Parkinson's Disease: A Comprehensive Overview of the Disease

*Ahed J. Khatib*

## **Abstract**

Parkinson's Disease (PD) is the most prevalent neurodegenerative disease following Alzheimer's disease. Its prevalence is increasing over time, and it is expected to reach a peak in 2030. The aim of the present study was to review the literature for various aspects of PD including general characteristics of the disease, its pathology, clinical features, therapeutic clinical trials, and animal models used to study PD. The results of this study showed that no curative therapy for PD has so far been developed. Altogether, PD is still a very hot area in medicine to be studied and to have new therapeutic options.

**Keywords:** PD, neurodegenerative disease, clinical trials, animal models, pathology of PD

## **1. Introduction**

Parkinson's disease (PD) is a chronic ailment that gradually worsens over time that affects a person's ability to move. It is the second most common cause of neurodegenerative disorders, after Alzheimer's disease [1].

PD is a progressive neurological disorder that is defined by a complicated set of symptoms characterized by tremor, stiffness, and bradykinesia, and as the condition advances, postural instability may appear in certain patients. James Parkinson was the one who originally defined it in 1817, and Jean-Martin Charcot was the one who further characterized it. Our current understanding of the PD is proceeding with its growth. PD is the second most common neurodegenerative disease after Alzheimer's disease (AD), with a prevalence of approximately 0.5–1% among those 65–69 years of age, rising to 1–3% among persons 80 years of age and older [2]. Alzheimer's disease is the most common neurodegenerative disease [3]. It is anticipated that the prevalence and incidence of PD would both rise by more than 30% by the year 2030 because of the aging of the population, which will result in both direct and indirect effects, costs imposed not only on individuals but also on society as a whole and the economy [4].

## **2. Pathology of PD**

PD is pathologically characterized by the loss of nigrostriatal dopaminergic innervation; however, neurodegeneration does not only impact cells located in the nigral dopaminergic neurons; rather, it also involves cells located in other parts of the neural network. Because it affects such a large percentage of the population, Parkinson's disease is a tremendously diverse ailment, for which there is now no reliable diagnostic test [5].

Dopaminergic neuronal death, α-synuclein aggregates, mitochondrial dysfunction, reactive oxygen species, apoptosis, and neuroinflammation are shown to be the pathological hallmarks of PD [6]. α-synuclein is a presynaptic neuronal protein in PD-related genes that ranges in size from 14 to 19 kDa and is responsible for regulating synaptic integrity and cellular activities [7]. α-synuclein is one of the pathogenic markers of PD; throughout the course of PD, α-synuclein accumulates in Lewy bodies and is associated with neuroinflammation [8].

The National Library of Medicine of the United States established the webbased registration known as "ClinicalTrials.gov" in the year 2000. This registry allows users to search for information regarding clinical trials, such as the study design, techniques, outcomes, estimated finish dates, and so on. The data are kept current or maintained by sponsors located all over the world. The list of clinical trials now includes around 2700 PD clinical studies as of this writing. Clinical trial outcomes and endpoints are considered to be comparative effectiveness research [9].

Outcomes can be achieved through the use of a number of different strategies, including cognitive or behavioral scores, magnetic resonance imaging, positron emission tomography, electrophysiological monitoring, or biological biomarkers. Each clinical trial is designed and evaluated for potential treatment advantages in an effort to reduce the occurrence of unfavorable outcomes [9]. In clinical trials, post-approval research is required for comparative research in order to compare clinical trials with accessible standard medicines or therapy. This provides quality of life, safety, and tolerance in order to collect efficient data in the larger patient population [9]. In clinical trials, it is necessary and sufficient to rely on primary endpoints to determine whether a treatment or medication is effective. In light of the primary goals, the secondary endpoints are adequate for claiming or labeling the efficacy of the clinical trial study, and the exploratory and tertiary endpoints provide support for descriptive information [10]. Although levodopa has been used to treat PD for over 50 years, the symptoms of levodopa therapy-induced dyskinesia have not been eliminated completely. As a result, it is of the utmost importance that we investigate the present state of each ongoing clinical study as well as its therapeutic strategy and find novel therapeutic techniques for the treatment of PD [10].

## **3. Diagnosis of PD**

The criteria for a diagnosis require the presence of two of the following clinical features: resting tremor, bradykinesia, rigidity, and/or postural instability. Currently, diagnosis is based on clinical symptoms, and the criteria for a diagnosis require the presence of two of these clinical features [5]. However, clinical criteria may participate in the diagnosis of possible PD [5].

*Parkinson's Disease: A Comprehensive Overview of the Disease DOI: http://dx.doi.org/10.5772/intechopen.109437*

Imaging of the brain, neurological indicators, and clinical symptoms are the three basic components that go into diagnosing PD [11]. The death of dopaminergic neurons in the substantia nigra of the midbrain creates a dopamine shortage in the striatum, which results in motor symptoms of PD [12]. Patients with PD may experience a variety of motor symptoms, such as slowness of movement, rigidity, tremor, freezing, muscle cramps, and dystonia [13]. Patients with idiopathic (typical) PD have an average age of onset between 65 and 70 years old [14]. Early-onset PD is characterized by the development of symptoms in a patient before the age of 50 [14]. The condition is frequently hereditary and has been linked to a number of different genetic alterations [15].

## **4. Treatment of PD**

There is presently no cure for PD, a progressive neurodegenerative disorder; however, treatments are available to relieve PD symptoms and maintain quality of life. PD (PD) affects the nervous system. In the year 2020, approximately 10 million people across the globe were coping with PD. In 1970, the Food and Drug Administration of the United States granted approval for the use of levodopa as a dopamine replacement in the treatment of PD (PD) motor symptoms; the levodopa-carbidopa combination was first made available on the market in 1975. Levodopa has been used to treat PD for more than 50 years, and it is still considered the therapy of choice. Unfortunately, the dyskinesia and OFF symptoms that were produced by levodopa medication have not been alleviated. As a result, it is imperative that we conduct an immediate assessment of the present status of each clinical study and its therapeutic strategy in order to identify new therapeutic approaches for the treatment of PD. From 2008 to June 16, 2021, we analyzed data from 293 clinical trials that were registered on ClinicalTrials. gov. Following the exclusion of levodopa/carbidopa derivative add-on medicines, our search for PD therapy medications or therapies resulted in the identification of 47 trials. Nineteen of them are currently in the phase I stage (41%), 25 are in the phase II stage (53%), and 3 are in the phase III stage (6%). The embryonic dopamine cell implant, the 5-HT1A receptor agonist known as sarizotan, and the adenosine A2A receptor antagonist are all used in the three phase-III clinical trials (caffeine). Each trial's therapeutic method reveals that small compounds are utilized, whereas monoclonal antibodies are utilized in plasma therapy, cell therapy, gene therapy, and herbal extract in the relevant proportions. In addition to this, we talk about the most effective drug or therapy out of all of these trials. We have high hopes that this review can bring novel concepts and fresh perspectives for the further development of PD treatments since it will carefully update the present trial status and conduct an analysis of the therapeutic options [16].

The majority of the treatment's emphasis is placed on providing symptomatic relief with medications that either try to increase the amount of dopamine present in the striatum or work on the region's post-synaptic dopamine receptors. Dopamine is not the sole neurotransmitter implicated in Parkinson's disease (PD), and as a result, several additional medications besides dopamine are also being utilized to target specific symptoms, such as depression and dementia. However, additional research on innovative medicines to slow the rate of neurodegeneration or even to replace dopaminergic cells that have been lost is still being conducted in the research context, and some of these medications are currently in the preliminary stages of clinical trials. The prospect for the development of disease-modifying medicines appears to be

encouraging as our understanding of the etiology of PD continues to advance and as more is understood about potential novel therapeutic targets [5].

## **5. Clinical features of PD**

The triad of motor symptoms, which includes tremor, stiffness, and bradykinesia, is the clinical hallmark that has traditionally been linked with PD. As the disease advances, postural instability frequently appears as well. However, PD is also linked to numerous other conditions [17]. Symptoms that are not related to the motor system, and these symptoms may come years or even decades before the motor symptoms. It is possible that the pre-motor or prodromal phase of PD could begin as early as 12–14 years before the actual diagnosis [18]. There is a growing body of evidence that suggests the disease may have its origins in the peripheral autonomic nervous system and/or the olfactory bulb. From there, the pathology may have spread to the central nervous system, where it affected the lower brainstem structures prior to affecting the substantia nigra [19]. The existence of hyposmia, constipation, and rapid eye movement sleep disturbances in people with Parkinson's disease may therefore be explained by this before the onset of motor symptoms. Patients who displayed symptoms of Parkinson's disease 5 years before their diagnosis, including tremor, balance issues, depression, constipation, fatigue, and urinary dysfunction, had a higher risk of developing the disease than patients who did not demonstrate these symptoms [20]. In addition, people who suffer from constipation or tremors are more likely to have a greater likelihood of developing PD during the subsequent 10 years of followup [20]. This presymptomatic stage of PD is garnering a growing amount of attention as researchers speculate that it may represent an optimal window of opportunity for treatment intervention. Patients with early PD, defined as those within 2 years of their diagnosis, are included in many clinical studies that investigate prospective therapeutics; nevertheless, even at this point, significant dopaminergic neuron loss has already occurred [21].

## **6. Etiology of PD**

PD is a multifactorial disease, with both genetic and environmental factors playing a role. Age is the biggest risk factor for PD, with the median age of onset being 60 years of age [22]. The incidence of the disease rises with age to 93.1 (per 100,000 person-years) in age groups between 70 and 79 years [23]. Additionally, there are cross-cultural variations, with higher prevalence reported in Europe, North America, and South America compared with African, Asian, and Arabic countries [2].

#### **6.1 Cigarette smoking**

Cigarette smoking has been extensively studied with respect to PD, with mostly consistent results. Most of the epidemiological reports are case–control studies showing a reduced risk of developing PD, with larger cohort studies also in agreement [24]. A large meta-analysis including 44 case–control studies and 8 cohort studies from 20 countries showed an inverse correlation between smoking and PD, with a pooled relative risk of 0.39 for current smokers [25]. Two other meta-analyses also reported an inverse correlation between smoking and PD, with a pooled odds ratio

ranging from 0.23 to 0.70, indicating a protective mechanism against PD [26, 27]. The reasons underlying this associated reduced risk are not fully understood. Activation of nicotinic acetylcholine receptors on dopaminergic neurons by nicotine or selective agonists has been shown to be neuroprotective in experimental models of PD [28, 29]. Nevertheless, nicotine can also stimulate the release of dopamine, which is involved in the reward mechanisms; it is, therefore, difficult to confirm whether smoking prevents PD or whether PD helps prevent the habitual use of cigarettes [30].

## **6.2 Caffeine**

Several studies have investigated the effect of caffeine on the development of PD and reported a reduced risk of developing PD among coffee drinkers. Caffeine is an adenosine A2A receptor antagonist, which is believed to be protective in PD [31] and has been shown to be neuroprotective in a mouse model of PD [32]. It has been previously reported that there is a 25% risk reduction in developing PD among coffee drinkers [33].

## **6.3 Genetics**

There is a minority of cases (10–15%) that record family history, and approximately 5% exhibit Mendelian inheritance. Although PD is typically an idiopathic condition, there is a minority of cases that report a family history [34]. In addition, an individual's risk of PD is partially the result of polygenic risk factors that have not been adequately characterized as of yet. The genes that have been identified as having the potential to produce PD each receive a "PARK" moniker in the order in which they were discovered. To date, 23 PARK genes have been associated with PD. The PARK genes have been shown to be susceptible to mutations. Either autosomal recessive inheritance (such as in SCNA, LRRK2, and VPS32) or autosomal dominant inheritance (e.g., PRKN, PINK1, and DJ-1). Some of these genes, including PARK5, PARK11, PARK13, PARK18, PARK21, and PARK23, have not been definitively linked to the disease, while others, including PARK3, PARK10, PARK12, PARK16, and PARK22, have been linked to the disease and are considered risk factors [35]. The mutations in GBA1, a gene that codes for glucocerebrosidase, a lysosomal enzyme that is responsible for the hydrolysis of glucocerebrosides are the genetic risk factors that predispose people to PD with the highest relative frequency [36].

## **7. Treatment**

Levodopa treatment is considered the gold standard for improving motor symptoms of PD. Casimir Funk, a scientist from Poland, was the one who first synthesized levodopa in 1911 [37]. According to Abbott [37], a clinical trial of levodopa in 20 PD patients in 1961 was conducted. During the trial, a remarkable improvement in motor function for a few hours was noted. Another clinical study showed that the oral version of levodopa was administered to 28 people with PD, and the results showed positive data for motor improvements [37]. The first combined version of levodopa and carbidopa was employed for the purpose of treating the motor symptoms [38]. Dopamine receptors are activated when levodopa in its combined form is administered. This results in improved motor function across the central nervous system as well as peripheral circulation [39]. Carbidopa functions as a decarboxylase inhibitor to increase the amount of levodopa that is readily available in the brain [39]. Nausea, motor issues, hallucinations, sadness, low

blood pressure, irregular sleep, and gambling compulsions are among the most prevalent adverse reactions brought on by the combination of levodopa and carbidopa [40].

#### **7.1 Dopamine receptor agonists**

Patients diagnosed with PD often benefit most from a therapeutic class known as dopamine receptor agonists [41]. All dopamine receptors are G protein-coupled receptors, and there are two different types of D1 and D2 dopamine receptors. These dopamine receptors interact with Gs on G proteins, which in turn activate the adenylyl cyclase system and stimulate the production of cAMP [42]. Both the D1 and D5 subtypes are contained within the D1 receptor, while the D2 receptor is made up of the D2, D3, and D4 subtypes [43]. Despite this, once oral dopamine receptor agonists are taken for an extended period of time, treatment stops being effective [44].

In the treatment of PD, we found six clinical trials that utilized four smallmolecule medicines that operate as a dopamine receptor agonists. PF-06412562 is a moderately strong, highly selective oral D1/D5 dopamine receptor partial agonist; PF-06412562 has good selectivity than other dopamine receptor subtypes [44]. Oral administration of PF-06412562 demonstrated potential antiparkinsonian efficacy in a phase I trial involving 13 PD patients (NCT03665454) [45]. This was accomplished without the significant acute changes in cardiovascular parameters that were reported with previous D1 agonists. The findings of the trial showed that individuals with advanced PD were able to tolerate PF-06412562 and that the drug fulfilled both the primary and secondary endpoints [46].

#### **7.2 Anti-synuclein aggregation therapy (ASAT)**

α-synuclein is an unfolded highly soluble protein that is found in presynaptic neurons throughout the brain [47]. Aggregation of α-synuclein is a pathologic hallmark of synucleinopathies, which can occur in spontaneous or inherited PD. A number of pathological illnesses are brought on by the aggregation of α-synuclein, including synaptic dysfunction, mitochondrial dysfunction, endoplasmic reticulum stress, and oxidative stress [48]. Autophagy and lysosomal disorders are also brought on by this process. All of the pathogenic situations ultimately result in the formation of proteinaceous cytoplasmic inclusions, which are referred to as Lewy bodies and Lewy neurites [48]. The treatment of anti-α-synuclein aggregation primarily works to boost the cellular clearance mechanisms and regulate Lewy bodies [49].

Postuma et al. [18] reported several clinical trials that use anti-α-synuclein aggregation therapy. Five of these clinical trials use monoclonal antibodies (ABVV-0805, BIIB054, and PRX002) or vaccines (AFFITOPE® PD01A). Two of these clinical trials use small molecules (ambroxol and Cu(II)ATSM). (NCT04127695). BIIB054 (cinpanemab) is an IgG1 protein that is produced from the memory B cells of elderly individuals who do not have disorders of the nervous system [18]. The therapy with BIIB054 demonstrated 800 times increased affinity for binding to α-synuclein, which reduced the spread or aggregation of the protein and enhanced motor balances [18].

#### **7.3 Plasma therapy for patients with PD**

Antibodies, protein complexes, salts, and chemical molecules are all components that can be found in plasma. As a result, plasma therapy has emerged as an effective treatment option for PD that is also safe and well-tolerated [21].

*Parkinson's Disease: A Comprehensive Overview of the Disease DOI: http://dx.doi.org/10.5772/intechopen.109437*

Plasma therapy may have limited effects since several factors are connected with the disease, including the fact that aggregation of α-synuclein is not the sole factor that contributes to the progression of PD [50]. However, plasma therapy is associated with a number of adverse health effects, including allergic reactions, difficulty breathing, infection with the human immunodeficiency virus (HIV), hepatitis B or hepatitis C virus, or even the possibility of infection with viruses that have not yet been identified [51].

## **7.4 Based on cells treatment**

In cell therapy, dopamine-producing cells are transplanted into the patient's brain in order to produce the desired therapeutic effect. In patients with PD, cell-based therapy is a viable approach that can reduce brain inflammation [52]. Spheramine, also known by its chemical name BAY86–5280, is a human retinal cultured epithelial pigment that is responsible for the production of levodopa [53].

## **7.5 Gene therapy (GT)**

The term "gene therapy" refers to the use of genetically designed therapeutic genes in the treatment of PD. These therapeutic genes actively replace, knockout, or fix the defective genes that are present in PD patients [54]. In gene therapy, numerous serotypes of genetically engineered viral vectors that do not replicate have been utilized [55]. Some examples of these vectors include the adeno-associated virus (AAV) and the lentivirus. Gene therapy has the potential to stop the death of dopaminergic neurons in the brain [56]. In the treatment of PD, gene treatments primarily attempt to restore patients' motor balance by elevating the stimulation of neurotrophic action in the brain [57]. In addition, gene therapy can be used to regulate glucocerebrosidase levels, which is another promising therapeutic method for the treatment of PD [58].

## **7.6 Agonists or antagonists of the serotonin receptor**

The serotonergic neurotransmission system is responsible for the regulation of cognitive and autonomic functions, as well as motor activities and depression [59]. As a result, medications that target serotonergic receptors can influence behavioral aspects and lead to improvements in motor balance [60]. Furthermore, not all of the serotonin receptor agonists are active or controlling in the process of mediating PD. In addition, some of the 5-HT2B receptor agonists were reported to have unwanted side effects. For example, fenfluramine, pergolide, and cabergoline were taken off the market by the pharmaceutical industry because they caused cardiac fibrosis [61].

## **7.7 Agonists of the muscarinic and nicotinic acetylcholine receptors**

Cholinergic receptors are comprised of muscarinic receptors, which are sensitive to muscarine, and nicotinic receptors, which are sensitive to nicotinic, and they are involved in both somatic and autonomic signal transductions in the nervous system [62].

## **7.8 N-methyl-d-aspartate receptor (NMDAR)**

Dysregulation of NMDAR in the cortical-striatal-pallidal-thalmo-cortical network as well as changes in the plasticity of the brain regions are also critical for cognitive function [63]. This is in addition to the loss of dopaminergic neuronal cells that occurs in PD. Synaptic plasticity is increased by NMDAR modulators [63]. NMDAR modulators were shown to have a number of negative side effects including irregular heartbeats, nausea, vomiting, psychosis, catalepsy, constipation, analgesia, and amnesia [64].

## **7.9 Anti-apoptotic drugs**

Apoptosis and necrosis are the two processes that contribute to the destruction of neurons that happens with the course of PD [65]. Two clinical trials involving the use of small molecule anti-apoptotic medicines were identified. These drugs include TCH346 and minocycline. Dibenz[b,f]oxepin-10-ylmethyl-prop-2-ynyl-amine hydrogen maleate salt is another name for TCH346, which is also a name for this compound. Novartis is developing TCH346, which is now in the midst of a phase I/II clinical trial in which 301 early-stage PD patients are participating; the trial status shows that it has been completed, but there are no published data available. According to the findings of the preclinical studies, TCH346 protected dopaminergic neurons against injury [66]. Minocycline is a neuroprotective synthetic tetracycline derivative that primarily targets anti-apoptotic pathways. It modifies microglial cells and lowers oxidative stress and neuroinflammation [67].

## **7.10 Antioxidants and medications derived from botanical sources**

Antioxidants have an action known as free radical scavenging, and this activity is the primary factor that protects dopaminergic neurons and improves mitochondrial function in both sporadic and inherited cases of PD [68]. Mitochondrial malfunction has been linked to the development of PD; free radical scavenging activity can remove damaged mitochondria through the process of mitophagy and provide neuroprotection in PD [69]. One of the pathological characteristics of neuroinflammation is a reduction in the amount of reduced glutathione seen in the brain of PD patients [70].

## **8. Animal models**

Animal models of PD have shown to be extremely useful in the identification of novel treatments for the motor symptoms of PD as well as in the quest for clues as to the underlying cause of the illness. Models that are based on certain disease-causing mechanisms could, in the future, pave the way for the creation of neuroprotective medications for PD that can halt or delay the progression of the disease. There is a wide variety of rodent models that are currently available. These models range from acute pharmacological models, like the rats that were treated with reserpine or haloperidol and displayed one or more parkinsonian signs, to models exhibiting destruction of the dopaminergic nigro-striatal pathway, like the traditional 6-hydroxydopamine (6-OHDA) rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (All of these have served as test beds for evaluating potential novel compounds for treating the motor symptoms of PD. In addition, the appearance of abnormal involuntary movements (AIMs) after repeated treatment of 6-OHDA-lesioned rats with L-DOPA has made it possible to investigate the mechanisms that are responsible for treatment-related dyskinesia in PD, as well as the identification of molecules that are able to prevent or reverse the appearance of these symptoms. The systemic

## *Parkinson's Disease: A Comprehensive Overview of the Disease DOI: http://dx.doi.org/10.5772/intechopen.109437*

administration of the pesticides rotenone and paraquat are examples of other toxin-based models of nigro-striatal tract degeneration. However, despite the fact that these models provide insights into the pathogenesis of the disease, they are not typically utilized in the drug development process. The MPTP-treated primate model of PD is without a doubt the most clinically relevant of all the models that are currently available because it closely resembles the clinical features of PD and because it is the model in which all of the anti-parkinsonian medications that are currently in use have been shown to be effective. When repeatedly exposed to L-DOPA, the MPTP-treated primate develops obvious dyskinesia, and these parkinsonian animals have exhibited reactions to novel dopaminergic drugs that are highly predictive of their effect in man. It is debatable whether or not non-dopaminergic medications demonstrate the same level of response predictability as dopaminergic treatments. New rodent models have been developed in tandem with our growing comprehension of the mechanisms underlying the progression of PD (PD). These agents include proteasome inhibitors such as PSI, lactacystin, and epoximycin, as well as inflammogens such as lipopolysaccharide (LPS). These agents have been shown to produce symptoms in rodents that are similar to those seen in humans. In addition, a new generation of models has emerged with the purpose of imitating the genetic factors that contribute to PD. Even while these more recent models have offered additional insights into the pathophysiology of the disease, researchers have not yet relied heavily on them when developing novel medications. Dopaminergic drug treatment of the illness, as well as the prevention and reversal of drug-related side effects that emerge with disease progression and chronic medication, have been dramatically altered as a result of the availability of experimental animal models of PD. This is something that can be said with a high degree of certainty. However, in terms of expanding into other pharmacological fields for the treatment of PD, we have not made a lot of headway so far. Furthermore, we have not developed models that reflect the progressive nature of the illness and its complexity in terms of the extent of pathology and biochemical change. It is only when this happens that we will have a chance of making progress in the development of medications that can stop or delay the advancement of the disease. In the search for more effective medication treatments for PD, the overriding question that connects all of these models is as follows: how accurately do they recapitulate the human situation, and how predictive are they of the successful translation of pharmaceuticals into the clinic? The purpose of this essay is to provide clarification on the current situation and highlight the strengths and shortcomings of the many models that are available [71].

Akinesia, bradykinesia, rigidity, tremor, and postural abnormalities are the classic motor symptoms of PD. These symptoms are associated with the loss of nigral dopaminergic cells and a decline in caudate-putamen dopamine content, which led to the development of dopamine replacement therapy. Because of this, animal models of PD have played a significant part in the creation of innovative pharmacological approaches to therapy, the development of new treatment methods, and the comprehension of the nature of the pathogenic processes involved in the loss of neuronal function. The discovery that giving rodents and rabbits reserpine or haloperidol led to a temporary parkinsonian-like state was quickly followed by the crucial discovery that giving these animals L-DOPA caused their symptoms to disappear. This was the first evidence that L-DOPA could be used to treat PD [72]. This paved the way for a new era in which animal models of PD were utilized to research the physiological underpinnings of symptomatic treatment. When it was discovered that the injection of 6-hydroxydopamine (6-OHDA) using a unilateral stereotaxic technique into the

substantia nigra or the medial forebrain bundle caused the destruction of the nigrostriatal pathway and, as a result, a loss of dopaminergic input to the striatum, this led to further success in the treatment of the condition. Because of this, the "circling" rat model of PD was developed, which went on to dominate research for a good number of years. This also marked the beginning of the era in which toxins were used to produce animal models of PD [73]. These advancements led to the development of novel approaches to treatment, such as the introduction of peripherally acting decarboxylase inhibitors, carbidopa, and benserazide, which limited the peripheral side effects of L-DOPA and allowed for a lowering of dose as more drugs entered the brain. Carbidopa and benserazide are examples of such novel approaches. More recently, the development of selective monoamine oxidase-B (MAO-B) inhibitors, selegiline, and rasagiline, which slow the degradation of dopamine formed from L-DOPA and prolong its duration of effect, as well as the more recent development of catechol-Omethyl-transferase (COMT) inhibitors, entacapone, and tolcapone, which stop either the peripheral or central metabolism of L-DOPA to 3-O-methyldo [22, 74].

Importantly, the chemical and toxin animal-based models of PD ushered in the age of the use of synthetic dopamine agonists, which sparked early interest in the production of anti-parkinsonian action through the stimulation of post-synaptic dopamine receptors in the striatum. A significant number of compounds were put through the available models' screening process, which, of course, resulted in a great number of unsuccessful attempts at both the preclinical and clinical levels. Apomorphine was the very first molecule to be tried out in clinical trials for the treatment of PD after its initial use in research [75]. An early dopamine agonist called piribedil was highly effective, but its clinical application in PD was not properly understood, and rapid dose escalation caused high levels of nausea, vomiting, and gastrointestinal disturbance that tainted its use. This is similar to the situation with many other ground-breaking molecules [76]. However, in the following years, ergot derivatives such as bromocriptine, pergolide, and cabergoline were introduced, which provided effective control of the motor symptoms of PD [77]. Ergots are no longer used because they were found to have valvular effects in the heart, which may represent the broad pharmacology of ergot derivatives and activity on 5-HT2B receptors. As a result, the use of ergots has been phased out [78]. Dopaminergic therapy in PD is presently centered on pramipexole, ropinirole, and rotigotine as oral and transdermal pharmaceuticals. However, non-ergot drugs were previously being used in the treatment of PD. These drugs were discovered by using animal models of the disease [79]. Dopamine receptor subtypes were cloned at the same time that most of the development of dopamine agonists was taking place, and animal models of PD were used as a testing ground to investigate the role that dopamine receptor subtypes play in regulating motor function. In particular, researchers were interested in determining how D1-like and D2-like receptors interact with one another, as well as how this interaction relates to the anti-parkinsonian activity and side effect profile [80].

## **8.1 Pharmacological models**

#### *8.1.1 Reserpine model*

One of the initial animal models used in research on PD was a mouse that had been given reserpine. This model was essential in initially proving the therapeutic efficacy of L-DOPA, which is still the treatment of gold standard for PD, despite the fact that it was fairly a primitive pharmacological mimic of the neurochemistry of PD.

## *Parkinson's Disease: A Comprehensive Overview of the Disease DOI: http://dx.doi.org/10.5772/intechopen.109437*

Carlsson et al. [81] were the ones who first established that L-DOPA, the endogenous dopamine precursor, has the power to counteract the effects of reserpine pretreatment that were at the time described as having a "tranquilizing" impact on mice. This was done in the late 1950s [81]. This effect was soon replicated in people [82], and the reserpine-treated mouse or, more commonly, the rat became established as a reliable screen for possible symptomatic efficacy of novel medications in PD. The reserpine model has also made substantial contributions to our knowledge of the relationship between monoamine depletion and parkinsonian symptoms from the standpoint of the disease. Reserpine acts by blocking the vesicular monoamine transporter, also known as VMAT2. The typical dose for this medication is four to five milligrams per kilogram subcutaneously. This results in a decrease in storage capacity and, as a consequence, depletion of monoamines in the brain and the peripheral nervous system. These monoamines include noradrenaline, 5-HT, and dopamine. Although the absence of selectivity for dopamine was once thought to be a flaw in the reserpine model's ability to accurately reflect the biochemistry of PD (PD), it was later discovered that the disease also affects the noradrenergic and serotonergic systems [83], which argues in favor of the reserpine model being a relatively good mimic of the disease biochemistry.

## *8.1.2 MPTP model*

Because of its potential to cause persistent Parkinsonism in humans, MPTP is a toxin that is frequently employed for the purpose of producing PD in rodents as well as primates [84]. Subsequent research in non-human primates determined that the pathological basis behind the observed motor deficits was the selective destruction of dopaminergic neurons of the nigro-striatal tract [85]. This led to the development of the most relevant animal model of PD that is still used today. In the study of PD (PD), the MPTP-treated primate model has had an unparalleled influence; nonetheless, we shall begin by concentrating on the application of MPTP in animals that are not primates. It is possible that the relatively rapid clearance of MPP+, which is the poisonous metabolite of MPTP, accounts for the resistance of a great number of animals, including rats, to the toxic effects of MPTP [86]. However, certain strains of mice, most notably black C57 and Swiss Webster, are sensitive to MPTP [86]. Because of this, the MPTP mouse model of PD was able to be developed using these mouse strains. The mechanism that underlies the neurotoxic activity of MPTP has been the focus of extensive research and is now considered to be rather well-known. After receiving a systemic injection often (intraperitoneally or subcutaneously), MPTP is a lipophilic protoxin that quickly penetrates the blood–brain barrier [87]. Once within the brain, MPTP is transformed by MAO-B, which is mostly found in glia and serotonergic neurons, into the intermediate, 1-methyl-4-phenyl-2,3,dihydropyridinium (MPDP+), before its rapid and spontaneous oxidation to the poisonous component, 1-methyl-4-phenylpyridinium (MPP+) [88]. After being released into the extracellular space, MPP+ is taken up by dopaminergic neurons via the DAT. Once inside these neurons, cytoplasmic MPP+ has the ability to stimulate the creation of ROS, which may contribute to the overall neurotoxicity of the compound [89]. On the other hand, the vast majority of MPP+ is finally stored inside mitochondria, which is where the primary harmful process takes place. When MPP+ reaches the mitochondria, it inhibits complex I of the electron transport chain, which in turn reduces the efficiency of mitochondrial respiration. Because of this action, the flow of electrons through the respiratory chain is disrupted, which results in a lower level of ATP

synthesis and the creation of reactive oxygen species (ROS), such as superoxide radicals. The combined effects of decreased cellular ATP and elevated ROS production are most likely responsible for the initiation of cell death-related signaling pathways. These pathways include p38 mitogen-activated kinase [90], c-jun N-terminal kinase (JNK) [91], and bax [92]. This model demonstrates a high degree of construct validity due to the fact that many of these mechanisms are also characteristics of the pathophysiology of PD.

## **8.2 Pesticide-induced models**

## *8.2.1 Rotenone model*

The rotenone model of PD is the most well-known of the models that have come out of this, but ever since it was initially presented [93], it has continued to be the subject of much dispute [94]. The pesticide rotenone is extremely lipophilic, just like MPTP, which allows it to easily pass through the blood–brain barrier and diffuse into neurons. Once there, it accumulates within the mitochondria and inhibits complex I in a manner that is very similar to how MPTP does it. However, the subsequent decreases in ATP are not regarded to be the origin of the toxicity; rather, it is believed that glutathione depletion leads to the generation of reactive oxygen species (ROS), which in turn induces oxidative stress [95]. There is no doubt that oxidative damage, in the form of protein carbonyl formation, was discovered in the midbrain, olfactory bulb, striatum, and cortex of rats that were treated with rotenone [95]. This finding is consistent with what is reported in the PD brain after death [96]. The extensive microglial activation that was observed in both the SNpc and striatum following rotenone infusion [97] is consistent with the inflammatory features found in idiopathic PD [98]. This lends support to the construct validity of this model. The recent observation that rotenone suppresses proteasomal activity [99] provides additional support for this theory. Proteasomal activity, which will be discussed further below, is also thought to have a role in PD.

## **8.3 Paraquat and Maneb model**

It is not surprising that attempts have been made to model PD using these agents given that exposure to the herbicide paraquat (1,1′-dimethyl-4,4′-bipyridinium) or the fungicide Maneb (manganese ethylene-bis-dithiocarbamate) has been associated with an increased incidence of PD [100, 101]. Before the Na+-dependent uptake into cells can take place, however, paraquat must first reach the brain through the neutral amino acid transporter [102]. Once it has entered the cell, paraquat causes both indirect mitochondrial toxicity through redox cycling and direct inhibition of complex I (at higher doses). This occurs because paraquat inhibits redox cycling [103]. Following its introduction into the brain, maneb, on the other hand, inhibits complex III of the mitochondrial respiratory chain in a selective manner [104]. It has been demonstrated that the combination of maneb and paraquat results in increased toxicity [105], which may be due to the fact that maneb raises the concentration of paraquat in the brain while simultaneously decreasing its clearance [106]. This provides a clear rationale for combining the administration of these pesticides in order to produce an animal model of PD. This is especially important when considering the fact that human exposure to just one of these pesticides is unlikely because they are used in the same geographical regions.

## **8.4 Genetic models of PD**

The first gene to be unequivocally linked to familial Parkinson's disease (PD) was the alpha-synuclein gene [107]. Researchers were able to zero in on a number of additional familial PD-linked genes after this discovery was made in 1997. These genes were associated with autosomal dominant or recessive forms of Parkinson's disease. These genes are included in this category: parkin [108], DJ-1 [109], PINK1 [110], and LRRK2 [111]. It is essential to note here that despite the fact that mutations in UCHL1 [112] and Omi/HtrA2 [113] have also been proposed to cause parkinsonism, the relevance of these mutations to Parkinson's disease is currently debatable. This is due to the fact that the supposed mutation that causes the disease is either extremely rare in occurrence (e.g., UCHL1 I93M) or present in control population at similar frequencies (e.g., Omi/HtrA2 G399S). Concerning the recently described ATP13A2-linked parkinsonism [114], the clinical phenotype that is associated with it (which is characterized by mild parkinsonism and prominent cognitive defects) is quite different from traditional Parkinson's disease, In general, PD-linked genes are expressed as transgenes in heterologous organisms if their pattern of inheritance in humans indicates that dominant transmission is likely to occur. This is because dominant transmission is the form of inheritance that causes Parkinson's disease. In the event that this cannot be accomplished, orthologous copies of the human gene are removed from animal genomes in order to replicate the recessive loss of gene function. In addition to models based on flies and worms, researchers have had success to this day in developing several mouse models of familial parkinsonism. Despite the fact that non-mammalian models of Parkinson's disease (PD) cannot fully replicate the phenotypic and pathologic characteristics of the human condition, these models are still able to reproduce certain important hallmarks of the disease, such as LB-like inclusions and DA neurodegeneration [115]. Parkinson's disease is a neurodegenerative disorder that affects the brain's dopaminergic neurons. As a consequence of this, these models are beneficial to the investigation of the connection between PD-linked genes and the operation of DA neurons. Noteworthy is the fact that each of the two hemispheres of the adult fly brain contains six clusters of DA neurons, but only one cluster of C neurons. Elegans has a total of eight DA neurons in its brain, and these neurons are split up into three different subsets. Importantly, the well-characterized genetics of these nonmammalian PD models offer a distinct advantage over the mouse model for the rapid identification of modifiers that could shed light on significant pathways involved in the pathogenesis of disease. This advantage cannot be found in any other model. The understanding that one obtains from these pathways might make it easier to create new kinds of therapeutics in the future [116].

## **8.5 Genetic environmental interactions models of PD**

It is generally accepted that the etiology of Parkinson's disease is largely influenced by the interactions that take place between genetic factors and environmental exposures. Even though such interactions are not well defined and are only partially understood, recent epidemiological studies have identified specific interactions that may be of potential importance to human Parkinson's disease (PD). This is despite the fact that such interactions are poorly defined [117].

The specifics of the interactions between genetic predisposition and environmental exposures are not well understood at this time, despite the fact that a large number of researchers believe that the majority of cases are influenced by both

genetic predisposition and environmental exposures. Despite this, there is evidence that suggests certain interactions between different factors. The current discussion is limited to those gene–environment interactions that have supporting or suggestive data, despite the fact that the number of gene–environment interactions that could bear pathogenic relevance to PD is extremely large, as is the diversity of those interactions [117].

To be able to have a direct effect on the nigrostriatal dopamine system, a toxicant must first be able to pass through the barrier that separates the blood and the brain (BBB). Due to the BBB's size and polarity requirements, it is highly unlikely that many toxic substances will be able to cross it [118]. It is possible that genetic alterations that change the permeability of the blood–brain barrier (BBB) could either increase the accumulation of toxic substances in the brain or make it possible for toxic substances to enter the brain that are normally kept out. The existence of human data lends credence to the possibility of such an interaction. P-glycoprotein is the product of the multidrug resistance gene (MDR1) and plays a role in the functioning of the blood–brain barrier (BBB). It is interesting to note that the distribution of the 3435 T/T genotype, which has been linked in the past to lower levels of P-glycoprotein expression and function, was highest in early-onset Parkinson's disease patients, second-highest in late-onset Parkinson's disease patients, and lowest in controls [119]. It has been suggested in additional reports that factors such as ethnicity, polymorphisms, and haplotype expression, which are relevant to MDR1, may modulate the risk of Parkinson's disease [120]. Changes in the expression of P-glycoproteins could very well be important to the uptake of toxicants. A positron emission tomography was performed to measure the brain uptake of [(11)C]-verapamil, which is normally expelled from the brain by P-glycoprotein. The results showed that PD patients had increased absorption in the midbrain [121]. According to the findings of this study, Parkinson's disease could be caused by a dysfunctional blood–brain barrier as well as P-glycoprotein. P-glycoprotein dysfunction was not found in early-onset Parkinson's disease patients by a separate imaging study, despite the fact that there was a large amount of variability [122]. Patients with Parkinson's disease had lower levels of MDR1 mRNA in the striatum in their postmortem tissue than controls did [123]. These studies point to a potential pathogenic role for decreased expression or function in Parkinson's disease (PD). It has been demonstrated that mice deficient in the MDR1 gene accumulate anticancer drugs, narcotics, and pesticides [124]. In MDR1/mice, accumulation may take place at much higher levels than in controls, or it may occur in compounds that are normally completely excluded but may gain access. This is dependent on the compound. The direct relevance to dopaminergic toxicants has not yet been established, and it is possible that altered brain entry of normally excluded endogenous factors is significantly more important in modulating PD risk than environmental exposures [117].

## **9. Pathologic features of PD from our studies**

Several studies have been conducted in our laboratories using mouse model. One of the studies aimed to investigate the level of inducible nitric oxide synthase (iNOS) expression in the skeletal muscles of mice with PD and to investigate the influence that training on a treadmill has on the level of iNOS expression in these skeletal muscles. The results showed that the expression of iNOS in the gastrocnemius muscle show a statistically significant increase in the sedentary PD (SPD) group compared to

## *Parkinson's Disease: A Comprehensive Overview of the Disease DOI: http://dx.doi.org/10.5772/intechopen.109437*

the sedentary control (SC) group (*P* = 0.05). There was an increase in the expression of iNOS in the soleus muscle of those in the SPD group when compared to those in the SC group, although the difference did not reach statistical significance (*P* = 0.08). Additionally, exercise did not result in a significant reduction of the expression of iNOS in the Parkinsonian group (*P* value 0.13). According to the findings that we have gathered so far, endurance exercise training appears to mitigate the changes in iNOS expression in skeletal muscles that are caused by PD. These findings could be significant when thinking about rehabilitation procedures for Parkinson's disease and the pathophysiology associated with it [125].

Another study was conducted in light of considerations that overexpression of heat shock protein 90 can result in the death of dopaminergic neuronal cells. The study purposed to gain a deeper understanding of the impact that heat shock protein 90 has on the body after it has been subjected to endurance exercise. The results of immunohistochemistry showed that exercise training significantly inhibited heat shock protein 90 overexpression in the soleus and gastrocnemius in rats with Parkinson's disease. This overexpression of heat shock protein 90 is a potential therapeutic target for ameliorating skeletal muscle abnormalities in Parkinson's disease [126].

In another study, Al-Jarrah et al. [127] purposed to analyze the expression of the inducible form of NO (iNOS), and compare it to neuronal nitric oxide (nNOS), in the brain of a chronic mice model of PD, and to investigate the influence that training for endurance will have on the expression of the aforementioned markers. The results showed that nNOS levels were significantly higher in the striatum (ST) of SPD animals in comparison to SC mice (*P* > 0.03). Although there was a lower expression of nNOS in the EC group of mice in comparison to the SC animals, this difference was not statistically significant (*P* > 0.8). When compared to SPD, the amount of nNOS in the EPD showed a substantial decrease as a result of exercise training (*P* > 0.04). Although the expression of iNOS followed a trend that was essentially identical to that of nNOS, the expression of iNOS did not significantly decrease as a result of exercise training in either the EC or EPD groups (*P* > 0.2 and 0.3, respectively). The findings of this research reveal that a period of 4 weeks spent running on a treadmill has a beneficial effect on the expression of nNOS and iNOS in the striatum of a model of Parkinson's disease (PD). It is possible that this could clear up some questions about the pathogenicity of the diseases and the beneficial effects of training on PD [127]. We found other findings from clinical observations in which two patients with PD received certain chemicals including magnesium, chromium, zinc, vitamin D, and tadalafil 5, the results of such an approach showed ameliorating effects of PD symptoms.

## **10. Conclusions**

PD is still a version area of research and clinical trials. There is no curative treatment for PD has been developed so far, a mater that opens the door for continuous inputting efforts to reach a therapeutic goal. In addition to the classical pathological picture of PD, we showed that certain molecular pathways play a major role in the pathogenesis of PD including inducible nitric oxide synthase, HSP90, and in the brain and other tissues of mice with PD. Furthermore, some clinical findings showed that the administration of tadalafil 5, magnesium, zinc, chromium, and vitamin D improves the clinical status of PD.

## **Author details**

Ahed J. Khatib1,2

1 Department of Legal Medicine, Toxicology and Forensic Medicine, Jordan University of Science and Technology, Irbid, Jordan

2 International Mariinskaya Academy, Department of Medicine and Critical Care, Department of Philosophy, Academician Secretary of the Department of Sociology, Irbid, Jordan

\*Address all correspondence to: ajalkhatib@just.edu.jo

© 2022 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.

## **References**

[1] Stührenberg M, Berghäuser CS, van Munster M, Pedrosa Carrasco AJ, Pedrosa DJ, on behalf of the iCARE-PD Consortium. Measuring quality of life in Parkinson's disease—A call to rethink conceptualizations and assessments. Journal of Personalized Medicine. 2022;**12**:804. DOI: 10.3390/jpm1205080

[2] Kalia LV, Lang AE. Parkinson's disease. Lancet. 2015;**386**(9996):896-912. DOI: 10.1016/S0140-6736(14)61393-3

[3] Koníˇcková D, Menšíková K, Tuˇcková L, Hényková E, Strnad M, Friedecký D, et al. Biomarkers of neurodegenerative diseases: Biology, taxonomy, clinical relevance, and current research status. Biomedicine. 2022;**10**:1760. DOI: 10.3390/ biomedicines10071760

[4] Wanneveich M, Moisan F, Jacqmin-Gadda H, Elbaz A, Joly P. Projections of prevalence, lifetime risk, and life expectancy of Parkinson's disease (2010- 2030) in France. Movement Disorders. Sep 2018;**33**(9):1449-1455. DOI: 10.1002/ mds.27447. Epub 2018 Aug 25. PMID: 30145805

[5] Kouli A, Torsney KM, Kuan WL. Chapter 1. Parkinson's disease: Etiology, neuropathology, and pathogenesis. In: Stoker TB, Greenland JC, editors. Parkinson's Disease: Pathogenesis and Clinical Aspects [Internet]. Brisbane, AU: Codon Publications; 2018. pp. 3-26. Available from: https://www.ncbi. nlm.nih.gov/books/NBK536722/. DOI: 10.15586/codonpublications. parkinsonsdisease.2018.ch1

[6] Prasad EM, Hung SY. Behavioral tests in neurotoxin-induced animal models of PD. Antioxidants. 2020;**9**:7. DOI: 10.3390/antiox9101007

[7] Maroteaux L, Campanelli JT, Scheller RH. Synuclein: A neuronspecific protein localized to the nucleus and presynaptic nerve terminal. The Journal of Neuroscience. 1988;**8**:2804. DOI: 10.1523/JNEUROSCI.08-08- 02804.1988

[8] Maguire-Zeiss KA. α-Synuclein: A therapeutic target for PD? Pharmaceutical Research. 2008;**58**:271- 280. DOI: 10.1016/j.phrs.2008.09.006

[9] Velentgas P., Dreyer N.A., Wu A.W. Developing a Protocol for Observational Comparative Effectiveness Research: A User's Guide. Agency for Healthcare Research and Quality (US); Rockville, MD, USA: 2013. Outcome definition and measurement.

[10] Merchant KM, Cedarbaum JM, Brundin P, Dave KD, Eberling J, Espay AJ, et al. A proposed roadmap for PD proof of concept clinical trials investigating compounds targeting alpha-synuclein. Journal of Parkinson's Disease. 2019;**9**:31- 61. DOI: 10.3233/JPD-181471

[11] Marino S, Ciurleo R, Di Lorenzo G, Barresi M, De Salvo S, Giacoppo S, et al. Magnetic resonance imaging markers for early diagnosis of PD. Neural Regeneration Research. 2012;**7**:611-619. DOI: 10.3969/j.issn.1673-5374.2012.08.009

[12] Dauer W, Przedborski S. PD: Mechanisms and models. Neuron. 2003;**39**:889-909. DOI: 10.1016/ S0896-6273(03)00568-3

[13] Rabinstein AA, Shulman LM. Management of behavioral and psychiatric problems in PD. Parkinsonism & Related Disorders. 2000;**7**:41-50. DOI: 10.1016/ S1353-8020(00)00039-0

[14] Horstink DMWIM. PD and parkinsonism in the elderly. Brain. 2000;**123**:2569-2571. DOI: 10.1093/ brain/123.12.2569

[15] Foltynie T, Sawcer S, Brayne C, Barker RA. The genetic basis of PD. Journal of Neurology, Neurosurgery, and Psychiatry. 2002;**73**:363-370. DOI: 10.1136/jnnp.73.4.363

[16] Prasad EM, Hung SY. Current therapies in clinical trials of PD: A 2021 update. Pharmaceuticals (Basel, Switzerland). 2021;**14**(8):717. DOI: 10.3390/ph14080717

[17] Maetzler W, Hausdorff JM. Motor signs in the prodromal phase of Parkinson's disease. Movement Disorders. 2012;**27**:627-633

[18] Postuma RB, Anang J, Pelletier A, Joseph L, Moscovich M, Grimes D, et al. Caffeine as symptomatic treatment for Parkinson disease (Café-PD): A randomized trial. Neurology. 2017;**89**:1795-1803. DOI: 10.1212/ WNL.0000000000004568

[19] Katzenschlager R, Head J, Schrag A, Ben-Shlomo Y, Evans A, Lees AJ, et al. Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD. Neurology. 12 Aug 2008;**71**(7):474-480. DOI: 10.1212/01.wnl.0000310812.43352.66

[20] Schrag A, Horsfall L, Walters K, Noyce A, Petersen I. Prediagnostic presentations of Parkinson's disease in primary care: A case-control study. Lancet Neurology. Jan 2015;**14**(1):57-64. DOI: 10.1016/S1474-4422(14)70287-X

[21] Ma SY, Röyttä M, Rinne JO, Collan Y, Rinne UK. Correlation between neuromorphometry in the substantia nigra and clinical features in Parkinson's disease using disector counts. Journal

of the Neurological Sciences. 3 Oct 1997;**151**(1):83-87. DOI: 10.1016/ S0022-510X(97)00100-7

[22] Lees AJ. Evidence-based efficacy comparison of tolcapone and entacapone as adjunctive therapy in Parkinson's disease. CNS Neuroscience & Therapeutics. 2008;**14**:83-93

[23] Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976-1990. Neurology. 12 Apr 1999;**52**(6):1214-1220. DOI: 10.1212/WNL.52.6.1214

[24] Hernán MA, Zhang SM, RuedadeCastro AM, Colditz GA, Speizer FE, Ascherio A. Cigarette smoking and the incidence of Parkinson's disease in two prospective studies. Annals of Neurology. Dec 2001;**50**(6):780-786. DOI: 10.1002/ ana.10028

[25] Hernán MA, Takkouche B, Caamaño-Isorna F, Gestal-Otero JJ. A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease. Annals of Neurology. Sep 2002;**52**(3):276-284. DOI: 10.1002/ ana.10277

[26] Ritz B, Ascherio A, Checkoway H, Marder KS, Nelson LM, Rocca WA, et al. Pooled analysis of tobacco use and risk of Parkinson disease. Archives of Neurology. Jul 2007;**64**(7):990-997. DOI: 10.1002/ana.10277

[27] Breckenridge CB, Berry C, Chang ET, Jr RLS, Mandel JS. Association between Parkinson's disease and cigarette smoking, rural living, well-water consumption, farming and pesticide use: Systematic review and meta-analysis. PLoS One. 7 Apr 2016;**11**(4):e0151841. DOI: 10.1371/ journal.pone.0151841

*Parkinson's Disease: A Comprehensive Overview of the Disease DOI: http://dx.doi.org/10.5772/intechopen.109437*

[28] Bordia T, McGregor M, Papke RL, Decker MW, McIntosh JM, Quik M. The α7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions. Experimental Neurology. Jan 2015;**263**:277-284. DOI: 10.1016/j. expneurol.2014.09.015

[29] Srinivasan R, Henley BM, Henderson BJ, Indersmitten T, Cohen BN, Kim CH, et al. Smoking-relevant nicotine concentration attenuates the unfolded protein response in dopaminergic neurons. The Journal of Neuroscience. 6 Jan 2016;**36**(1):65-79. DOI: 10.1523/ JNEUROSCI.2126-15.2016

[30] Ritz B, Lee P-C, Lassen CF, Arah OA. Parkinson disease and smoking revisited: Ease of quitting is an early sign of the disease. Neurology. 14 Oct 2014;**83**(16):1396-1402. DOI: 10.1212/ WNL.0000000000000879

[31] Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, et al. Association of coffee and caffeine intake with the risk of Parkinson disease. Journal of the American Medical Association. 24 May 2000;**283**(20):2674-2679. DOI: 10.1001/ jama.283.20.2674

[32] Chen JF, Xu K, Petzer JP, Staal R, Xu YH, Beilstein M, et al. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. The Journal of Neuroscience. 15 May 2001;**21**(10):RC143. DOI: 10.1523/ JNEUROSCI.21-10-j0001.2001

[33] Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, et al. Metaanalysis of early nonmotor features and risk factors for Parkinson disease. Annals of Neurology. Dec 2012;**72**(6):893-901. DOI: 10.1002/ana.23687

[34] Deng H, Wang P, Jankovic J. The genetics of Parkinson disease. Ageing Research Reviews. 1 Mar 2018;**42**:72-85. DOI: 10.1016/j.arr.2017.12.007

[35] Schulte C, Gasser T. Genetic basis of Parkinson's disease: Inheritance, penetrance, and expression. The Application of Clinical Genetics. 1 Jun 2011;**4**:67-80

[36] Nichols WC, Pankratz N, Marek DK, Pauciulo MW, Elsaesser VE, Halter CA, et al. Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. Neurology. 27 Jan 2009;**72**(4):310-316. DOI: 10.1212/01.wnl.0000327823. 81237.d1

[37] Abbott A. Levodopa: The story so far. Nature. 2010;**466**:S6-S7. DOI: 10.1038/466S6a

[38] Lesser RP, Fahn S, Snider SR, Cote LJ, Isgreen WP, Barrett RE. Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy. Neurology. 1979;**29**:1253-1260. DOI: 10.1212/WNL.29.9\_Part\_1.1253

[39] Guebila MB, Thiele I. Model-based dietary optimization for late-stage, levodopa-treated, PD patients. NPJ Systems Biology and Applications. 2016;**2**:16013. DOI: 10.1038/npjsba. 2016.13

[40] Dodd ML, Klos KJ, Bower JH, Geda YE, Josephs KA, Ahlskog JE. Pathological gambling caused by drugs used to treat parkinson disease. Archives of Neurology. 2005;**62**:1377-1381. DOI: 10.1001/archneur.62.9.noc50009

[41] Annus Á, Vécsei L. Spotlight on opicapone as an adjunct to levodopa in PD: Design, development and potential place in therapy. Drug Design, Development and Therapy.

2017;**11**:143-151. DOI: 10.2147/DDDT. S104227

[42] Gurevich EV, Gainetdinov RR, Gurevich VV. G protein-coupled receptor kinases as regulators of dopamine receptor functions. Pharmaceutical Research. 2016;**111**:1-16. DOI: 10.1016/j. phrs.2016.05.010

[43] Beaulieu JM, Gainetdinov RR. The physiology, signaling and pharmacology of dopamine receptors. Pharmacy Review. 2011;**63**:182-217. DOI: 10.1124/ pr.110.002642

[44] Ghiglieri V, Bagetta V, Pendolino V, Picconi B, Calabresi P. Corticostriatal plastic changes in experimental L-DOPAinduced dyskinesia. Parkinson's Disease. 2012;**2012**:358176. DOI: 10.1155/ 2012/358176

[45] Papapetropoulos S, Liu W, Duvvuri S, Thayer K, Gray DL. Evaluation of D1/D5 partial agonist PF-06412562 in PD following oral administration. Neurodegenerative Diseases. 2018;**18**:262-269. DOI: 10.1159/000492498

[46] Huang X, Lewis MM, Van Scoy LJ, De Jesus S, Eslinger PJ, Arnold AC, et al. The D1/D5 dopamine partial agonist PF-06412562 in advanced-stage PD: A feasibility study. Journal of Parkinson's Disease. 2020;**10**:1515-1527. DOI: 10.3233/JPD-202188

[47] Silveira CRA, MacKinley J, Coleman K, Li Z, Finger E, Bartha R, et al. Ambroxol as a novel disease-modifying treatment for PD dementia: Protocol for a single-centre, randomized, doubleblind, placebo-controlled trial. BMC Neurology. 2019;**19**:20. DOI: 10.1186/ s12883-019-1252-3

[48] Parashos SA, Luo S, Biglan KM, Bodis-Wollner I, He B, Liang GS, et al. Measuring disease progression in early Parkinson disease: The national institutes of health exploratory trials in Parkinson disease (NET-PD) experience. JAMA Neurology. 2014;**71**:710-716. DOI: 10.1001/jamaneurol.2014.391

[49] Schwarzschild MA, Schwid SR, Marek K, Watts A, Lang AE, Oakes D, et al. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Archives of Neurology. 2008;**65**:716-723. DOI: 10.1001/archneur.2008.65.6.nct70003

[50] Kaplitt MG, Feigin A, Tang C, Fitzsimons HL, Mattis P, Lawlor PA, et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for PD: An open label, phase I trial. Lancet. 2007;**369**:2097-2105. DOI: 10.1016/S0140-6736(07)60982-9

[51] Bartus RT, Baumann TL, Siffert J, Herzog CD, Alterman R, Boulis N, et al. Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology. 2013;**80**:1698-1701. DOI: 10.1212/ WNL.0b013e3182904faa

[52] Marks WJ Jr, Bartus RT, Siffert J, Davis CS, Lozano A, Boulis N, et al. Gene delivery of AAV2-neurturin for PD: A double-blind, randomised, controlled trial. Lancet Neurology. 2010;**9**:1164-1172. DOI: 10.1016/ S1474-4422(10)70254-4

[53] Ghosh S, Won SJ, Wang J, Fong R, Butler NJM, Moss A, et al. α-Synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism. Progress in Neurobiology. 2021;**202**:102070. DOI: 10.1016/j. pneurobio.2021.102070

[54] Gordon PH, Yu Q, Qualls C, Winfield H, Dillon S, Greene PE, et al. *Parkinson's Disease: A Comprehensive Overview of the Disease DOI: http://dx.doi.org/10.5772/intechopen.109437*

Reaction time and movement time after embryonic cell implantation in Parkinson disease. Archives of Neurology. 2004;**61**:858-861. DOI: 10.1001/ archneur.61.6.858

[55] McRae C, Cherin E, Yamazaki TG, Diem G, Vo AH, Russell D, et al. Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Archives of General Psychiatry. 2004;**61**:412-420. DOI: 10.1001/archpsyc.61.4.412

[56] Politis M, Lindvall O. Clinical application of stem cell therapy in PD. BMC Medicine. 2012;**10**:1. DOI: 10.1186/1741-7015-10-1

[57] Axelsen TM, Woldbye DPD. Gene therapy for PD, an update. Journal of Parkinson's Disease. 2018;**8**:195-215. DOI: 10.3233/JPD-181331

[58] Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Annals of Neurology. 2006;**59**:459-466. DOI: 10.1002/ana.20737

[59] Sangkuhl K, Klein TE, Altman RB. Selective serotonin reuptake inhibitors pathway. Pharmacogenetics and Genomics. 2009;**19**:907-909. DOI: 10.1097/FPC.0b013e32833132cb

[60] Baumgarten HG, Grozdanovic Z. Psychopharmacology of central serotonergic systems. Pharmacopsychiatry. 1995;**28**:73-79

[61] Brea J, Castro-Palomino J, Yeste S, Cubero E, Párraga A, Domínguez E, et al. Emerging opportunities and concerns for drug discovery at serotonin 5-HT2B receptors. Current Topics in Medicinal Chemistry. 2010;**10**:493-503. DOI: 10.2174/156802610791111524

[62] Carlson AB, Kraus GP. StatPearls. Treasure Island, FL: StatPearls Publishing LLC.; 2020. Physiology, cholinergic receptors

[63] Barth AL, Schneider JS, Johnston TH, Hill MP, Brotchie JM, Moskal JR, et al. NYX-458 improves cognitive performance in a primate PD model. Movement Disorders. 2020;**35**:640-649. DOI: 10.1002/ mds.27962

[64] Olivares D, Deshpande VK, Shi Y, Lahiri DK, Greig NH, Rogers JT, et al. N-methyl D-aspartate (NMDA) receptor antagonists and memantine treatment for Alzheimer's disease, vascular dementia and PD. Current Alzheimer Research. 2012;**9**:746-758. DOI: 10.2174/156720 512801322564

[65] Ribeiro H, Sarmento-Ribeiro AB, Andrade JP, Dourado M. Apoptosis and (in) pain—potential clinical implications. Biomedicine. 2022;**10**:1255. DOI: 10.3390/biomedicines10061255

[66] Andringa G, Eshuis S, Perentes E, Maguire RP, Roth D, Ibrahim M, et al. TCH346 prevents motor symptoms and loss of striatal FDOPA uptake in bilaterally MPTP-treated primates. Neurobiology of Disease. 2003;**14**:205-217. DOI: 10.1016/ S0969-9961(03)00125-6

[67] Grotegut P, Perumal N, Kuehn S, Smit A, Dick HB, Grus FH, et al. Minocycline reduces inflammatory response and cell death in a S100B retina degeneration model. Journal of Neuroinflammation. 2020;**17**:375. DOI: 10.1186/s12974-020-02012-y

[68] Kumar H, Lim H-W, More SV, Kim B-W, Koppula S, Kim IS, et al. The role of free radicals in the aging brain and PD: Convergence and parallelism. International Journal of Molecular

Sciences. 2012;**13**:10478-10504. DOI: 10.3390/ijms130810478

[69] Lin M-W, Lin CC, Chen Y-H, Yang H-B, Hung S-Y. Celastrol inhibits dopaminergic neuronal death of PD through activating mitophagy. Antioxidants. 2020;**9**:37. DOI: 10.3390/ antiox9010037

[70] Sechi G, Deledda MG, Bua G, Satta WM, Deiana GA, Pes GM, et al. Reduced intravenous glutathione in the treatment of early PD. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1996;**20**: 1159-1170. DOI: 10.1016/S0278-5846 (96)00103-0

[71] Duty S, Jenner P. Animal models of PD: A source of novel treatments and clues to the cause of the disease. British Journal of Pharmacology. 2011;**164**(4):1357-1391. DOI: 10.1111/j. 1476-5381.2011.01426.x

[72] Lees AJ, Tolosa E, Olanow CW. Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr. Movement Disorders. 2015;*30*(1):19-36. DOI: 10.1002/mds.26120

[73] Ungerstedt U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. European Journal of Pharmacology. 1968;**5**:107-110

[74] Fernandez HH, Chen JJ. Monoamine oxidase-B inhibition in the treatment of Parkinson's disease. Pharmacotherapy. 2007;**27**:174S-185S

[75] Lees AJ. Dopamine agonists in Parkinson's disease: A look at apomorphine. Fundamental & Clinical Pharmacology. 1993;**7**:121-128

[76] Rondot P, Ziegler M. Activity and acceptability of piribedil in Parkinson's disease: A multicentre study. Journal of Neurology. 1992;**239**(Suppl. 1):S28-S34

[77] Montastruc JL, Rascol O, Senard JM. Current status of dopamine agonists in Parkinson's disease management. Drugs. 1993;**46**:384-393

[78] Elangbam CS. Drug-induced valvulopathy: An update. Toxicologic Pathology. 2010;**38**:837-848

[79] Bonuccelli U, Del DP, Rascol O. Role of dopamine receptor agonists in the treatment of early Parkinson's disease. Parkinsonism & Related Disorders. 2009;**15**(Suppl. 4):S44-S53

[80] Jenner P. The rationale for the use of dopamine agonists in Parkinson's disease. *Neurology*. 1995;**45**:S6-S12

[81] Carlsson A, Lindqvist M, Magnusson T. 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature. 1957;**180**:1200

[82] Degkwitz R, Frowein R, Kulenkampff C, et al. Uber die Wirkungen von L-DOPA beim Menschen und deren Beeinflussung durch Reserpin, Chlorpromazin, Ipronazid und Vitamin B6. Klinische Wochenschrift. 1960;**38**:120-123

[83] Jellinger KA. Pathology of Parkinson's disease. Changes other than the nigrostriatal pathway. Molecular and Chemical Neuropathology. 1991;**14**:153-197

[84] Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;**219**:979-980

[85] Jenner P, Rupniak NM, Rose S, Kelly E, Kilpatrick G, Lees A, et al. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridineinduced parkinsonism in the common

*Parkinson's Disease: A Comprehensive Overview of the Disease DOI: http://dx.doi.org/10.5772/intechopen.109437*

marmoset. Neuroscience Letters. 1984;**50**:85-90

[86] Johannessen JN, Chiueh CC, Burns RS, Markey SP. Differences in the metabolism of MPTP in the rodent and primate parallel differences in sensitivity to its neurotoxic effects. Life Sciences. 1985;**36**:219-224

[87] Riachi NJ, LaManna JC, Harik SI. Entry of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine into the rat brain. Journal of Pharmacology and Experimental Therapeutics. 1989;**249**:744-748. [PubMed] [Google Scholar]

[88] Chiba K, Trevor A, Castagnoli N Jr. Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochemical and Biophysical Research Communications. 1984;**120**:574-578

[89] Javitch JA, D'Amato RJ, Strittmatter SM, Snyder SH. Parkinsonism-inducing neurotoxin, *N*-methyl-4-phenyl-1,2,3,6 tetrahydropyridine: Uptake of the metabolite *N*-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proceedings of the National Academy of Sciences of the United States of America. 1985;**82**:2173-2177

[90] Karunakaran S, Saeed U, Mishra M, Valli RK, Joshi SD, Meka DP, et al. Selective activation of p38 mitogenactivated protein kinase in dopaminergic neurons of substantia nigra leads to nuclear translocation of p53 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinetreated mice. The Journal of Neuroscience. 2008;**28**:12500-12509

[91] Saporito MS, Thomas BA, Scott RW. MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons

in vivo. Journal of Neurochemistry. 2000;**75**:1200-1208

[92] Tatton NA, Kish SJ. In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining. Neuroscience. 1997;**77**:1037-1048

[93] Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neuroscience. 2000;**3**:1301-1306

[94] Greenamyre JT, Cannon JR, Drolet R, Mastroberardino PG. Lessons from the rotenone model of Parkinson's disease. Trends in Pharmacological Sciences. 2010;**31**:141-142. author reply 142-143

[95] Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, et al. Mechanism of toxicity in rotenone models of Parkinson's disease. The Journal of Neuroscience. 2003;**23**:10756-10764

[96] Alam ZI, Daniel SE, Lees AJ, Marsden DC, Jenner P, Halliwell B. A generalised increase in protein carbonyls in the brain in Parkinson's but not incidental Lewy body disease. Journal of Neurochemistry. 1997;**69**:1326-1329. DOI: 10.1046/j.1471-4159.1997.69031326.x

[97] Sherer TB, Betarbet R, Kim JH, Greenamyre JT. Selective microglial activation in the rat rotenone model of Parkinson's disease. Neuroscience Letters. 2003;**341**:87-90

[98] Tansey MG, Goldberg MS. Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention. Neurobiology of Disease. 2010;**37**:510-518

[99] Wang XF, Li S, Chou AP, Bronstein JM. Inhibitory effects of pesticides on proteasome activity: Implication in Parkinson's disease. Neurobiology of Disease. 2006;**23**:198-205

[100] Ascherio A, Chen H, Weisskopf MG, O'Reilly E, McCullough ML, Calle EE, et al. Pesticide exposure and risk for Parkinson's disease. Annals of Neurology. 2006;**60**:197-203

[101] Costello S, Cockburn M, Bronstein J, Zhang X, Ritz B. Parkinson's disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. American Journal of Epidemiology. 2009;**169**:919-926

[102] Shimizu K, Ohtaki K, Matsubara K, Aoyama K, Uezono T, Saito O, et al. Carrier-mediated processes in blood– brain barrier penetration and neural uptake of paraquat. Brain Research. 2001;**906**:135-142

[103] Miller GW. Paraquat: The red herring of Parkinson's disease research. Toxicological Sciences. 2007;**100**:1-2

[104] Zhang J, Fitsanakis VA, Gu G, Jing D, Ao M, Amarnath V, et al. Manganese ethylene-bis-dithiocarbamate and selective dopaminergic neurodegeneration in rat: A link through mitochondrial dysfunction. Journal of Neurochemistry. 2003;**84**:336-346

[105] Thiruchelvam M, Brockel BJ, Richfield EK, Baggs RB, Cory-Slechta DA. Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: Environmental risk factors for Parkinson's disease? Brain Research. 2000;**873**:225-234

[106] Barlow BK, Thiruchelvam MJ, Bennice L, Cory-Slechta DA, Ballatori N, Richfield EK. Increased synaptosomal dopamine content and brain

concentration of paraquat produced by selective dithiocarbamates. Journal of Neurochemistry. 2003;**85**:1075-1086

[107] Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alphasynuclein gene identified in families with Parkinson's disease. Science. 1997;**276**:2045-2047

[108] Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;**392**:605-608

[109] Bonifati V, Rizzu P, Van Baren MJ, Schaap O, Breedveld GJ, Krieger E, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism. Science. 2002;**299**:256-259

[110] Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004;**304**:1158-1160

[111] Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. Mutations in LRRK2 cause autosomaldominant parkinsonism with pleomorphic pathology. Neuron. 2004;**44**:601-607

[112] Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, et al. The ubiquitin pathway in Parkinson's disease. Nature. 1998;**395**:451-452

[113] Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Human Molecular Genetics. 2005;**14**:2099-2111

[114] Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal

*Parkinson's Disease: A Comprehensive Overview of the Disease DOI: http://dx.doi.org/10.5772/intechopen.109437*

type 5 P-type ATPase. Nature Genetics. 2006;**38**:1184-1191

[115] Lakso M, Vartiainen S, Moilanen AM, Sirvio J, Thomas JH, Nass R, et al. Dopaminergic neuronal loss and motor deficits in *Caenorhabditis elegans* overexpressing human alphasynuclein. Journal of Neurochemistry. 2003;**86**:165-172

[116] Lim K-L, Ng C-H. Genetic models of Parkinson disease. Biochimica et Biophysica Acta. 2009;**1792**:604-615

[117] Cannon JR, Greenamyre JT. Geneenvironment interactions in Parkinson's disease: Specific evidence in humans and mammalian models. Neurobiology of Disease. 2013;**57**:38-46. DOI: 10.1016/j. nbd.2012.06.025

[118] Pardridge WM. The blood-brain barrier: Bottleneck in brain drug development. NeuroRx. 2005;**2**:3-14

[119] Furuno T, Landi MT, Ceroni M, Caporaso N, Bernucci I, Nappi G, et al. Expression polymorphism of the bloodbrain barrier component P-glycoprotein (MDR1) in relation to Parkinson's disease. Pharmacogenetics. 2002;**12**(7):529-534. DOI: 10.1097/ 00008571-200210000-00004 PMID: 12360103

[120] Tan EK, Chan DK, Ng PW, Woo J, Teo YY, Tang K, et al. Effect of MDR1 haplotype on risk of Parkinson disease. Archives of Neurology. 2005;**62**(3):460- 464. DOI: 10.1001/archneur.62.3.460 PMID: 15767512

[121] Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Annals of Neurology. 2005;**57**(2):176-179. DOI: 10.1002/ ana.20369 PMID: 15668963

[122] Bartels AL, van Berckel BN, Lubberink M, Luurtsema G, Lammertsma AA, Leenders KL. Bloodbrain barrier P-glycoprotein function is not impaired in early Parkinson's disease. Parkinsonism & Related Disorders. 2008;**14**(6):505-508. DOI: 10.1016/j. parkreldis.2007.11.007. Epub 2008 Mar 5. PMID: 18325822

[123] Westerlund M, Belin AC, Olson L, Galter D. Expression of multi-drug resistance 1 mRNA in human and rodent tissues: Reduced levels in Parkinson patients. Cell and Tissue Research Nov 2008;**334**(2):179-185. DOI: 10.1007/ s00441-008-0686-5. Epub 2008 Oct 15. PMID: 18855017

[124] Schinkel AH, Wagenaar E, Mol CA, van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. The Journal of Clinical Investigation. 1996;**1;97**(11):2517- 2524. DOI: 10.1172/JCI118699. PMID: 8647944; PMCID: PMC507337

[125] Erekat N, Al Khatib A, Al-Jarrah M. Endurance exercise training attenuates the up regulation of iNOS in the skeletal muscles of chronic/progressive mouse model of Parkinson's disease. Journal of Neurology Research. 2013;**3**(3-4):108-113

[126] Erekat N, Al-Khatib A, Al-Jarrah M. Heat shock protein 90 is a potential therapeutic target for ameliorating skeletal muscle abnormalities in Parkinson's disease. Neural Regeneration Research. 2014;**9**(6):616-621

[127] Al-Jarrah M, Obaidat H, Bataineh Z, Walton L, Al-Khateeb A. Endurance exercise training protects against the upregulation of nitric oxide in the striatum of MPTP/probenecid mouse model of Parkinson's disease. NeuroRehabilitation. 2013;**32**(1):141-147. DOI: 10.3233/NRE-130831. PMID: 23422467

## **Chapter 2**
