase of glutamate levels or of NMDA activity would also be responsible for the scopolamine-induced cognitive disturbances [66].

Knowing that agmatine blocks NMDA receptors and also interferes with the pathways of NO, NOS, and L-arginine, it was assumed that the removal of scopolamine-induced cognitive deficits can be attributed to its modulating effect on NO/NOS activity, on L-arginine, and also to the antagonization of NMDA receptors, with subsequent suppression of excessive glutamatergic activity [61, 65].

Abnormal release and disturbances of neuromodulatory activities due to variation in cerebral agmatine levels may be correlated to different CNS diseases (such as schizophrenia). Interactions of agmatine with other central neurotransmitter systems (such as glutamatergic and nitrergic) appear to be particularly important in the pathophysiological mechanisms of CNS disorders associated with brain damage and cognitive functions deficit.

#### 6. The opioid system

impairment of the activity of mitochondrial enzyme complexes I, II, and IV were also noted [28]. The treatment with moxonidine resulted in the alleviation of disturbances caused on animal weight, motor activity, gripping ability, anxiety, impairment of learning ability and memory, and biochemical disturbances, thus indicating that substances modifying the activity of I1 receptors may be potential pharmacological agents for the treatment of degenerative brain disorders [55]. The effects of clonidine have also been evaluated in mice with subacute brain ischemia obtained after permanent ligation of common carotid arteries. The subsequent brain damages consisted of expansion of cerebral infarction areas, assessed by

computed tomography scans. This experimentally induced chronic cerebral hypoperfusion was associated with a significant impairment of animal's learning ability and memory in the Morris swimming test [25, 28]. Subacute treatment with clonidine for 7 days increases the expression of neuronal nuclei, glutamic aciddecarboxylase-67, and gamma-aminobutyric acid (GABA) B receptor (GABAB1) in hippocampal subregion cornu amonis (CA1) but does not influence the level of these elements in the hippocampal area CA3, nor in the dentate gyrus. These data support the idea that clonidine exerts neuroprotective effects on chronic cerebral ischemic lesions, by regulating GABAB1 receptors and the activity of glutamic acid-

Additionally, the decrease in superoxide dismutase (SOD), catalase (CAT), and glutathione levels as well as the increase of both malondialdehyde (MDA) level and cerebral acetylcholinesterase activity were noted in animals with brain ischemic

Both moxonidine and clonidine have shown a decrease in histopathological changes, oxidative stress, central cholinesterase activity, as well as a reduction in memory disturbances and learning deficits in mice with vascular dementia induced by subacute ischemia after permanent bilateral cerebral artery ligation [28, 40]. In vitro cell culture studies from the rat frontal cortex with glutamate-induced neurotoxicity revealed the partial neuroprotective effects of moxonidine, with a significant decrease in the number of dead cells [26]. Moxonidine has shown beneficial effects on cerebral spasm in an experimental rabbit model of subarachnoid

5. The interrelations between the imidazoline system and the oxidative

Different pathological conditions of the body, as well as the physiological process of aging, can cause cognitive impairment and free oxygen radicals production, being responsible for abnormal functioning and cell death. Subsequently, a new idea has emerged claiming that nitric oxide (NO), along with the free radicals, plays a key role in the aging process, due to neurotoxic effects on the brain exerted by its excessive levels [57]. Nitric oxide is generated from L-arginine under the action of nitric oxide synthase (NOS). The three isoforms of NOS have different roles in the body: neuronal NOS (nNOS) is responsible for synaptic plasticity, learning and memory processes; endothelial NOS (eNOS) provides stabilization and regulation of vascular micro-environment and contributes to neuroplasticity [58]; and induc-

ible NOS (iNOS) is involved in various pathophysiological conditions [57].

functions [19, 60, 61], while exhibiting neuroprotective effects [38, 39].

Numerous experimental researches reveal that NOS activity is significantly elevated in the brain of elderly rats, being associated with existing cognitive alterations [57, 59]. Mediated by the competitive inhibition of nNOS and iNOS, and correlated with the stimulation of NOS, agmatine contributes to the improvement of cognitive

stress in the mediation of cognitive functions

decarboxylase-67 [25].

hemorrhage [40, 56].

20

lesions [28].

Neuroprotection

Neurodegeneration can be caused by chronic disease progression or by acute injury (cerebral ischemia—stroke or trauma) [67]. Ischemic stroke represents a vascular ailment with neurological consequences produced by the obstruction of the arteries in a part of the brain, therefore by blood supply privation [68]. Stroke can determine long-term neurological and psychiatric impairments, its therapy being focused on confining secondary injury processes [67].

In a recent review article, Chamorro presented that ischemic stroke is "the first cause of permanent disability in adult people, the second single most frequent cause of death for people older than 60 years, the second most common cause of dementia, representing approximately 3% to 7% of the total health-care expenditure in high income countries" [69].

A superpose of pathologies in different neurological disorders was proposed since NDDs and ischemic stroke are frequently concomitant, hence the neuroprotective therapy could be similar [70].

Opioids are substances with morphine-like action binding to specific opioid receptors (ORs). In the early 1990s, three important opioid receptor families [μ (MOR), κ (KOR), and δ (DOR)] were identified, and in 1994 another opioid receptor was discovered [nociceptin, orphanin FQ receptor (NOP), or the opioid receptor-like orphan receptor (ORL)]. ORs are found in the nervous system, lungs, heart, liver, and gastrointestinal and reproductive tracts. They have been intensively studied and it was emphasized that they not only are related to


Different studies using a mouse MCAO stroke model reported that biphalin reduced brain edema and infarction, ROS production, and NMDA-induced excitotoxicity. It also increased locomotor activities and neurological score after stroke resembled to saline-treated animals [72, 81, 85, 86]. Biphalin notably dimin-

It has been hypothesized that biphalin's neuroprotective effects are more intense compared to subtype-selective agonists due to concomitant activation of the three

Various pharmacological substances influencing the pathways of the main neu-

Deciphering the roles of the neurotransmitters in central nervous system activity

neuroprotection, being validated in different in vitro researches and in vivo experi-

other than the signaling function will represent a starting point to deepen the knowledge about the complex mechanisms of the brain functions and to obtain new agents useful for protection of ischemic neurons and for preventing their irrevers-

, 2Cl cotransporter (NKCC), and the trans-

, K<sup>+</sup>

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators…

location of the conventional isoforms of protein kinase C [81].

rotransmitters have confirmed valuable effects in neurogenesis and

mental animal models of limited or extensive ischemic brain lesions.

ished penumbral expression of Na<sup>+</sup>

DOI: http://dx.doi.org/10.5772/intechopen.81951

types of OR [72, 85].

7. Conclusion

ible damage.

23

#### Table 2.

Opioid receptors and their agonists tested for neuroprotective action.

antinociceptive action, but also have a role in cell proliferation, ionic homeostasis, emotional response, immune function, epileptic seizures, feeding, obesity, respiratory and cardiovascular control, hibernation, and neuroprotection [71, 72].

In the last decades, researches have pointed out that the opioid system can be promising to get neuroprotective treatment in the event of stroke, through OR agonists at lower doses, to avoid tolerance and/or physical dependency. DOR agonists followed by KOR agonists have revealed the most intense neuroprotective efficacy [64]. Major OR agonists tested for neuroprotection are listed in Table 2 [71, 72].

DOR activation is beneficial against ischemic, hypoxic, and excitotoxic injuries [73]; recent studies promote DOR and especially DADLE (an analog of endogenous delta-opioid enkephalin) as promising targets for treating NDDs like stroke and PD [74–76].

DADLE alleviates apoptotic pathways, supports not only cell survival of peripheral organs (such as lung, heart, kidney, and liver) but also neuronal survival, and protects neurons and glial cells from ischemia-induced cell death [76–78].

In a cellular model of PD, DADLE administration augmented cell survivability with concurrent downregulation of the unfolded protein response stress sensors and protein aggregates [79].

Findings from a rat middle cerebral artery occlusion (MCAO) stroke model proposed that neuroprotection of DADLE treatment was based on the activation of PI3K-Akt pathway by reducing nerve cell apoptosis [80].

Non-selective opioid receptor agonists were also tested: LYS739 (fluorinated enkephalin-fentanyl derivative) and the most promising compound—biphalin which proved to be effective both in vitro and in vivo stroke models [72].

The latter is a dimeric enkephalin analog (Tyr-D-Ala-Gly-Phe-NH-)2 with high potency and affinity for MOR and DOR and low affinity for KOR. Biphalin crosses blood-brain barrier reaching spinal and supraspinal sites expressing OR and produces less physical dependence and tolerance compared to morphine [72, 81–84].

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators… DOI: http://dx.doi.org/10.5772/intechopen.81951

Different studies using a mouse MCAO stroke model reported that biphalin reduced brain edema and infarction, ROS production, and NMDA-induced excitotoxicity. It also increased locomotor activities and neurological score after stroke resembled to saline-treated animals [72, 81, 85, 86]. Biphalin notably diminished penumbral expression of Na<sup>+</sup> , K<sup>+</sup> , 2Cl cotransporter (NKCC), and the translocation of the conventional isoforms of protein kinase C [81].

It has been hypothesized that biphalin's neuroprotective effects are more intense compared to subtype-selective agonists due to concomitant activation of the three types of OR [72, 85].

#### 7. Conclusion

antinociceptive action, but also have a role in cell proliferation, ionic homeostasis, emotional response, immune function, epileptic seizures, feeding, obesity, respira-

μ DAMGO [D-Ala2,N-MePhe4,Gly-ol]-enkephalin

In the last decades, researches have pointed out that the opioid system can be promising to get neuroprotective treatment in the event of stroke, through OR agonists at lower doses, to avoid tolerance and/or physical dependency. DOR agonists followed by KOR agonists have revealed the most intense neuroprotective efficacy [64]. Major OR agonists tested for neuroprotection are listed in Table 2

DOR activation is beneficial against ischemic, hypoxic, and excitotoxic injuries [73]; recent studies promote DOR and especially DADLE (an analog of endogenous delta-opioid enkephalin) as promising targets for treating NDDs like stroke and PD

DADLE alleviates apoptotic pathways, supports not only cell survival of peripheral organs (such as lung, heart, kidney, and liver) but also neuronal survival, and

In a cellular model of PD, DADLE administration augmented cell survivability with concurrent downregulation of the unfolded protein response stress sensors and

Findings from a rat middle cerebral artery occlusion (MCAO) stroke model proposed that neuroprotection of DADLE treatment was based on the activation of

Non-selective opioid receptor agonists were also tested: LYS739 (fluorinated enkephalin-fentanyl derivative) and the most promising compound—biphalin—

The latter is a dimeric enkephalin analog (Tyr-D-Ala-Gly-Phe-NH-)2 with high potency and affinity for MOR and DOR and low affinity for KOR. Biphalin crosses blood-brain barrier reaching spinal and supraspinal sites expressing OR and produces less physical dependence and tolerance compared to morphine [72, 81–84].

protects neurons and glial cells from ischemia-induced cell death [76–78].

which proved to be effective both in vitro and in vivo stroke models [72].

PI3K-Akt pathway by reducing nerve cell apoptosis [80].

tory and cardiovascular control, hibernation, and neuroprotection [71, 72].

Opioid receptor Agonist

κ BRL 52537

Opioid receptors and their agonists tested for neuroprotective action.

δ DADLE [D-Ala2, D-Leu5]-enkephalin

SNC80 Tan-67 Remifentanil

CI-977 GR89696 Salvinorin A U-50,488H Dynorphin

Morphine

DPDPE (D-Pen2,D-Pen5)-enkephalin

Endorphin 1 and 2 (EM 1/2),

[71, 72].

Table 2.

Neuroprotection

[74–76].

22

protein aggregates [79].

Various pharmacological substances influencing the pathways of the main neurotransmitters have confirmed valuable effects in neurogenesis and neuroprotection, being validated in different in vitro researches and in vivo experimental animal models of limited or extensive ischemic brain lesions.

Deciphering the roles of the neurotransmitters in central nervous system activity other than the signaling function will represent a starting point to deepen the knowledge about the complex mechanisms of the brain functions and to obtain new agents useful for protection of ischemic neurons and for preventing their irreversible damage.

#### Author details

Liliana Mititelu-Tartau1†, Maria Bogdan<sup>2</sup> \*†, Victor Gheorman<sup>3</sup> , Liliana Foia<sup>1</sup> , Ancuta Goriuc<sup>1</sup> , Gabriela Rusu1 , Beatrice Buca<sup>1</sup> , Liliana Pavel<sup>4</sup> , Ana Cristofor<sup>1</sup> , Cosmin-Gabriel Tartau<sup>1</sup> and Gratiela Eliza Popa5†

References

hydrolytic products in

disorders. Translational Neurodegeneration. 2017;6:25

MF. Psychopharmacological

[1] Jaafaru MS, Abd Karim NA, Enas ME, Rollin P, Mazzon E, Abdull Razis AF. Protective effect of glucosinolates

DOI: http://dx.doi.org/10.5772/intechopen.81951

imidazoline-2 receptor ligand, in rat

[10] Nechifor M. Imidazoline receptors— Normal and pathological factors. Revista Medico-Chirurgicala a Societatii de Medici Si Naturalisti din Iasi. 2001;105:

[11] Dardonville C, Rozas I, Callado LF, Meana JJ. I(2)-imidazoline binding site affinity of a structurally different type of ligands. Bioorganic & Medicinal Chemistry. 2002;10:1525-1533

[12] Pypendop BH, Silverstein D,

Hopper K. 2 agonists and antagonists. In: Small Animal Critical Care Medicine. 2nd ed. Missouri: Saunders Inc.; 2015. pp. 866-871.Ch 165. SRC - BaiduScholar

[13] Thorn DA, An X-F, Zhang Y, Pigini M, Li J-X. Characterization of the hypothermic effects of imidazoline I2 receptor agonists in rats. British Journal of Pharmacology. 2012;166:1936-1945

[14] Smith KL, Jessop DS, Finn DP. Modulation of stress by imidazoline binding sites: Implications for psychiatric

disorders. Stress (Amsterdam, Netherlands). 2009;12:97-114

[15] Ciubotariu D, Nechifor M. Involvement of imidazoline system in drug addiction. Revista Medico-Chirurgicala a Societatii de Medici Si Naturalisti din Iasi. 2012;116:1118-1122

[16] Halaris A, Plietz J. Agmatine: Metabolic pathway and spectrum of activity in brain. CNS Drugs. 2007;21:

[17] Haenisch B, von Kügelgen I, Bönisch H, Göthert M, Sauerbruch T, Schepke M, et al. Regulatory mechanisms underlying agmatine homeostasis in

885-900

models of inflammatory and neuropathic pain. Journal of Pain

Research. 2011;4:111-125

438-443

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators…

neurodegenerative diseases (NDDs). Nutrients. 2018;10(5), 580:1-15

[2] Cummings J. Disease modification and neuroprotection in neurodegenerative

[3] Lauterbach EC, Victoroff J, Coburn KL, Shillcutt SD, Doonan SM, Mendez

neuroprotection in neurodegenerative disease: Assessing the preclinical data. The Journal of Neuropsychiatry and Clinical Neurosciences. 2010;22:8-18

[4] Gitler AD, Dhillon P, Shorter J. Neurodegenerative disease: Models, mechanisms, and a new hope. Disease Models & Mechanisms. 2017;10:499-502

progressive: Uncontrolled inflammation drives disease progression. Trends in Immunology. 2008;29:357-365

[7] Wiendl H, Elger C, Förstl H, Hartung H-P, Oertel W, Reichmann H, et al. Gaps between aims and achievements in therapeutic modification of neuronal

[8] Cummings J, Fox N. Defining disease modifying therapy for Alzheimer's disease. The Journal of Prevention of Alzheimer's Disease. 2017;4:109-115

[9] Ferrari F, Fiorentino S, Mennuni L, Garofalo P, Letari O, Mandelli S, et al. Analgesic efficacy of CR4056, a novel

[6] Ropper A, Samuels M, Klein J. Adams and Victor's Principles of Neurology. 10th ed. Boston: McGraw-Hill Education; 2014. pp. 1060-1131

damage ("Neuroprotection"). Neurotherapeutics. 2015;12:449-454

25

[5] Gao HM, Hong JS. Why neurodegenerative diseases are

1 Faculty of Medicine, "Gr. T. Popa" University of Medicine and Pharmacy, Iasi, Romania

2 Faculty of Pharmacy, University of Medicine and Pharmacy, Craiova, Romania

3 Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania

4 Faculty of Medicine, "Dunarea de Jos" University of Medicine and Pharmacy, Galati, Romania

5 Faculty of Pharmacy, "Gr. T. Popa" University of Medicine and Pharmacy, Iasi, Romania

\*Address all correspondence to: bogdanfmaria81@yahoo.com

† These authors contributed equally to this work.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators… DOI: http://dx.doi.org/10.5772/intechopen.81951

#### References

[1] Jaafaru MS, Abd Karim NA, Enas ME, Rollin P, Mazzon E, Abdull Razis AF. Protective effect of glucosinolates hydrolytic products in neurodegenerative diseases (NDDs). Nutrients. 2018;10(5), 580:1-15

[2] Cummings J. Disease modification and neuroprotection in neurodegenerative disorders. Translational Neurodegeneration. 2017;6:25

[3] Lauterbach EC, Victoroff J, Coburn KL, Shillcutt SD, Doonan SM, Mendez MF. Psychopharmacological neuroprotection in neurodegenerative disease: Assessing the preclinical data. The Journal of Neuropsychiatry and Clinical Neurosciences. 2010;22:8-18

[4] Gitler AD, Dhillon P, Shorter J. Neurodegenerative disease: Models, mechanisms, and a new hope. Disease Models & Mechanisms. 2017;10:499-502

[5] Gao HM, Hong JS. Why neurodegenerative diseases are progressive: Uncontrolled inflammation drives disease progression. Trends in Immunology. 2008;29:357-365

[6] Ropper A, Samuels M, Klein J. Adams and Victor's Principles of Neurology. 10th ed. Boston: McGraw-Hill Education; 2014. pp. 1060-1131

[7] Wiendl H, Elger C, Förstl H, Hartung H-P, Oertel W, Reichmann H, et al. Gaps between aims and achievements in therapeutic modification of neuronal damage ("Neuroprotection"). Neurotherapeutics. 2015;12:449-454

[8] Cummings J, Fox N. Defining disease modifying therapy for Alzheimer's disease. The Journal of Prevention of Alzheimer's Disease. 2017;4:109-115

[9] Ferrari F, Fiorentino S, Mennuni L, Garofalo P, Letari O, Mandelli S, et al. Analgesic efficacy of CR4056, a novel

imidazoline-2 receptor ligand, in rat models of inflammatory and neuropathic pain. Journal of Pain Research. 2011;4:111-125

[10] Nechifor M. Imidazoline receptors— Normal and pathological factors. Revista Medico-Chirurgicala a Societatii de Medici Si Naturalisti din Iasi. 2001;105: 438-443

[11] Dardonville C, Rozas I, Callado LF, Meana JJ. I(2)-imidazoline binding site affinity of a structurally different type of ligands. Bioorganic & Medicinal Chemistry. 2002;10:1525-1533

[12] Pypendop BH, Silverstein D, Hopper K. 2 agonists and antagonists. In: Small Animal Critical Care Medicine. 2nd ed. Missouri: Saunders Inc.; 2015. pp. 866-871.Ch 165. SRC - BaiduScholar

[13] Thorn DA, An X-F, Zhang Y, Pigini M, Li J-X. Characterization of the hypothermic effects of imidazoline I2 receptor agonists in rats. British Journal of Pharmacology. 2012;166:1936-1945

[14] Smith KL, Jessop DS, Finn DP. Modulation of stress by imidazoline binding sites: Implications for psychiatric disorders. Stress (Amsterdam, Netherlands). 2009;12:97-114

[15] Ciubotariu D, Nechifor M. Involvement of imidazoline system in drug addiction. Revista Medico-Chirurgicala a Societatii de Medici Si Naturalisti din Iasi. 2012;116:1118-1122

[16] Halaris A, Plietz J. Agmatine: Metabolic pathway and spectrum of activity in brain. CNS Drugs. 2007;21: 885-900

[17] Haenisch B, von Kügelgen I, Bönisch H, Göthert M, Sauerbruch T, Schepke M, et al. Regulatory mechanisms underlying agmatine homeostasis in

Author details

Neuroprotection

Ancuta Goriuc<sup>1</sup>

Galati, Romania

Romania

24

Romania

Liliana Mititelu-Tartau1†, Maria Bogdan<sup>2</sup>

, Gabriela Rusu1

Cosmin-Gabriel Tartau<sup>1</sup> and Gratiela Eliza Popa5†

\*†, Victor Gheorman<sup>3</sup>

, Liliana Pavel<sup>4</sup>

, Beatrice Buca<sup>1</sup>

1 Faculty of Medicine, "Gr. T. Popa" University of Medicine and Pharmacy, Iasi,

2 Faculty of Pharmacy, University of Medicine and Pharmacy, Craiova, Romania

3 Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Romania

4 Faculty of Medicine, "Dunarea de Jos" University of Medicine and Pharmacy,

5 Faculty of Pharmacy, "Gr. T. Popa" University of Medicine and Pharmacy, Iasi,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: bogdanfmaria81@yahoo.com

† These authors contributed equally to this work.

provided the original work is properly cited.

, Liliana Foia<sup>1</sup>

, Ana Cristofor<sup>1</sup>

,

,

humans. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2008;295:G1104-G1110

[18] Reis DJ, Regunathan S. Is agmatine a novel neurotransmitter in brain? Trends in Pharmacological Sciences. 2000;21: 187-193

[19] Mun CH, Lee WT, Park KA, Lee JE. Regulation of endothelial nitric oxide synthase by agmatine after transient global cerebral ischemia in rat brain. Anatomy & Cell Biology. 2010;43: 230-240

[20] Nissim I, Horyn O, Daikhin Y, Chen P, Li C, Wehrli SL, et al. The molecular and metabolic influence of long term agmatine consumption. The Journal of Biological Chemistry. 2014;289: 9710-9729

[21] Mancinelli F, Ragonese F, Cataldi S, Ceccarini MR, Iannitti RG, Arcuri C, et al. Inhibitory effects of agmatine on monoamine oxidase (MAO) activity: Reconciling the discrepancies. The EuroBiotech Journal. 2018;2:121-127

[22] Sirvanci-Yalabik M, Sehirli AO, Utkan T, Aricioglu F. Agmatine, a metabolite of arginine, improves learning and memory in streptozotocininduced Alzheimer's disease model in rats. Bulletin of Clinical Psychopharmacology. 2016;26(4): 342-354

[23] Neis VB, Rosa PB, Olescowicz G, Rodrigues ALS. Therapeutic potential of agmatine for CNS disorders. Neurochemistry International. 2017; 108:318e331

[24] Moretti M, Neis VB, Matheus FC, Cunha MP, Rosa PB, Ribeiro CM, et al. Effects of agmatine on depressive-like behavior induced by intracerebroventricular administration of 1-methyl-4-phenylpyridinium (MPP (+)). Neurotoxicity Research. 2015;28: 222-231

[25] Lu Y, Li C, Zhou M, Luo P, Huang P, Tan J, et al. Clonidine ameliorates cognitive impairment induced by chronic cerebral hypoperfusion via upregulation of the GABABR1 and GAD67 in hippocampal CA1 in rats. Pharmacology, Biochemistry, and Behavior. 2015;132:96-102

[32] Zhu M-Y, Wang W-P, Cai Z-W, Regunathan S, Ordway G. Exogenous agmatine has neuroprotective effects against restraint-induced structural changes in the rat brain. The European Journal of Neuroscience. 2008;27:

DOI: http://dx.doi.org/10.5772/intechopen.81951

and hippocampal apoptosis. European Journal of Pharmacology. 2010;634:

[40] Li YF, Gong ZH, Cao JB, Wang HL, Luo ZP, Li J. Antidepressant-like effect of agmatine and its possible mechanism. European Journal of Pharmacology.

[41] Martel J, Chopin P, Colpaert F, Marien M. Neuroprotective effects of the alpha2-adrenoceptor antagonists, (+)-efaroxan and (+/)-idazoxan, against quinolinic acid-induced lesions of the rat striatum. Experimental Neurology. 1998;154:595-601

[42] Wang X-S, Fang H-L, Chen Y, Liang S-S, Zhu Z-G, Zeng Q-Y, et al. Idazoxan reduces blood-brain barrier damage during experimental autoimmune encephalomyelitis in mouse. European Journal of Pharmacology. 2014;736:

[43] Chopin P, Debeir T, Raisman-Vozari R, Colpaert FC, Marien MR. Protective effect of the alpha2-

[44] Pauwels PJ, Rauly I, Wurch T. Dissimilar pharmacological responses by a new series of imidazoline derivatives at precoupled and ligand-activated alpha 2A-adrenoceptor states: Evidence for effector pathway-dependent differential antagonism. The Journal of Pharmacology and Experimental Therapeutics. 2003;305:1015-1023

[45] Rizk P, Salazar J, Raisman-Vozari R, Marien M, Ruberg M, Colpaert F, et al. The alpha2-adrenoceptor antagonist dexefaroxan enhances hippocampal neurogenesis by increasing the survival and differentiation of new granule cells. Neuropsychopharmacology. 2006;31:

adrenoceptor antagonist, dexefaroxan, against spatial memory deficit induced by cortical devascularization in the adult rat. Experimental Neurology. 2004;185:

84-88

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators…

70-76

198-200

1146-1157

2003;469(1–3):81-88

[33] Aricioglu F, Regunathan S. Agmatine attenuates stress- and lipopolysaccharide-induced fever in rats. Physiology & Behavior. 2005;85:

memory deficits produced by phencyclidine administration to rats. Psychopharmacology (Berl). 2004;175:

[34] Jeutsch JD, Anzivino LA. A low dose of the alpha2 agonist clonidine ameliorates the visual attention and spatial working

[35] Bardget ME, Points M, Ramsey-Faulkner C. The effects of clonidine on discrete-trial delayed spatial alternation in two rat models of memory loss. Neuropsychopharmacology. 2008;33:

[36] Marrs W, Kuperman J, Avedian T,

Roth RH, Jentsch JD. Alpha-2 adrenoceptor activation inhibits phencyclidine-induced deficits of spatial working memory in rats. Neuropsychopharmacology. 2005;30:

[37] Unal G, Ates A, Aricioglu F. Agmatine-attenuated cognitive and social deficits in subchronic MK-801 model of schizophrenia in rats.

Psychopharmacology. 2018:1-10

[38] Bergin DH, Liu P. Agmatine protects against beta-amyloid25–35 induced memory impairments in the rat. Neuroscience. 2010;169:794-811

[39] Zarifkar A, Choopani S, Ghasemi R, Naghdi N, Maghsoudi AH, Maghsoudi N, et al. Agmatine prevents LPSinduced spatial memory impairment

Psychiatry and Clinical

1320-1332

370-375

76-83

1980-1991

1500-1510

27

[26] Bakuridze K, Savli E, Gongadze N, Baş DB, Gepdiremen A. Protection in glutamate-induced neurotoxicity by imidazoline receptor agonist moxonidine. The International Journal of Neuroscience. 2009;119:1705-1717

[27] Head GA, Mayorov DN. Imidazoline receptors, novel agents and therapeutic potential. Cardiovascular & Hematological Agents in Medicinal Chemistry. 2006;4:17-32

[28] Gupta S, Sharma B. Pharmacological modulation of I(1)-imidazoline and α2 adrenoceptors in sub acute brain ischemia induced vascular dementia. European Journal of Pharmacology. 2014;723:80-90

[29] Matheus FC, Aguiar AS, Castro AA, Villarinho JG, Ferreira J, Figueiredo CP, et al. Neuroprotective effects of agmatine in mice infused with a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioural Brain Research. 2012;235:263-272

[30] Kang S, Kim C-H, Jung H, Kim E, Song H-T, Lee JE. Agmatine ameliorates typ. 2 diabetes induced-Alzheimer's disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling. Neuropharmacology. 2017;113:467-479

[31] Aricioglu F, Ercil E, Dulger G. Agmatine inhibits naloxone-induced contractions in morphine-dependent Guinea pig ileum. Annals of the New York Academy of Sciences. 2003;1009: 147-151

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators… DOI: http://dx.doi.org/10.5772/intechopen.81951

[32] Zhu M-Y, Wang W-P, Cai Z-W, Regunathan S, Ordway G. Exogenous agmatine has neuroprotective effects against restraint-induced structural changes in the rat brain. The European Journal of Neuroscience. 2008;27: 1320-1332

humans. American Journal of

187-193

Neuroprotection

230-240

9710-9729

Physiology. Gastrointestinal and Liver Physiology. 2008;295:G1104-G1110

[25] Lu Y, Li C, Zhou M, Luo P, Huang P, Tan J, et al. Clonidine ameliorates cognitive impairment induced by chronic cerebral hypoperfusion via upregulation of the GABABR1 and GAD67

[26] Bakuridze K, Savli E, Gongadze N, Baş DB, Gepdiremen A. Protection in glutamate-induced neurotoxicity by

moxonidine. The International Journal of Neuroscience. 2009;119:1705-1717

[27] Head GA, Mayorov DN. Imidazoline receptors, novel agents and therapeutic

[28] Gupta S, Sharma B. Pharmacological modulation of I(1)-imidazoline and α2 adrenoceptors in sub acute brain ischemia induced vascular dementia. European Journal of Pharmacology.

[29] Matheus FC, Aguiar AS, Castro AA, Villarinho JG, Ferreira J, Figueiredo CP,

[30] Kang S, Kim C-H, Jung H, Kim E, Song H-T, Lee JE. Agmatine ameliorates typ. 2 diabetes induced-Alzheimer's disease-like alterations in high-fat diet-fed mice via reactivation of blunted insulin signalling. Neuropharmacology.

[31] Aricioglu F, Ercil E, Dulger G. Agmatine inhibits naloxone-induced contractions in morphine-dependent Guinea pig ileum. Annals of the New York Academy of Sciences. 2003;1009:

et al. Neuroprotective effects of agmatine in mice infused with a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioural Brain Research.

in hippocampal CA1 in rats. Pharmacology, Biochemistry, and

Behavior. 2015;132:96-102

imidazoline receptor agonist

potential. Cardiovascular & Hematological Agents in Medicinal

Chemistry. 2006;4:17-32

2014;723:80-90

2012;235:263-272

2017;113:467-479

147-151

[18] Reis DJ, Regunathan S. Is agmatine a novel neurotransmitter in brain? Trends in Pharmacological Sciences. 2000;21:

[19] Mun CH, Lee WT, Park KA, Lee JE. Regulation of endothelial nitric oxide synthase by agmatine after transient global cerebral ischemia in rat brain. Anatomy & Cell Biology. 2010;43:

[20] Nissim I, Horyn O, Daikhin Y, Chen P, Li C, Wehrli SL, et al. The molecular and metabolic influence of long term agmatine consumption. The Journal of Biological Chemistry. 2014;289:

[21] Mancinelli F, Ragonese F, Cataldi S, Ceccarini MR, Iannitti RG, Arcuri C, et al. Inhibitory effects of agmatine on monoamine oxidase (MAO) activity: Reconciling the discrepancies. The EuroBiotech Journal. 2018;2:121-127

[22] Sirvanci-Yalabik M, Sehirli AO, Utkan T, Aricioglu F. Agmatine, a metabolite of arginine, improves learning and memory in streptozotocininduced Alzheimer's disease model in

Psychopharmacology. 2016;26(4):

[23] Neis VB, Rosa PB, Olescowicz G, Rodrigues ALS. Therapeutic potential of

Neurochemistry International. 2017;

[24] Moretti M, Neis VB, Matheus FC, Cunha MP, Rosa PB, Ribeiro CM, et al. Effects of agmatine on depressive-like

intracerebroventricular administration of 1-methyl-4-phenylpyridinium (MPP (+)). Neurotoxicity Research. 2015;28:

agmatine for CNS disorders.

rats. Bulletin of Clinical

342-354

108:318e331

222-231

26

behavior induced by

[33] Aricioglu F, Regunathan S. Agmatine attenuates stress- and lipopolysaccharide-induced fever in rats. Physiology & Behavior. 2005;85: 370-375

[34] Jeutsch JD, Anzivino LA. A low dose of the alpha2 agonist clonidine ameliorates the visual attention and spatial working memory deficits produced by phencyclidine administration to rats. Psychopharmacology (Berl). 2004;175: 76-83

[35] Bardget ME, Points M, Ramsey-Faulkner C. The effects of clonidine on discrete-trial delayed spatial alternation in two rat models of memory loss. Neuropsychopharmacology. 2008;33: 1980-1991

[36] Marrs W, Kuperman J, Avedian T, Roth RH, Jentsch JD. Alpha-2 adrenoceptor activation inhibits phencyclidine-induced deficits of spatial working memory in rats. Neuropsychopharmacology. 2005;30: 1500-1510

[37] Unal G, Ates A, Aricioglu F. Agmatine-attenuated cognitive and social deficits in subchronic MK-801 model of schizophrenia in rats. Psychiatry and Clinical Psychopharmacology. 2018:1-10

[38] Bergin DH, Liu P. Agmatine protects against beta-amyloid25–35 induced memory impairments in the rat. Neuroscience. 2010;169:794-811

[39] Zarifkar A, Choopani S, Ghasemi R, Naghdi N, Maghsoudi AH, Maghsoudi N, et al. Agmatine prevents LPSinduced spatial memory impairment

and hippocampal apoptosis. European Journal of Pharmacology. 2010;634: 84-88

[40] Li YF, Gong ZH, Cao JB, Wang HL, Luo ZP, Li J. Antidepressant-like effect of agmatine and its possible mechanism. European Journal of Pharmacology. 2003;469(1–3):81-88

[41] Martel J, Chopin P, Colpaert F, Marien M. Neuroprotective effects of the alpha2-adrenoceptor antagonists, (+)-efaroxan and (+/)-idazoxan, against quinolinic acid-induced lesions of the rat striatum. Experimental Neurology. 1998;154:595-601

[42] Wang X-S, Fang H-L, Chen Y, Liang S-S, Zhu Z-G, Zeng Q-Y, et al. Idazoxan reduces blood-brain barrier damage during experimental autoimmune encephalomyelitis in mouse. European Journal of Pharmacology. 2014;736: 70-76

[43] Chopin P, Debeir T, Raisman-Vozari R, Colpaert FC, Marien MR. Protective effect of the alpha2 adrenoceptor antagonist, dexefaroxan, against spatial memory deficit induced by cortical devascularization in the adult rat. Experimental Neurology. 2004;185: 198-200

[44] Pauwels PJ, Rauly I, Wurch T. Dissimilar pharmacological responses by a new series of imidazoline derivatives at precoupled and ligand-activated alpha 2A-adrenoceptor states: Evidence for effector pathway-dependent differential antagonism. The Journal of Pharmacology and Experimental Therapeutics. 2003;305:1015-1023

[45] Rizk P, Salazar J, Raisman-Vozari R, Marien M, Ruberg M, Colpaert F, et al. The alpha2-adrenoceptor antagonist dexefaroxan enhances hippocampal neurogenesis by increasing the survival and differentiation of new granule cells. Neuropsychopharmacology. 2006;31: 1146-1157

[46] Debeir T, Marien M, Ferrario J, Rizk P, Prigent A, Colpaert F, et al. In vivo upregulation of endogenous NGF in the rat brain by the alpha2-adrenoreceptor antagonist dexefaroxan: Potential role in the protection of the basalocortical cholinergic system during neurodegeneration. Experimental Neurology. 2004;190:384-395

[47] Francis BM, Yang J, Hajderi E, Brown ME, Michalski B, McLaurin J, et al. Reduced tissue levels of noradrenaline are associated with behavioral phenotypes of the TgCRND8 mouse model of Alzheimer's disease. Neuropsychopharmacology. 2012;37: 1934-1944

[48] Condello S, Monica Currò M, Ferlazzo N, Caccamo D, Satriano J, Lentile R. Agmatine effects on mitochondrial membrane potential and NF-κB activation protect against rotenone-induced cell damage in human neuronal-like SH-SY5Y cells. Journal of Neurochemistry. 2011;116(1):67-75

[49] Park YM, Lee WT, Bokara KK, Seo SK, Park SH, Kim JH, et al. The multifaceted effects of agmatine on functional recovery after spinal cord injury through modulations of BMP-2/4/7 expressions in neurons and glial cells. PLoS One. 2013;8:e53911

[50] Tohidi V, Hassanzadeh B, Sherwood B, Ma W, Rosenberg M, Gilad V, et al. Effect of agmatine sulfate on neuropathic pain. Neurology. 2014;82 (Suppl. 10):P7.094

[51] Piletz JE, Aricioglu F, Cheng JT, Fairbanks CA, Gilad VH, Haenisch B, et al. Agmatine: Clinical applications after 100 years in translation. Drug Discovery Today. 2013;18(17–18): 880-893

[52] Keynan O, Mirovsky Y, Dekel S, Gilad VH, Gilad GM. Safety and efficacy of dietary agmatine sulfate in lumbar disc-associated radiculopathy. An openlabel, dose-escalating study followed by a randomized, double-blind, placebocontrolled trial. Pain Medicine. 2010; 11(3):356-368

L-citrulline and agmatine in the rat brain. Hippocampus. 2009;19:597-602

DOI: http://dx.doi.org/10.5772/intechopen.81951

Experimental Medicine and Biology.

[69] Chamorro A. Neuroprotectants in the era of reperfusion therapy. Journal

[70] Wu Q J, Tymianski M. Targeting NMDA receptors in stroke: New hope in neuroprotection. Molecular Brain. 2018;

[71] Feng Y, He X, Yang Y, Chao D, Lazarus LH, Xia Y. Current research on opioid receptor function. Current Drug

[72] Vaidya B, Sifat AE, Karamyan VT, Abbruscato TJ. The neuroprotective role of the brain opioid system in stroke injury. Drug Discovery Today. 2018;23:

[73] Yang Y, Zhi F, He X, Moore ML, Kang X, Chao D, et al. Delta-opioid receptor activation and microRNA expression of the rat cortex in hypoxia.

[74] Grant Liska M, Crowley MG, Lippert T, Corey S, Borlongan CV. Delta opioid receptor and peptide: A dynamic

neurological disorders. In: Handbook of Experimental Pharmacology. Berlin,

[75] Staples M, Acosta S, Tajiri N, Pabon M, Kaneko Y, Borlongan CV. Delta opioid receptor and its peptide: A receptor-ligand neuroprotection. International Journal of Molecular Sciences. 2013;14(9):17410-17419

[76] Liu H, Chen B, Li S, Yao J. Dosedependent neuroprotection of deltaopioid peptide [D-Ala(2), D-Leu(5)]

therapy for stroke and other

Heidelberg: Springer; 2017

Targets. 2012;13:230-246

PLoS One. 2012;7:e51524

of Stroke. 2018;20(2):197-207

[68] Xiong XY, Liu L, Yang QW. Refocusing neuroprotection in cerebral reperfusion era: New challenges and strategies. Frontiers in Neurology. 2018;

2017;964:133-152

9:249

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators…

11(1):15

1385-1395

[61] Moosavi M, Khales GY, Abbasi L, Zarifkar A, Rastegar K. Agmatine protects against scopolamine-induced water maze performance impairment and hippocampal ERK and Akt inactivation. Neuropharmacology.

[62] Stewart LS, McKay BE. Acquisition deficit and time-dependent retrograde

conditioning in agmatine-treated rats. Behavioural Pharmacology. 2000;11:

[63] McKay BE, Lado WE, Martin LJ, Galic MA, Fournier NM. Learning and memory in agmatine-treated rats. Pharmacology, Biochemistry, and

[64] Utkan T, Gocmez SS, Regunathan S, Aricioglu F. Agmatine, a metabolite of L-arginine, reverses scopolamineinduced learning and memory impairment in rats. Pharmacology, Biochemistry, and Behavior. 2012;102:

[65] Knox LT, Jing Y, Fleete MS, Collie ND, Zhang H, Liu P. Scopolamine impairs behavioural function and arginine metabolism in the rat dentate gyrus. Neuropharmacology. 2011;61:

[66] Barber TA, Haggarty MK. Memantine ameliorates scopolamineinduced amnesia in chicks trained on taste-avoidance learning. Neurobiology of Learning and Memory. 2010;93:

[67] Nguyen L, Lucke-Wold BP, Mookerjee S, Kaushal N, Matsumoto

neurodegenerative diseases: Towards a hypothesis of sigma-1 receptors as amplifiers of neurodegeneration and neuroprotection. Advances in

RR. Sigma-1 receptors and

2012;62(5–6):2018-2023

amnesia for contextual fear

Behavior. 2002;72:551-557

93-97

578-584

1452-1462

540-545

29

[53] Himmelseher S, Kochs EF. Neuroprotection by dexmedetomidine. In: Gullo A, editor. Anaesthesia, Pain, Intensive Care and Emergency A.P.I.C.E. Italia: Springer-Verlag; 2006. pp. 633-639. Ch. 56

[54] Coull JT, Sahakian BJ, Hodges JR. The α2 antagonist idazoxan remediates certain attentional and executive dysfunction in patients with dementia of frontal type. Psychopharmacology. 1996;123:239-249

[55] Gupta S, Sharma B. Pharmacological benefit of I(1)-imidazoline receptors activation and nuclear factor kappa-B (NF-κB) modulation in experimental Huntington's disease. Brain Research Bulletin. 2014;102:57-68

[56] Ilik MK, Kocaogullar Y, Koc O, Esen H. Beneficial effects of moxonidine on cerebral vasospasm after experimental subarachnoid. Turkish Neurosurgery. 2014;24(6):873-879

[57] Liu P, Smith PF, Appleton I, Darlington CL, Bilkey DK. Potential involvement of NOS and arginase in age-related behavioural impairments. Experimental Gerontology. 2004;39: 1207-1222

[58] Rushaidhi M, Collie ND, Zhang H, Liu P. Agmatine selectively improves behavioural function in aged male Sprague-Dawley rats. Neuroscience. 2012;218:206-215

[59] Gupta N, Jing Y, Collie ND, Zhang H, Liu P. Ageing alters behavioural function and brain arginine metabolism in male Sprague-Dawley rats. Neuroscience. 2012;226:178-196

[60] Liu P, Jing Y, Collie ND, Chary S, Zhang H. Memory-related changes in

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators… DOI: http://dx.doi.org/10.5772/intechopen.81951

L-citrulline and agmatine in the rat brain. Hippocampus. 2009;19:597-602

[46] Debeir T, Marien M, Ferrario J, Rizk P, Prigent A, Colpaert F, et al. In vivo upregulation of endogenous NGF in the rat brain by the alpha2-adrenoreceptor antagonist dexefaroxan: Potential role in the protection of the basalocortical

label, dose-escalating study followed by a randomized, double-blind, placebocontrolled trial. Pain Medicine. 2010;

Neuroprotection by dexmedetomidine. In: Gullo A, editor. Anaesthesia, Pain, Intensive Care and Emergency

A.P.I.C.E. Italia: Springer-Verlag; 2006.

[54] Coull JT, Sahakian BJ, Hodges JR. The α2 antagonist idazoxan remediates certain attentional and executive dysfunction in patients with dementia of frontal type. Psychopharmacology.

[55] Gupta S, Sharma B. Pharmacological benefit of I(1)-imidazoline receptors activation and nuclear factor kappa-B (NF-κB) modulation in experimental Huntington's disease. Brain Research

[56] Ilik MK, Kocaogullar Y, Koc O, Esen H. Beneficial effects of moxonidine on cerebral vasospasm after experimental subarachnoid. Turkish Neurosurgery.

[57] Liu P, Smith PF, Appleton I, Darlington CL, Bilkey DK. Potential involvement of NOS and arginase in age-related behavioural impairments. Experimental Gerontology. 2004;39:

[58] Rushaidhi M, Collie ND, Zhang H, Liu P. Agmatine selectively improves behavioural function in aged male Sprague-Dawley rats. Neuroscience.

[59] Gupta N, Jing Y, Collie ND, Zhang H, Liu P. Ageing alters behavioural function and brain arginine metabolism

[60] Liu P, Jing Y, Collie ND, Chary S, Zhang H. Memory-related changes in

in male Sprague-Dawley rats. Neuroscience. 2012;226:178-196

[53] Himmelseher S, Kochs EF.

11(3):356-368

pp. 633-639. Ch. 56

1996;123:239-249

Bulletin. 2014;102:57-68

2014;24(6):873-879

1207-1222

2012;218:206-215

cholinergic system during

Neuroprotection

neurodegeneration. Experimental Neurology. 2004;190:384-395

[47] Francis BM, Yang J, Hajderi E, Brown ME, Michalski B, McLaurin J,

[48] Condello S, Monica Currò M, Ferlazzo N, Caccamo D, Satriano J, Lentile R. Agmatine effects on

mitochondrial membrane potential and NF-κB activation protect against

rotenone-induced cell damage in human neuronal-like SH-SY5Y cells. Journal of Neurochemistry. 2011;116(1):67-75

[50] Tohidi V, Hassanzadeh B, Sherwood B, Ma W, Rosenberg M, Gilad V, et al.

neuropathic pain. Neurology. 2014;82

[51] Piletz JE, Aricioglu F, Cheng JT, Fairbanks CA, Gilad VH, Haenisch B, et al. Agmatine: Clinical applications after 100 years in translation. Drug Discovery Today. 2013;18(17–18):

[52] Keynan O, Mirovsky Y, Dekel S, Gilad VH, Gilad GM. Safety and efficacy of dietary agmatine sulfate in lumbar disc-associated radiculopathy. An open-

Effect of agmatine sulfate on

(Suppl. 10):P7.094

880-893

28

[49] Park YM, Lee WT, Bokara KK, Seo SK, Park SH, Kim JH, et al. The multifaceted effects of agmatine on functional recovery after spinal cord injury through modulations of BMP-2/4/7 expressions in neurons and glial cells. PLoS One. 2013;8:e53911

et al. Reduced tissue levels of noradrenaline are associated with behavioral phenotypes of the TgCRND8 mouse model of Alzheimer's disease. Neuropsychopharmacology. 2012;37:

1934-1944

[61] Moosavi M, Khales GY, Abbasi L, Zarifkar A, Rastegar K. Agmatine protects against scopolamine-induced water maze performance impairment and hippocampal ERK and Akt inactivation. Neuropharmacology. 2012;62(5–6):2018-2023

[62] Stewart LS, McKay BE. Acquisition deficit and time-dependent retrograde amnesia for contextual fear conditioning in agmatine-treated rats. Behavioural Pharmacology. 2000;11: 93-97

[63] McKay BE, Lado WE, Martin LJ, Galic MA, Fournier NM. Learning and memory in agmatine-treated rats. Pharmacology, Biochemistry, and Behavior. 2002;72:551-557

[64] Utkan T, Gocmez SS, Regunathan S, Aricioglu F. Agmatine, a metabolite of L-arginine, reverses scopolamineinduced learning and memory impairment in rats. Pharmacology, Biochemistry, and Behavior. 2012;102: 578-584

[65] Knox LT, Jing Y, Fleete MS, Collie ND, Zhang H, Liu P. Scopolamine impairs behavioural function and arginine metabolism in the rat dentate gyrus. Neuropharmacology. 2011;61: 1452-1462

[66] Barber TA, Haggarty MK. Memantine ameliorates scopolamineinduced amnesia in chicks trained on taste-avoidance learning. Neurobiology of Learning and Memory. 2010;93: 540-545

[67] Nguyen L, Lucke-Wold BP, Mookerjee S, Kaushal N, Matsumoto RR. Sigma-1 receptors and neurodegenerative diseases: Towards a hypothesis of sigma-1 receptors as amplifiers of neurodegeneration and neuroprotection. Advances in

Experimental Medicine and Biology. 2017;964:133-152

[68] Xiong XY, Liu L, Yang QW. Refocusing neuroprotection in cerebral reperfusion era: New challenges and strategies. Frontiers in Neurology. 2018; 9:249

[69] Chamorro A. Neuroprotectants in the era of reperfusion therapy. Journal of Stroke. 2018;20(2):197-207

[70] Wu Q J, Tymianski M. Targeting NMDA receptors in stroke: New hope in neuroprotection. Molecular Brain. 2018; 11(1):15

[71] Feng Y, He X, Yang Y, Chao D, Lazarus LH, Xia Y. Current research on opioid receptor function. Current Drug Targets. 2012;13:230-246

[72] Vaidya B, Sifat AE, Karamyan VT, Abbruscato TJ. The neuroprotective role of the brain opioid system in stroke injury. Drug Discovery Today. 2018;23: 1385-1395

[73] Yang Y, Zhi F, He X, Moore ML, Kang X, Chao D, et al. Delta-opioid receptor activation and microRNA expression of the rat cortex in hypoxia. PLoS One. 2012;7:e51524

[74] Grant Liska M, Crowley MG, Lippert T, Corey S, Borlongan CV. Delta opioid receptor and peptide: A dynamic therapy for stroke and other neurological disorders. In: Handbook of Experimental Pharmacology. Berlin, Heidelberg: Springer; 2017

[75] Staples M, Acosta S, Tajiri N, Pabon M, Kaneko Y, Borlongan CV. Delta opioid receptor and its peptide: A receptor-ligand neuroprotection. International Journal of Molecular Sciences. 2013;14(9):17410-17419

[76] Liu H, Chen B, Li S, Yao J. Dosedependent neuroprotection of deltaopioid peptide [D-Ala(2), D-Leu(5)]

enkephalin on spinal cord ischemiareperfusion injury by regional perfusion into the abdominal aorta in rabbits. Journal of Vascular Surgery. 2016;63(4): 1074-1081

[77] Lee JY, Liska MG, Crowley M, Xu K, Acosta SA, Borlongan CV, et al. Multifaceted effects of delta opioid receptors and DADLE in diseases of the nervous system. Current Drug Discovery Technologies. 2018;15(2): 94-108

[78] Crowley MG, Liska MG, Lippert T, Corey S, Borlongan CV. Utilizing delta opioid receptors and peptides for cytoprotection: Implications in stroke and other neurological disorders. CNS & Neurological Disorders Drug Targets. 2017;16(4):414-424

[79] Moghal ETB, Venkatesh K, Sen D. The delta opioid peptide D-Alanine 2, Leucine 5 Enkephaline (DADLE) induces neuroprotection through crosstalk between the UPR and pro-survival MAPK-NGF-Bcl2 signaling pathways via modulation of several micro-RNAs in SH-SY5Y cells subjected to ER stress. Cell Biology International. 2018;42(5): 543-569

[80] Lv MR, Li B, Wang MG, Meng FG, Yu JJ, Guo F, et al. Activation of the PI3K-Akt pathway promotes neuroprotection of the delta-opioid receptor agonist against cerebral ischemia-reperfusion injury in rat models. Biomedicine & Pharmacotherapy. 2017;93:230-237

[81] Yang L, Shah K, Wang H, Karamyan VT, Abbruscato TJ. Characterization of neuroprotective effects of biphalin, an opioid receptor agonist, in a model of focal brain ischemia. The Journal of Pharmacology and Experimental Therapeutics. 2011;339(2):499-508

[82] Kawalec M, Kowalczyk JE, Beresewicz M, Lipkowski AW, Zablocka B. Neuroprotective potential of

biphalin, multireceptor opioid peptide, against excitotoxic injury in hippocampal organotypic culture. Neurochemical Research. 2011;36(11): 2091-2095

[83] Remesic M, Macedonio G, Mollica A, Porreca F, Hruby V, Lee YS. Cyclic biphalin analogues with a novel linker lead to potent agonist activities at mu, delta, and kappa opioid receptors. Bioorganic & Medicinal Chemistry. 2018;26(12):3664-3667

[84] Popiolek-Barczyk K, Piotrowska A, Makuch W, Mika J. Biphalin, a dimeric enkephalin, alleviates LPS-induced activation in rat primary microglial cultures in opioid receptor-dependent and receptor-independent manners. Neural Plasticity. 2017;2017:3829472

[85] Yang L, Islam MR, Karamyan VT, Abbruscato TJ. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtypeselective opioid receptor agonists for stroke treatment. Brain Research. 1609; 2015:1-11

[86] Islam MR, Yang L, Lee YS, Hruby VJ, Karamyan VT, Abbruscato TJ. Enkephalin-fentanyl multifunctional opioids as potential neuroprotectants for ischemic stroke treatment. Current Pharmaceutical Design. 2016;22: 6459-6468

**31**

**Chapter 3**

**Abstract**

caffeine and theophylline.

**1. Introduction**

neuroprotective, natural compounds

tors are coupled to stimulatory G proteins [2].

The Role and Development of the

Adenosine is a neuromodulator that regulates the body's response to dopamine and another neurotransmitter in the brain that is responsible for motoric, emotion, learning, and memory function. Adenosine is a G-protein-coupled receptor and has four subtypes, which are A1, A2A, A2B, and A3. Adenosine A2A is located in the striatum of the brain. Antagonist interferes with GABA releasing, modulates acetylcholine and releases dopamine, and also facilitates dopamine receptor's signaling. Therefore, it can reduce motoric symptoms in Parkinson's disease. Adenosine A2A antagonist is also believed to have neuroprotective effects. Several compounds have been reported and have undergone clinical test as selective adenosine A2A antagonists, including istradefylline, preladenant, tozadenant, vipadenant, ST-1535, and SYN-115. Nonselective adenosine A2A antagonists from natural compounds are

**Keywords:** adenosine A2A, selective adenosine A2A antagonists, Parkinson's disease,

Adenosine is a neuromodulator that coordinates responses to dopamine and other neurotransmitters in areas of the brain responsible for motor function, mood, learning, and memory [1]. Adenosine consists of four receptor subtypes: A1, A2A, A2B, and A3 belonging to the superfamily of G-protein-coupled receptor. Adenosine A1 and A3 receptors are coupled to inhibitory G proteins, while A2A and A2B recep-

Adenosine A1 receptor can be found in adipose tissue, heart muscle, and inflammatory cells. The receptor mostly expressed by the central nervous system such as neocortex, cerebellum, hippocampus, and dorsal horn of the spinal cord [3]. The pre- and postsynaptic nerve terminals, mast cells, airway smooth muscle, and circulating leukocytes are the places where adenosine A2 receptor can be found. As the more widely dispersed receptor, adenosine A2 is divided into two receptors on the basis of high- and low-affinity for adenosine, A2A and A2B [4]. Striatal neurons are where the adenosine A2A are highly enriched; however its lower levels can also be found in glial cells and neurons outside the striatum [5]. The adenosine A2B receptors are highly expressed in the gastrointestinal tract, bladder, lung, and on mast

Antagonist of Adenosine A2A in

*Widya Dwi Aryati, Nabilah Nurtika Salamah,* 

Parkinson's Disease

*Rezi Riadhi Syahdi and Arry Yanuar*

#### **Chapter 3**

enkephalin on spinal cord ischemiareperfusion injury by regional perfusion into the abdominal aorta in rabbits. Journal of Vascular Surgery. 2016;63(4): biphalin, multireceptor opioid peptide,

[83] Remesic M, Macedonio G, Mollica A, Porreca F, Hruby V, Lee YS. Cyclic biphalin analogues with a novel linker lead to potent agonist activities at mu, delta, and kappa opioid receptors. Bioorganic & Medicinal Chemistry.

[84] Popiolek-Barczyk K, Piotrowska A, Makuch W, Mika J. Biphalin, a dimeric enkephalin, alleviates LPS-induced activation in rat primary microglial cultures in opioid receptor-dependent and receptor-independent manners. Neural Plasticity. 2017;2017:3829472

[85] Yang L, Islam MR, Karamyan VT, Abbruscato TJ. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtypeselective opioid receptor agonists for stroke treatment. Brain Research. 1609;

[86] Islam MR, Yang L, Lee YS, Hruby VJ, Karamyan VT, Abbruscato TJ. Enkephalin-fentanyl multifunctional opioids as potential neuroprotectants for ischemic stroke treatment. Current Pharmaceutical Design. 2016;22:

against excitotoxic injury in hippocampal organotypic culture. Neurochemical Research. 2011;36(11):

2018;26(12):3664-3667

2091-2095

2015:1-11

6459-6468

[77] Lee JY, Liska MG, Crowley M, Xu K,

[78] Crowley MG, Liska MG, Lippert T, Corey S, Borlongan CV. Utilizing delta opioid receptors and peptides for cytoprotection: Implications in stroke and other neurological disorders. CNS & Neurological Disorders Drug Targets.

[79] Moghal ETB, Venkatesh K, Sen D. The delta opioid peptide D-Alanine 2, Leucine 5 Enkephaline (DADLE) induces neuroprotection through crosstalk between the UPR and pro-survival MAPK-NGF-Bcl2 signaling pathways via modulation of several micro-RNAs in SH-SY5Y cells subjected to ER stress. Cell Biology International. 2018;42(5):

[80] Lv MR, Li B, Wang MG, Meng FG, Yu JJ, Guo F, et al. Activation of the PI3K-Akt pathway promotes neuroprotection of the delta-opioid receptor agonist against cerebral ischemia-reperfusion injury in rat

Pharmacotherapy. 2017;93:230-237

[82] Kawalec M, Kowalczyk JE,

B. Neuroprotective potential of

[81] Yang L, Shah K, Wang H, Karamyan VT, Abbruscato TJ. Characterization of neuroprotective effects of biphalin, an opioid receptor agonist, in a model of focal brain ischemia. The Journal of Pharmacology and Experimental Therapeutics. 2011;339(2):499-508

Beresewicz M, Lipkowski AW, Zablocka

models. Biomedicine &

Acosta SA, Borlongan CV, et al. Multifaceted effects of delta opioid receptors and DADLE in diseases of the

nervous system. Current Drug Discovery Technologies. 2018;15(2):

1074-1081

Neuroprotection

94-108

543-569

30

2017;16(4):414-424

## The Role and Development of the Antagonist of Adenosine A2A in Parkinson's Disease

*Widya Dwi Aryati, Nabilah Nurtika Salamah, Rezi Riadhi Syahdi and Arry Yanuar*

#### **Abstract**

Adenosine is a neuromodulator that regulates the body's response to dopamine and another neurotransmitter in the brain that is responsible for motoric, emotion, learning, and memory function. Adenosine is a G-protein-coupled receptor and has four subtypes, which are A1, A2A, A2B, and A3. Adenosine A2A is located in the striatum of the brain. Antagonist interferes with GABA releasing, modulates acetylcholine and releases dopamine, and also facilitates dopamine receptor's signaling. Therefore, it can reduce motoric symptoms in Parkinson's disease. Adenosine A2A antagonist is also believed to have neuroprotective effects. Several compounds have been reported and have undergone clinical test as selective adenosine A2A antagonists, including istradefylline, preladenant, tozadenant, vipadenant, ST-1535, and SYN-115. Nonselective adenosine A2A antagonists from natural compounds are caffeine and theophylline.

**Keywords:** adenosine A2A, selective adenosine A2A antagonists, Parkinson's disease, neuroprotective, natural compounds

#### **1. Introduction**

Adenosine is a neuromodulator that coordinates responses to dopamine and other neurotransmitters in areas of the brain responsible for motor function, mood, learning, and memory [1]. Adenosine consists of four receptor subtypes: A1, A2A, A2B, and A3 belonging to the superfamily of G-protein-coupled receptor. Adenosine A1 and A3 receptors are coupled to inhibitory G proteins, while A2A and A2B receptors are coupled to stimulatory G proteins [2].

Adenosine A1 receptor can be found in adipose tissue, heart muscle, and inflammatory cells. The receptor mostly expressed by the central nervous system such as neocortex, cerebellum, hippocampus, and dorsal horn of the spinal cord [3]. The pre- and postsynaptic nerve terminals, mast cells, airway smooth muscle, and circulating leukocytes are the places where adenosine A2 receptor can be found. As the more widely dispersed receptor, adenosine A2 is divided into two receptors on the basis of high- and low-affinity for adenosine, A2A and A2B [4]. Striatal neurons are where the adenosine A2A are highly enriched; however its lower levels can also be found in glial cells and neurons outside the striatum [5]. The adenosine A2B receptors are highly expressed in the gastrointestinal tract, bladder, lung, and on mast

cells. The most widely dispersed receptor is the A3 receptor which can be found in the kidney, testis, lung, mast cells, eosinophils, neutrophils, heart, and the brain cortex [4].

Adenosine A2A receptors are found to be concentrates in GABAergic mediumsized spiny neurons in the dopamine-rich regions of the brain. The protein translated in the adenosine A2A is carried by many other tissues such as blood vessels, endothelial, lymphoid cells, smooth muscle cells, and several neurons in sympathetic and parasympathetic systems [6]. Therefore, the dispersion of adenosine A2A is not limited to the medium spiny neurons in the basal ganglia. It stimulates the modulation of cAMP production and increases the level of adenylyl cyclase. This receptor is essential in giving the medium of vasodilation of coronary arteries which then supports the combination of new blood vessels and giving protection for tissues from indirect inflammatory damage [7]. The role of the A2A in the brain includes influencing the activity within the indirect pathway of the basal ganglia. The A2A has complicated actions because it colocalizes and is physically combined with other unrelated G-protein-coupled receptors. Therefore, it can form heterodimers such as dopamine D2/A2A, and D3/A2A, cannabinoid CB1/A2A, and glutamate mGluR5/A2A, as well as CB1/A2A/D2 heterotrimers [7].

The pathways which give signals used by the A2A receptor depend on the location of the cell and tissue, the specific G protein which couples it, and the signaling in the cell. The brain also carries the A2A receptor in which it plays an important role in regulating the glutamate and releasing the dopamine [8]. In the striatopallidal neurons, dopamine D2 receptors are colocalized with adenosine A2A receptors. Adenosine A2A receptor activity that mediates stimulation and D2 receptors that mediate inhibition in the striatopallidal pathway are balanced [9]. The adenosine A2A

**33**

**Figure 2.**

*intracellular loop (IL2) are modeled in dashed line.*

*The Role and Development of the Antagonist of Adenosine A2A in Parkinson's Disease*

likely affects motor activity by acting at different levels of the basal ganglia network. The basal ganglia comprise the striatum (putamen), the globus pallidus externa (GPe), the globus pallidus interna (GPi), substantia nigra pars compacta (SNc), substantia nigra reticulata (SNr), and the subthalamic nucleus (STN). The striatum is represented by medium-sized spiny projection neurons (MSNs), accounting for almost 95% of striatal neurons and using γ-aminobutyric acid (GABA) as neurotransmitter. The GABAergic spiny neurons give rise to the two main striatal efferent circuits: the striatonigral and the striatopallidal pathway. The neurons of the striatonigral (direct) pathway contain the neuropeptide substance P and dynorphin and mainly express D1 receptors; this pathway directly projects from the striatum to the GPi/SNr. The neurons of the striatopallidal (indirect) pathway containing the neuropeptide, enkephalin (ENK), predominantly express D2 receptors; this circuit connects the striatum with the GPi/SNr via synaptic connections in the GPe and STN in **Figure 1**. Dopamine modulates motor coordination and fine movements by facilitating the action of the direct pathway on stimulatory D1 receptors and by inhibiting indirect pathway function acting on inhibitory D2 receptors [10].

The adenosine A2A receptor has agonists and antagonists of which the roles are potentiating and inhibiting, respectively. The D2 receptor agonist has effects on motor activity, the releasing of neurotransmitter, and the expression of striatal of c-Fos, a factor of transcription which is used as neuronal activity's indirect marker [11]. The adenosine A2A receptor has a key role in regulating the striatal dopaminergic neurotransmission which produces substances that are valuable to treat neuro-

The topology of G-protein-coupled receptor is displayed in the structure of the adenosine A2A receptor. These receptors have a central core which consists of seven

*Crystal structure of the adenosine A2A receptor (4EIY) shown in the membrane structure. The extracellular and intracellular parts of the membrane are shown in red and blue beads, respectively. The disorder residues of* 

logical disorders that are relevant with dopaminergic dysfunction.

*DOI: http://dx.doi.org/10.5772/intechopen.84272*

**Figure 1.** *Basal ganglia circuitry in normal conditions.*

#### *The Role and Development of the Antagonist of Adenosine A2A in Parkinson's Disease DOI: http://dx.doi.org/10.5772/intechopen.84272*

likely affects motor activity by acting at different levels of the basal ganglia network. The basal ganglia comprise the striatum (putamen), the globus pallidus externa (GPe), the globus pallidus interna (GPi), substantia nigra pars compacta (SNc), substantia nigra reticulata (SNr), and the subthalamic nucleus (STN). The striatum is represented by medium-sized spiny projection neurons (MSNs), accounting for almost 95% of striatal neurons and using γ-aminobutyric acid (GABA) as neurotransmitter. The GABAergic spiny neurons give rise to the two main striatal efferent circuits: the striatonigral and the striatopallidal pathway. The neurons of the striatonigral (direct) pathway contain the neuropeptide substance P and dynorphin and mainly express D1 receptors; this pathway directly projects from the striatum to the GPi/SNr. The neurons of the striatopallidal (indirect) pathway containing the neuropeptide, enkephalin (ENK), predominantly express D2 receptors; this circuit connects the striatum with the GPi/SNr via synaptic connections in the GPe and STN in **Figure 1**. Dopamine modulates motor coordination and fine movements by facilitating the action of the direct pathway on stimulatory D1 receptors and by inhibiting indirect pathway function acting on inhibitory D2 receptors [10].

The adenosine A2A receptor has agonists and antagonists of which the roles are potentiating and inhibiting, respectively. The D2 receptor agonist has effects on motor activity, the releasing of neurotransmitter, and the expression of striatal of c-Fos, a factor of transcription which is used as neuronal activity's indirect marker [11]. The adenosine A2A receptor has a key role in regulating the striatal dopaminergic neurotransmission which produces substances that are valuable to treat neurological disorders that are relevant with dopaminergic dysfunction.

The topology of G-protein-coupled receptor is displayed in the structure of the adenosine A2A receptor. These receptors have a central core which consists of seven

#### **Figure 2.**

*Neuroprotection*

cortex [4].

cells. The most widely dispersed receptor is the A3 receptor which can be found in the kidney, testis, lung, mast cells, eosinophils, neutrophils, heart, and the brain

Adenosine A2A receptors are found to be concentrates in GABAergic mediumsized spiny neurons in the dopamine-rich regions of the brain. The protein translated in the adenosine A2A is carried by many other tissues such as blood vessels, endothelial, lymphoid cells, smooth muscle cells, and several neurons in sympathetic and parasympathetic systems [6]. Therefore, the dispersion of adenosine A2A is not limited to the medium spiny neurons in the basal ganglia. It stimulates the modulation of cAMP production and increases the level of adenylyl cyclase. This receptor is essential in giving the medium of vasodilation of coronary arteries which then supports the combination of new blood vessels and giving protection for tissues from indirect inflammatory damage [7]. The role of the A2A in the brain includes influencing the activity within the indirect pathway of the basal ganglia. The A2A has complicated actions because it colocalizes and is physically combined with other unrelated G-protein-coupled receptors. Therefore, it can form heterodimers such as dopamine D2/A2A, and D3/A2A, cannabinoid CB1/A2A, and glutamate

The pathways which give signals used by the A2A receptor depend on the location of the cell and tissue, the specific G protein which couples it, and the signaling in the cell. The brain also carries the A2A receptor in which it plays an important role in regulating the glutamate and releasing the dopamine [8]. In the striatopallidal neurons, dopamine D2 receptors are colocalized with adenosine A2A receptors. Adenosine A2A receptor activity that mediates stimulation and D2 receptors that mediate inhibition in the striatopallidal pathway are balanced [9]. The adenosine A2A

mGluR5/A2A, as well as CB1/A2A/D2 heterotrimers [7].

**32**

**Figure 1.**

*Basal ganglia circuitry in normal conditions.*

*Crystal structure of the adenosine A2A receptor (4EIY) shown in the membrane structure. The extracellular and intracellular parts of the membrane are shown in red and blue beads, respectively. The disorder residues of intracellular loop (IL2) are modeled in dashed line.*

transmembrane helices (7TM). Each of the TM is mainly α-helical and consists of 20–27 amino acids. Three intracellular (IL1, IL2, and IL3) and three extracellular (EL1, EL2, and EL3) loops connect each of the TM domain. A short helix TM8 runs parallel to the cytoplasmic surface of the membrane. The adenosine A2A receptor has differences in length and N-terminal extracellular domain function, their domain of C-terminal intracellular, and their loops of intracellular/extracellular. These differences are shown in **Figure 2**.

### **2. The role of adenosine A2A in Parkinson's disease**

Parkinson's disease (PD) is a chronic neurodegenerative disorder in the brain, marked by motoric symptoms [12]. The motoric symptoms in PD are resting tremor, rigidity, bradykinesia, and postural disorder. Besides motoric symptoms, PD also has non-motoric symptoms such as depression, hallucination, sleeping disorder, and decreasing cognitive and sensory functions. The main pathological characteristic of PD is the loss of dopaminergic neurons in *substantia nigra pars compacta*, a region in the brain that controls all the body movement and forms the dopamine. The development of PD also includes the formation of Lewy body, a deposit of cytoplasmic, eosinophilic neuronal inclusions, composed of the presynaptic protein α-synuclein [13, 14].

The current therapy of PD is targeted at dopamine replacement, thereby decreasing the motor symptoms. It includes precursor of dopamine (levodopa), dopamine agonists [15, 16] monoamine oxidase type B (MAO-B) inhibitors [17], and catechol-O-methyltransferase (COMT) inhibitors [17, 18]. These agents produce undesirable side effects such as on-off effects, hallucinations, and dyskinesia. These effects get more severe as the treatment continued. The efficacy of these agents is also decreasing as the disease progressed [19].

Because of the undesirable side effects of dopamine replacement therapy, the non-dopaminergic therapy is continuously being explored. One of the approaches is selective adenosine A2A antagonist [20, 21]. Adenosine A2A receptors are found mainly in the striatum of rat [22, 23], which has similar distribution with the human brain [24, 25]. In the striatum, adenosine A2A receptors are colocalized with dopamine D2 receptors. These two receptors have opposite effect on motoric function [26]. The activation of adenosine A2A receptors will inhibit the signaling of dopamine D2 receptors, and conversely, the inhibition of signaling of adenosine A2A receptors will increase the activation of dopamine D2 receptors, therefore facilitating dopamine D2-mediated responses [11]. The inhibition of adenosine A2A receptors showed motoric improvement in animal models of PD [27–30]. This also has desirable effect on long-term levodopa treatment such as decreasing the dyskinesia and increasing the therapeutic effect on levodopa [31, 32].

#### **3. Adenosine A2A receptor antagonist as a neuroprotective**

For years, adenosine-dopamine interactions have been investigated in order to observe their relevance for treatment of central nervous system (CNS) disorders [33]. It is assumed that adenosine A1 receptors (A1Rs) play an important role in neuroprotection as their activation at the onset of neuronal injury has shown to reduce brain damage in adult animal model. Vice versa, their blockade aggravates the damage. In other hand, adenosine A2 receptors (A2ARs) are shown to be upregulated in harmful brain conditions, and their blockade shows brain neuroprotection in studied animals [34]. The blockade of A2ARs alleviates the long-term

**35**

*The Role and Development of the Antagonist of Adenosine A2A in Parkinson's Disease*

burden of brain disorders in different neurodegenerative conditions, namely, ischemia, epilepsy, and Parkinson's and Alzheimer's disease, through its control

A2ARs have been shown to be viable in serving as alternative non-dopaminergic strategy of Parkinson's disease treatment because of their limited distribution in the striatum and the intense interaction between adenosine and dopamine receptors in the brain. A2ARs antagonists were shown to improve motor function in different animal models (primates and rodents), alone or co-administered with dopaminomimetic drugs, levodopa, or dopamine agonists [35]. Based on rigorous preclinical animal studies, istradefylline (KW6002) has shown its promising ability to increase motor activity in PD of the advanced stage in clinical phase IIB trial [36]. It became the first therapeutic agent developed to target A2ARs, and other similar compounds

The recent meta-analysis (n = 6) suggested that 20 mg of istradefylline improves

In the case of Parkinson's disease, microglia has been suggested to be the most likely cell type to be targeted by A2ARs antagonists [40]. In vitro and in vivo studies showed that local neuroinflammation make glial cells (especially microglial cells) particularly sensitive to A2AR modulation [41]. Previous research done by Gao and Phillis is the first study to demonstrate nonselective A2AR antagonist action in reducing cerebral ischemic injury in the gerbil, following global forebrain ischemia [42]. After that, many studies have reported the neuroprotective of A2AR antago-

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is indicated by the progressive loss of memory and other cognitive functions, leading to dementia [44, 45]. Adenosine can control and integrate cognition and memory [46]. Both A1Rs and A2ARs, mainly located in synapses, control the release of neurotransmitters which are involved in memory or other cognitive processes [34, 47]. Methylxanthine was discovered to act as nonselective adenosine receptors antagonist. Caffeine, the most famous methylxanthine found in common beverages, is the most widely consumed psychoactive drug. Maia and de Mendonca presented the first epidemiological data showing that the incidence of AD is inversely proportioned with coffee consumption [48]. Several other studies also show this inverse relationship [49–51]. Animal models also shown that caffeine intake may be beneficial for AD. In a study, a 6-month period of 0.3 g/L caffeine intake alleviated the cognitive deficits found in AD transgenic mice (APPsw). Furthermore, these mice culture neurons showed the reduced production of Aβ1–40 and Aβ1–42 peptides [52]. A2ARs antagonists and/or caffeine prophylactic and long-term neuroprotective process are suggested to be based on inhibition of reactive oxygen species activity,

A2ARs antagonist may also serve as antidepressants, as observed in animal model of antidepressants screening test done by El-Yacoubi et al. [54, 55]. In both tests, A2ARs antagonists prolong escape-directed behavior. Additionally, potential role as antidepressants was also observed in attenuated behavioral despairs displayed in both tests [55]. The relation between adenosine and depression in preclinical models was obtained from the genetic manipulation model of A2AR. Genetic depletion of A2ARs resulted in antidepressant-like phenotype in animal models [55]. The

unified Parkinson's disease ranking scale (UPDRS) III. Meanwhile at 40 mg per day, istradefylline could alleviate off time and motor symptoms derived from Parkinson's disease [38]. Phase 3 study (613 randomized patients), done by Isaacson et al. concluded that greater reduction from baseline in total hours off time/day were shown at all-time points for istradefylline 20 and 40 mg/day, compared to placebo. However, future development is needed as the study has not yet reached

*DOI: http://dx.doi.org/10.5772/intechopen.84272*

on neuronal cell death [35].

will be available in near future [37].

statistical significance [39].

nists in different models of ischemia [43].

tau pathology, and Aβ production by neuronal cells [53].

*The Role and Development of the Antagonist of Adenosine A2A in Parkinson's Disease DOI: http://dx.doi.org/10.5772/intechopen.84272*

burden of brain disorders in different neurodegenerative conditions, namely, ischemia, epilepsy, and Parkinson's and Alzheimer's disease, through its control on neuronal cell death [35].

A2ARs have been shown to be viable in serving as alternative non-dopaminergic strategy of Parkinson's disease treatment because of their limited distribution in the striatum and the intense interaction between adenosine and dopamine receptors in the brain. A2ARs antagonists were shown to improve motor function in different animal models (primates and rodents), alone or co-administered with dopaminomimetic drugs, levodopa, or dopamine agonists [35]. Based on rigorous preclinical animal studies, istradefylline (KW6002) has shown its promising ability to increase motor activity in PD of the advanced stage in clinical phase IIB trial [36]. It became the first therapeutic agent developed to target A2ARs, and other similar compounds will be available in near future [37].

The recent meta-analysis (n = 6) suggested that 20 mg of istradefylline improves unified Parkinson's disease ranking scale (UPDRS) III. Meanwhile at 40 mg per day, istradefylline could alleviate off time and motor symptoms derived from Parkinson's disease [38]. Phase 3 study (613 randomized patients), done by Isaacson et al. concluded that greater reduction from baseline in total hours off time/day were shown at all-time points for istradefylline 20 and 40 mg/day, compared to placebo. However, future development is needed as the study has not yet reached statistical significance [39].

In the case of Parkinson's disease, microglia has been suggested to be the most likely cell type to be targeted by A2ARs antagonists [40]. In vitro and in vivo studies showed that local neuroinflammation make glial cells (especially microglial cells) particularly sensitive to A2AR modulation [41]. Previous research done by Gao and Phillis is the first study to demonstrate nonselective A2AR antagonist action in reducing cerebral ischemic injury in the gerbil, following global forebrain ischemia [42]. After that, many studies have reported the neuroprotective of A2AR antagonists in different models of ischemia [43].

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is indicated by the progressive loss of memory and other cognitive functions, leading to dementia [44, 45]. Adenosine can control and integrate cognition and memory [46]. Both A1Rs and A2ARs, mainly located in synapses, control the release of neurotransmitters which are involved in memory or other cognitive processes [34, 47]. Methylxanthine was discovered to act as nonselective adenosine receptors antagonist. Caffeine, the most famous methylxanthine found in common beverages, is the most widely consumed psychoactive drug. Maia and de Mendonca presented the first epidemiological data showing that the incidence of AD is inversely proportioned with coffee consumption [48]. Several other studies also show this inverse relationship [49–51]. Animal models also shown that caffeine intake may be beneficial for AD. In a study, a 6-month period of 0.3 g/L caffeine intake alleviated the cognitive deficits found in AD transgenic mice (APPsw). Furthermore, these mice culture neurons showed the reduced production of Aβ1–40 and Aβ1–42 peptides [52]. A2ARs antagonists and/or caffeine prophylactic and long-term neuroprotective process are suggested to be based on inhibition of reactive oxygen species activity, tau pathology, and Aβ production by neuronal cells [53].

A2ARs antagonist may also serve as antidepressants, as observed in animal model of antidepressants screening test done by El-Yacoubi et al. [54, 55]. In both tests, A2ARs antagonists prolong escape-directed behavior. Additionally, potential role as antidepressants was also observed in attenuated behavioral despairs displayed in both tests [55]. The relation between adenosine and depression in preclinical models was obtained from the genetic manipulation model of A2AR. Genetic depletion of A2ARs resulted in antidepressant-like phenotype in animal models [55]. The

*Neuroprotection*

These differences are shown in **Figure 2**.

aptic protein α-synuclein [13, 14].

**2. The role of adenosine A2A in Parkinson's disease**

agents is also decreasing as the disease progressed [19].

and increasing the therapeutic effect on levodopa [31, 32].

**3. Adenosine A2A receptor antagonist as a neuroprotective**

transmembrane helices (7TM). Each of the TM is mainly α-helical and consists of 20–27 amino acids. Three intracellular (IL1, IL2, and IL3) and three extracellular (EL1, EL2, and EL3) loops connect each of the TM domain. A short helix TM8 runs parallel to the cytoplasmic surface of the membrane. The adenosine A2A receptor has differences in length and N-terminal extracellular domain function, their domain of C-terminal intracellular, and their loops of intracellular/extracellular.

Parkinson's disease (PD) is a chronic neurodegenerative disorder in the brain,

marked by motoric symptoms [12]. The motoric symptoms in PD are resting tremor, rigidity, bradykinesia, and postural disorder. Besides motoric symptoms, PD also has non-motoric symptoms such as depression, hallucination, sleeping disorder, and decreasing cognitive and sensory functions. The main pathological characteristic of PD is the loss of dopaminergic neurons in *substantia nigra pars compacta*, a region in the brain that controls all the body movement and forms the dopamine. The development of PD also includes the formation of Lewy body, a deposit of cytoplasmic, eosinophilic neuronal inclusions, composed of the presyn-

The current therapy of PD is targeted at dopamine replacement, thereby decreasing the motor symptoms. It includes precursor of dopamine (levodopa), dopamine agonists [15, 16] monoamine oxidase type B (MAO-B) inhibitors [17], and catechol-O-methyltransferase (COMT) inhibitors [17, 18]. These agents produce undesirable side effects such as on-off effects, hallucinations, and dyskinesia. These effects get more severe as the treatment continued. The efficacy of these

Because of the undesirable side effects of dopamine replacement therapy, the non-dopaminergic therapy is continuously being explored. One of the approaches is selective adenosine A2A antagonist [20, 21]. Adenosine A2A receptors are found mainly in the striatum of rat [22, 23], which has similar distribution with the human brain [24, 25]. In the striatum, adenosine A2A receptors are colocalized with dopamine D2 receptors. These two receptors have opposite effect on motoric function [26]. The activation of adenosine A2A receptors will inhibit the signaling of dopamine D2 receptors, and conversely, the inhibition of signaling of adenosine A2A receptors will increase the activation of dopamine D2 receptors, therefore facilitating dopamine D2-mediated responses [11]. The inhibition of adenosine A2A receptors showed motoric improvement in animal models of PD [27–30]. This also has desirable effect on long-term levodopa treatment such as decreasing the dyskinesia

For years, adenosine-dopamine interactions have been investigated in order to observe their relevance for treatment of central nervous system (CNS) disorders [33]. It is assumed that adenosine A1 receptors (A1Rs) play an important role in neuroprotection as their activation at the onset of neuronal injury has shown to reduce brain damage in adult animal model. Vice versa, their blockade aggravates the damage. In other hand, adenosine A2 receptors (A2ARs) are shown to be upregulated in harmful brain conditions, and their blockade shows brain neuroprotection in studied animals [34]. The blockade of A2ARs alleviates the long-term

**34**

A2ARs blockade also relieves stress-induced early hippocampal modifications [56]. However, the effect of adenosine neuromodulation system in depression is complex, as it has the ability to modulate several other neurotransmission systems [35].

As addressed in previous paragraphs, A2AR emerges as potential target candidate in various disorders. This is majorly caused by its unique interaction with D2 receptors, a major psychoactive drug target. Important roles of A2AR were also observed in its robust neuroprotective activity, in which it mainly acts in the normalization of glutaminergic synapses, the control of mitochondria-induced apoptosis, and the control of neuroinflammation [35].

#### **4. Current sources of the adenosine A2A antagonist**

The treatment of PD currently focuses on symptom management with dopaminergic therapy, such as dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) (in combination with peripheral decarboxylase inhibitors) and dopamine agonists [57]. Although L-DOPA is beneficial in patients with PD, with time, the span of the effect is shortened), the response becomes less probable, and involuntary muscle movements or, in a severe situation, dystonia can emerge [57]. These problems highlight the urgent medical need for an alternative mode of therapeutic intervention that can relieve the symptoms of the disorder while also allowing a decrease in the occurrence of side effects.

Among the non-dopaminergic therapies investigated for the treatment of PD, the adenosine A2A receptor antagonists show very convincingly for two main reasons: their selective and restricted localization in the basal ganglia circuitry and their interaction with dopaminergic receptors. In another word, inhibition of the interaction of adenosine with the A2A receptor may provide a potential treatment for PD.

**37**

*The Role and Development of the Antagonist of Adenosine A2A in Parkinson's Disease*

Many highly selective A2A antagonists, both xanthine and non-xanthine derivatives, have been created, and some of them are being investigated as treatment for subjects with PD in various stage of clinical trials (**Figure 3**) [7, 19, 58–61]. Caffeine as a xanthine derivate is developed as a lead compound for the design of antagonist of adenosine A2A receptor [62]. Experimental model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism is known to be an evidence that caffeine have a protective effect in Parkinson's disease [36, 63]. Some A2A antagonists have progressed to clinical trials by various pharmaceutical companies including istradefylline [59], PBS-509, ST1535 and its metabolite ST4206, tozadenant, V81444, preladenant, and vipadenant [64]. Several studies of novel series of 2-aminoimidazo[4,5-b]pyridine-derivatives [65], arylindenopyrimidine [66], and bicyclic aminoquinazoline derivatives [67] as adenosine A2A antagonists

Various computational methods were used to study neuroprotective effect from adenosine A2A antagonists such as pharmacophore model [68], QSAR, molecular docking [69–71], and molecular dynamics [72, 73]. Orally bioavailable adenosine A2A receptor antagonists have been studied for its QSAR and pharmacokinetics

The study of structure-kinetics relationship (SKR) is done as a complement to a SAR analysis at the adenosine A2A receptor. The series of 24 triazolotriazine derivatives showing a similar binding kinetics to the putative antagonist ZM241385 (4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino) ethyl)phenol) revealed minor affinity changes, although they varied substantially

Various studies have been conducted in the discovery of Parkinson's drugs against the target A2A receptors. The discovery of drugs assisted by computers has accelerated in obtaining lead compounds. Apparently, this method takes a lot of consideration before entering the preclinical and clinical phases. It is because this computational method is more able to describe the answer in preparing the next design. This method can also make various predictions of activities that are difficult to do in the absence of chemical compounds before they are synthesized. In silico prediction of various pharmacokinetic parameters and toxicity can also be done faster. All of these things can provide a better picture of getting a cure for

A2A receptors emerge as potential target candidate in various disorders, caused

This work was supported by *Hibah Publikasi Internasional Terindeks Untuk Tugas* 

by its unique interaction with D2 receptors, a major psychoactive drug target. Various studies have been conducted in the discovery of Parkinson's drugs against the target A2A receptors. In silico study brings a new approach of study with A2A

*Akhir Mahasiswa UI* (PITTA) 2018 by Universitas Indonesia.

*DOI: http://dx.doi.org/10.5772/intechopen.84272*

in their dissociation rates from the receptor [75].

**5. Future direction of drug discovery of Parkinson's disease**

are reported.

properties [74].

Parkinson's disease.

**6. Conclusions**

**Acknowledgements**

receptors.

**Figure 3.** *Adenosine A2A inhibitors.*

*The Role and Development of the Antagonist of Adenosine A2A in Parkinson's Disease DOI: http://dx.doi.org/10.5772/intechopen.84272*

Many highly selective A2A antagonists, both xanthine and non-xanthine derivatives, have been created, and some of them are being investigated as treatment for subjects with PD in various stage of clinical trials (**Figure 3**) [7, 19, 58–61]. Caffeine as a xanthine derivate is developed as a lead compound for the design of antagonist of adenosine A2A receptor [62]. Experimental model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism is known to be an evidence that caffeine have a protective effect in Parkinson's disease [36, 63]. Some A2A antagonists have progressed to clinical trials by various pharmaceutical companies including istradefylline [59], PBS-509, ST1535 and its metabolite ST4206, tozadenant, V81444, preladenant, and vipadenant [64]. Several studies of novel series of 2-aminoimidazo[4,5-b]pyridine-derivatives [65], arylindenopyrimidine [66], and bicyclic aminoquinazoline derivatives [67] as adenosine A2A antagonists are reported.

Various computational methods were used to study neuroprotective effect from adenosine A2A antagonists such as pharmacophore model [68], QSAR, molecular docking [69–71], and molecular dynamics [72, 73]. Orally bioavailable adenosine A2A receptor antagonists have been studied for its QSAR and pharmacokinetics properties [74].

The study of structure-kinetics relationship (SKR) is done as a complement to a SAR analysis at the adenosine A2A receptor. The series of 24 triazolotriazine derivatives showing a similar binding kinetics to the putative antagonist ZM241385 (4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino) ethyl)phenol) revealed minor affinity changes, although they varied substantially in their dissociation rates from the receptor [75].

#### **5. Future direction of drug discovery of Parkinson's disease**

Various studies have been conducted in the discovery of Parkinson's drugs against the target A2A receptors. The discovery of drugs assisted by computers has accelerated in obtaining lead compounds. Apparently, this method takes a lot of consideration before entering the preclinical and clinical phases. It is because this computational method is more able to describe the answer in preparing the next design. This method can also make various predictions of activities that are difficult to do in the absence of chemical compounds before they are synthesized. In silico prediction of various pharmacokinetic parameters and toxicity can also be done faster. All of these things can provide a better picture of getting a cure for Parkinson's disease.

#### **6. Conclusions**

*Neuroprotection*

control of neuroinflammation [35].

decrease in the occurrence of side effects.

**4. Current sources of the adenosine A2A antagonist**

A2ARs blockade also relieves stress-induced early hippocampal modifications [56]. However, the effect of adenosine neuromodulation system in depression is complex, as it has the ability to modulate several other neurotransmission systems [35].

The treatment of PD currently focuses on symptom management with dopaminergic therapy, such as dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) (in combination with peripheral decarboxylase inhibitors) and dopamine agonists [57]. Although L-DOPA is beneficial in patients with PD, with time, the span of the effect is shortened), the response becomes less probable, and involuntary muscle movements or, in a severe situation, dystonia can emerge [57]. These problems highlight the urgent medical need for an alternative mode of therapeutic intervention that can relieve the symptoms of the disorder while also allowing a

Among the non-dopaminergic therapies investigated for the treatment of PD, the adenosine A2A receptor antagonists show very convincingly for two main reasons: their selective and restricted localization in the basal ganglia circuitry and their interaction with dopaminergic receptors. In another word, inhibition of the interaction of adenosine with the A2A receptor may provide a potential treatment for PD.

As addressed in previous paragraphs, A2AR emerges as potential target candidate in various disorders. This is majorly caused by its unique interaction with D2 receptors, a major psychoactive drug target. Important roles of A2AR were also observed in its robust neuroprotective activity, in which it mainly acts in the normalization of glutaminergic synapses, the control of mitochondria-induced apoptosis, and the

**36**

**Figure 3.**

*Adenosine A2A inhibitors.*

A2A receptors emerge as potential target candidate in various disorders, caused by its unique interaction with D2 receptors, a major psychoactive drug target. Various studies have been conducted in the discovery of Parkinson's drugs against the target A2A receptors. In silico study brings a new approach of study with A2A receptors.

#### **Acknowledgements**

This work was supported by *Hibah Publikasi Internasional Terindeks Untuk Tugas Akhir Mahasiswa UI* (PITTA) 2018 by Universitas Indonesia.

*Neuroprotection*

### **Conflict of interest**

The authors declare that they have no conflict of interest or involvement with any organization of affiliation.

#### **Author details**

Widya Dwi Aryati, Nabilah Nurtika Salamah, Rezi Riadhi Syahdi and Arry Yanuar\* Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia

\*Address all correspondence to: arry.yanuar@ui.ac.id

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**39**

*The Role and Development of the Antagonist of Adenosine A2A in Parkinson's Disease*

[10] Schapira AHV. Present and future drug treatment for Parkinson's disease. Journal of Neurology, Neurosurgery, and Psychiatry. 2005;**76**:1472-1478

[11] Pollack AE, Fink JS. Adenosine antagonists potentiate D2 dopaminedependent activation of Fos in the striatopallidal pathway. Neuroscience.

[12] Lozano AM, Lang AE, Hutchison WD, Dostrovsky JO. New developments

Parkinson's disease and in its treatment. Current Opinion in Neurobiology.

[13] Savitt JM. Diagnosis and treatment of Parkinson disease: Molecules to medicine. Journal of Clinical Investigation. 2006;**116**:1744-1754

[14] Dauer W, Przedborski S. Parkinson's disease. Neuron. 2003;**39**:889-909

[15] Antonini A, Tolosa E, Mizuno Y, Yamamoto M, Poewe WH. A reassessment of risks and benefits of dopamine agonists in Parkinson's

disease. Lancet Neurology.

[16] Yamamoto M, Schapira AH. Dopamine agonists in

Parkinson's disease. Expert Review of Neurotherapeutics. 2008;**8**:671-677

[17] Olanow CW, Stocchi F. COMT inhibitors in Parkinson's disease: Can they prevent and/or reverse levodopainduced motor complications? Neurology. 2004;**62**:S72-S81

[18] Gordin A, Brooks DJ. Clinical pharmacology and therapeutic use of COMT inhibition in Parkinson's disease. Journal of Neurology.

[19] Shook BC, Jackson PF. Adenosine A2A receptor antagonists and Parkinson's

2007;**254**:IV37-IV48

2009;**8**:929-937

in understanding the etiology of

1995;**68**:721-728

1998;**8**:783-790

*DOI: http://dx.doi.org/10.5772/intechopen.84272*

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[2] Stiles GL. Adenosine receptors. Journal of Biological Chemistry.

[3] Townsend-Nicholson A, Baker E, Schofield PR, Sutherland

GR. Localization of the adenosine A1 receptor subtype gene (ADORA1) to chromosome 1q32.1. Genomics.

[4] Livingston M, Heaney LG, Ennis M. Adenosine, inflammation and asthma? A review. Inflammation Research. 2004;**53**:171-178

[5] Boison D, Singer P, Shen H-Y, Feldon J, Yee BK. Adenosine hypothesis of schizophrenia—Opportunities for pharmacotherapy. Neuropharmacology.

1992;**267**:6451-6454

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2012;**62**:1527-1543

[6] Fredholm BB, Cunha RA, Svenningsson P. Pharmacology of adenosine A2A receptors and therapeutic

applications. Current Topics in Medicinal Chemistry. 2003;**3**:413-426

Chemistry. 2014;**57**:3623-3650

2000;**58**:771-777

[7] de Lera Ruiz M, Lim Y-H, Zheng J. Adenosine A2A receptor as a drug discovery target. Journal of Medicinal

[8] Kull B, Svenningsson P, Fredholm BB. Adenosine A2A receptors are colocalized with and activate golf in rat striatum. Molecular Pharmacology.

[9] Torvinen M et al. Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/ D3 heteromeric complexes. Molecular Pharmacology. 2005;**67**:400-407

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*The Role and Development of the Antagonist of Adenosine A2A in Parkinson's Disease DOI: http://dx.doi.org/10.5772/intechopen.84272*

#### **References**

*Neuroprotection*

**Conflict of interest**

any organization of affiliation.

**38**

**Author details**

and Arry Yanuar\*

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

The authors declare that they have no conflict of interest or involvement with

Widya Dwi Aryati, Nabilah Nurtika Salamah, Rezi Riadhi Syahdi

Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia

\*Address all correspondence to: arry.yanuar@ui.ac.id

[1] Latini S, Pedata F. Adenosine in the central nervous system: Release mechanisms and extracellular concentrations. Journal of Neurochemistry. 2008;**79**:463-484

[2] Stiles GL. Adenosine receptors. Journal of Biological Chemistry. 1992;**267**:6451-6454

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[4] Livingston M, Heaney LG, Ennis M. Adenosine, inflammation and asthma? A review. Inflammation Research. 2004;**53**:171-178

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[6] Fredholm BB, Cunha RA, Svenningsson P. Pharmacology of adenosine A2A receptors and therapeutic applications. Current Topics in Medicinal Chemistry. 2003;**3**:413-426

[7] de Lera Ruiz M, Lim Y-H, Zheng J. Adenosine A2A receptor as a drug discovery target. Journal of Medicinal Chemistry. 2014;**57**:3623-3650

[8] Kull B, Svenningsson P, Fredholm BB. Adenosine A2A receptors are colocalized with and activate golf in rat striatum. Molecular Pharmacology. 2000;**58**:771-777

[9] Torvinen M et al. Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/ D3 heteromeric complexes. Molecular Pharmacology. 2005;**67**:400-407

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[11] Pollack AE, Fink JS. Adenosine antagonists potentiate D2 dopaminedependent activation of Fos in the striatopallidal pathway. Neuroscience. 1995;**68**:721-728

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[13] Savitt JM. Diagnosis and treatment of Parkinson disease: Molecules to medicine. Journal of Clinical Investigation. 2006;**116**:1744-1754

[14] Dauer W, Przedborski S. Parkinson's disease. Neuron. 2003;**39**:889-909

[15] Antonini A, Tolosa E, Mizuno Y, Yamamoto M, Poewe WH. A reassessment of risks and benefits of dopamine agonists in Parkinson's disease. Lancet Neurology. 2009;**8**:929-937

[16] Yamamoto M, Schapira AH. Dopamine agonists in Parkinson's disease. Expert Review of Neurotherapeutics. 2008;**8**:671-677

[17] Olanow CW, Stocchi F. COMT inhibitors in Parkinson's disease: Can they prevent and/or reverse levodopainduced motor complications? Neurology. 2004;**62**:S72-S81

[18] Gordin A, Brooks DJ. Clinical pharmacology and therapeutic use of COMT inhibition in Parkinson's disease. Journal of Neurology. 2007;**254**:IV37-IV48

[19] Shook BC, Jackson PF. Adenosine A2A receptor antagonists and Parkinson's disease. ACS Chemical Neuroscience. 2011;**2**:555-567

[20] Schwarzschild MA, Agnati L, Fuxe K, Chen J-F, Morelli M. Targeting adenosine A2A receptors in Parkinson's disease. Trends in Neurosciences. 2006;**29**:647-654

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[24] Ishiwata K et al. First visualization of adenosine A2A receptors in the human brain by positron emission tomography with [11C]TMSX. Synapse. 2005;**55**:133-136

[25] Svenningsson P, Hall H, Sedvall G, Fredholm BB. Distribution of adenosine receptors in the postmortem human brain: An extended autoradiographic study. Synapse. 1997;**27**:322-335

[26] Fink JS et al. Molecular cloning of the rat A2 adenosine receptor: Selective co-expression with D2 dopamine receptors in rat striatum. Molecular Brain Research. 1992;**14**:186-195

[27] Chen J-F et al. Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of Parkinson's disease. Journal of Neuroscience. 2001;**21**:RC143-RC143

[28] Grondin R et al. Antiparkinsonian effect of a new selective adenosine A2A

receptor antagonist in MPTP-treated monkeys. Neurology. 1999;**52**:1673-1673

[29] Ongini E et al. Dual actions of A2A adenosine receptor antagonists on motor dysfunction and neurodegenerative processes. Drug Development Research. 2001;**52**:379-386

[30] Ikeda K, Kurokawa M, Aoyama S, Kuwana Y. Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease. Journal of Neurochemistry. 2002;**80**:262-270

[31] Kanda T et al. Combined use of the adenosine A2A antagonist KW-6002 with l-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Experimental Neurology. 2000;**162**:321-327

[32] Hauser RA, Hubble JP, Truong DD. Randomized trial of the adenosine A2A receptor antagonist istradefylline in advanced PD. Neurology. 2003;**61**:297-303

[33] Fuxe K et al. Adenosine-dopamine interactions in the pathophysiology and treatment of CNS disorders. CNS Neuroscience and Therapeutics. 2010;**16**:e18-e42

[34] Cunha RA. Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade. Purinergic Signal. 2005;**1**:111-134

[35] Gomes CV, Kaster MP, Tomé AR, Agostinho PM, Cunha RA. Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration. Biochimica et Biophysica Acta (BBA)— Biomembranes. 2011;**1808**:1380-1399

[36] Kalda A, Yu L, Oztas E, Chen J-F. Novel neuroprotection by caffeine and adenosine A2A receptor antagonists

**41**

*The Role and Development of the Antagonist of Adenosine A2A in Parkinson's Disease*

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[46] Cunha RA, Agostinho PM. Chronic caffeine consumption prevents memory

disturbance in different animal models of memory decline. Journal of Alzheimer's Disease. 2010;**20**:S95-S116

[47] Ribeiro JA, Sebastião AM, de Mendonça A. Adenosine receptors in the nervous system: Pathophysiological implications. Progress in Neurobiology.

[48] Maia L, de Mendonça A. Does caffeine intake protect from Alzheimer's disease? Europen Journal of Neurology.

[49] Ritchie K et al. The neuroprotective effects of caffeine: A prospective population study (the Three City Study). Neurology. 2007;**69**:536-545

[50] Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N. Caffeine intake and dementia: systematic review and meta-analysis. Journal of Alzheimer's

Disease. 2010;**20**:S187-S204

community sample. Human Psychopharmacology Clinical and Experimental. 2009;**24**:29-34

2006;**142**:941-952

Research. 2015;**10**:205

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[52] Arendash GW et al. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain β-amyloid production. Neuroscience.

[53] Marzagalli R, Castorina A. The seeming paradox of adenosine receptors as targets for the treatment of Alzheimer′s disease: Agonists or antagonists? Neural Regeneration

[54] Cantwell R, Cox JL. Psychiatric disorders in pregnancy and the

2014;**298**:789-791

2002;**68**:377-392

2002;**9**:377-382

*DOI: http://dx.doi.org/10.5772/intechopen.84272*

in animal models of Parkinson's disease. Journal of the Neurological Sciences.

[37] Yamada K, Kobayashi M, Kanda T. Chapter Fifteen - Involvement of Adenosine A2A Receptors in Depression and Anxiety. International Review of Neurobiology. 2014;**119**:373-393. DOI: 10.1016/B978-0-12-801022-8.00015-5

[38] Sako W, Murakami N, Motohama K, Izumi Y, Kaji R. The effect of istradefylline for Parkinson's disease: A meta-analysis. Scientific Reports.

[39] Isaacson S et al. Efficacy and safety of istradefylline in moderate to severe Parkinson's disease: A phase 3, multinational, randomized, doubleblind, placebo-controlled trial (i-step study). Journal of the Neurological

Sciences. 2017;**381**:351-352

A2A receptor antagonists in neurodegenerative diseases: Huge potential and huge challenges. Frontiers

in Psychiatry. 2018;**9**(1-5)

Design. 2008;**14**:1490-1499

1994;**55**:PL61-PL65

2014;**805198**:2014

2008;**7**:812-826

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[41] Chen J-F, Pedata F. Modulation of ischemic brain injury and

neuroinflammation by adenosine A2A receptors. Current Pharmaceutical

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[43] Pedata F et al. Adenosine A2A receptors modulate acute injury and neuroinflammation in brain ischemia. Mediators of Inflammation.

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2006;**248**:9-15

2017;**7**:18018

*The Role and Development of the Antagonist of Adenosine A2A in Parkinson's Disease DOI: http://dx.doi.org/10.5772/intechopen.84272*

in animal models of Parkinson's disease. Journal of the Neurological Sciences. 2006;**248**:9-15

*Neuroprotection*

2011;**2**:555-567

2006;**29**:647-654

1998;**401**:163-186

1998;**19**:46-47

2005;**55**:133-136

[22] Rosin DL, Robeva A,

of adenosine A2A receptors in the rat central nervous system. Journal of Comparative Neurology.

[23] Fredholm BB, Svenningsson P. Striatal adenosine A2A receptors— Where are they? What do they do? Trends in Pharmacological Sciences.

[24] Ishiwata K et al. First visualization of adenosine A2A receptors in the human brain by positron emission tomography with [11C]TMSX. Synapse.

[25] Svenningsson P, Hall H, Sedvall G, Fredholm BB. Distribution of adenosine receptors in the postmortem human brain: An extended autoradiographic study. Synapse. 1997;**27**:322-335

[26] Fink JS et al. Molecular cloning of the rat A2 adenosine receptor: Selective co-expression with D2 dopamine receptors in rat striatum. Molecular Brain Research. 1992;**14**:186-195

[27] Chen J-F et al. Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of Parkinson's disease. Journal of Neuroscience.

[28] Grondin R et al. Antiparkinsonian effect of a new selective adenosine A2A

2001;**21**:RC143-RC143

disease. ACS Chemical Neuroscience.

receptor antagonist in MPTP-treated monkeys. Neurology. 1999;**52**:1673-1673

[29] Ongini E et al. Dual actions of A2A adenosine receptor antagonists on motor dysfunction and neurodegenerative processes. Drug Development Research.

[30] Ikeda K, Kurokawa M, Aoyama S, Kuwana Y. Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease. Journal of Neurochemistry.

[31] Kanda T et al. Combined use of the adenosine A2A antagonist KW-6002 with l-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Experimental Neurology.

[32] Hauser RA, Hubble JP, Truong DD. Randomized trial of the adenosine A2A receptor antagonist istradefylline

[33] Fuxe K et al. Adenosine-dopamine interactions in the pathophysiology and treatment of CNS disorders. CNS Neuroscience and Therapeutics.

[34] Cunha RA. Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade. Purinergic Signal. 2005;**1**:111-134

[35] Gomes CV, Kaster MP, Tomé AR, Agostinho PM, Cunha

RA. Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration. Biochimica et Biophysica Acta (BBA)—

Biomembranes. 2011;**1808**:1380-1399

[36] Kalda A, Yu L, Oztas E, Chen J-F. Novel neuroprotection by caffeine and adenosine A2A receptor antagonists

in advanced PD. Neurology.

2001;**52**:379-386

2002;**80**:262-270

2000;**162**:321-327

2003;**61**:297-303

2010;**16**:e18-e42

[21] Salamone JD. Facing dyskinesia in Parkinson disease: Nondopaminergic approaches. Drugs Future. 2010;**35**:567

Woodard RL, Guyenet PG, Linden J. Immunohistochemical localization

[20] Schwarzschild MA, Agnati L, Fuxe K, Chen J-F, Morelli M. Targeting adenosine A2A receptors in Parkinson's disease. Trends in Neurosciences.

**40**

[37] Yamada K, Kobayashi M, Kanda T. Chapter Fifteen - Involvement of Adenosine A2A Receptors in Depression and Anxiety. International Review of Neurobiology. 2014;**119**:373-393. DOI: 10.1016/B978-0-12-801022-8.00015-5

[38] Sako W, Murakami N, Motohama K, Izumi Y, Kaji R. The effect of istradefylline for Parkinson's disease: A meta-analysis. Scientific Reports. 2017;**7**:18018

[39] Isaacson S et al. Efficacy and safety of istradefylline in moderate to severe Parkinson's disease: A phase 3, multinational, randomized, doubleblind, placebo-controlled trial (i-step study). Journal of the Neurological Sciences. 2017;**381**:351-352

[40] Franco R, Navarro G. Adenosine A2A receptor antagonists in neurodegenerative diseases: Huge potential and huge challenges. Frontiers in Psychiatry. 2018;**9**(1-5)

[41] Chen J-F, Pedata F. Modulation of ischemic brain injury and neuroinflammation by adenosine A2A receptors. Current Pharmaceutical Design. 2008;**14**:1490-1499

[42] Gao Y, Phillis JW. CGS 15943, An adenosine A2 receptor antagonist, reduces cerebral ischemic injury in the Mongolian gerbil. Life Sciences. 1994;**55**:PL61-PL65

[43] Pedata F et al. Adenosine A2A receptors modulate acute injury and neuroinflammation in brain ischemia. Mediators of Inflammation. 2014;**805198**:2014

[44] Kalaria RN et al. Alzheimer's disease and vascular dementia in developing countries: Prevalence, management, and risk factors. The Lancet Neurology. 2008;**7**:812-826

[45] Lesne S. Toxic oligomer species of amyloid-β in Alzheimer's disease, a timing issue. Swiss Medical Weekly. 2014;**298**:789-791

[46] Cunha RA, Agostinho PM. Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline. Journal of Alzheimer's Disease. 2010;**20**:S95-S116

[47] Ribeiro JA, Sebastião AM, de Mendonça A. Adenosine receptors in the nervous system: Pathophysiological implications. Progress in Neurobiology. 2002;**68**:377-392

[48] Maia L, de Mendonça A. Does caffeine intake protect from Alzheimer's disease? Europen Journal of Neurology. 2002;**9**:377-382

[49] Ritchie K et al. The neuroprotective effects of caffeine: A prospective population study (the Three City Study). Neurology. 2007;**69**:536-545

[50] Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N. Caffeine intake and dementia: systematic review and meta-analysis. Journal of Alzheimer's Disease. 2010;**20**:S187-S204

[51] Smith AP. Caffeine, cognitive failures and health in a non-working community sample. Human Psychopharmacology Clinical and Experimental. 2009;**24**:29-34

[52] Arendash GW et al. Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain β-amyloid production. Neuroscience. 2006;**142**:941-952

[53] Marzagalli R, Castorina A. The seeming paradox of adenosine receptors as targets for the treatment of Alzheimer′s disease: Agonists or antagonists? Neural Regeneration Research. 2015;**10**:205

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puerperium. Current Obstetrics & Gynaecology. 2006;**16**:14-20

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s11302-016-9549-9

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**45**

**Chapter 4**

Disease

**Abstract**

neuroinflammation

**1. Introduction**

Adrenergic Receptors as

Pharmacological Targets

*Monika Sharma and Patrick M. Flood*

for Neuroinflammation and

Neurodegeneration in Parkinson's

Inflammation is a key component of the dopaminergic neurodegeneration seen in progressive Parkinson's disease (PD). The presence of activated glial cells, the participation of innate immune system, increased inflammatory molecules such as cytokines and chemokines, and increased oxidative stress and reactive oxygen species are the main neuroinflammatory characteristics present in progressive PD. Therapeutic targets which suppress pro-inflammatory responses by glial cells (mainly microglia) have been shown to be effective treatments for slowing or eliminating the progressive degeneration of neurons within the substantia nigra. In this chapter, we will detail a specific anti-inflammatory therapy using agonists to β2-adrenergic receptors that have been shown to be effective treatments for models of dopaminergic neurodegeneration and that have had efficacy in patients with progressive PD. We will also detail the possible molecular mechanisms of action of

this therapeutic in stopping or reversing inflammation within the CNS.

There are a number of neurological disorders that fall under the umbrella of neurodegeneration, with the major ones including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), spinal cord injury (SCI), and others. Currently, there are no generally effective treatments available to slow down or reverse the debilitating effects of these diseases, and the long-term effects of these diseases are the progressive degeneration and death of neurons. A majority of the neurodegenerative diseases are linked with inflammation in CNS [1], and the presence of activated glial cells, infiltration and activation of adaptive and innate immune cells, increased presence of inflammatory molecules such as cytokines and chemokines, and increased oxidative stress and reactive oxygen species (ROS) are the main neuroinflammatory characteristics present in lesions associated with

**Keywords:** β2-adrenergic receptor, Parkinson's disease, microglia,

#### **Chapter 4**
