Preface

Neuroprotection is a key approach to maintaining brain health to prevent the retraction of synapses, accumulation of neurodegenerative proteins (tau, β-amyloid peptide, α-synuclein, huntingtin, or any misfolded proteins), activation of neuroinflammation, or even the breakdown of the blood-brain barrier. Neuroprotection can be applied to chronic neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Lewy's body diseases, Huntington's disease, amyotrophic lateral sclerosis, or even brain tumors), acute neurological disorders (brain trauma, stroke, transient ischemia, epilepsy, or cerebral hemorrhage), or even mental disorders (psychosis, depression, or schizophrenia). The traditional view of neuroprotection is often restricted to the use of agonists or antagonists of neurotransmitter receptors. While this is still a great approach to safeguard neurons, neuroprotection strategy is not limited to modulating neurotransmitter receptors. Neuroprotection can be accomplished by (1) natural products, (2) herbal medicine, (3) different forms of exercise, (4) learning new skills or languages, or (5) even good sleeping patterns. From all these new perspectives, the concept of neuroprotection is limited not only to the protection of neurons in the pathogenesis of diseases but also to the prevention of any detrimental factors leading to neuronal cell loss.

The major aim of this book is to focus on different approaches to achieve neuroprotection. In this book, most of our authors review the advantages of neurotransmitter receptors. Mititelu-Tartau and Bogdan's group reviews the imidazoline ligands and opioid ligands in Alzheimer's disease. They review the neuroprotective effects of agmatine on memory. In addition, they also summarize the findings of using different opioid receptor ligands to elicit neuroprotection. Similarly, Yanuar's group reviews the beneficial effects of the adenosine A2A receptor antagonist. It has been reported that the adenosine receptor antagonist elicits neuroprotective effects, partially because of its signaling pathways to activate the cytosolic fraction of cAMP. Yanuar's group reviews how A2A antagonists provide neuroprotection.

Apart from modulating neurotransmitter receptors, Flood's group reviews another very important pathological factor leading to neurodegeneration: neuroinflammation. Microglial cells are the major line of cells to be activated to produce cytokines and free radicals to damage neurons. Interestingly, Flood's group reviews how different adrenergic receptor agonists and antagonists modulate microglial responses. This independent review suggests that modulation of neuroinflammation can also be achieved by intervening neurotransmitter receptors and their associated signaling events.

Neuroprotection can be disease specific but use different approaches. Nian and Lo review the neuroprotection of aging eyes, in which aging-associated macular degeneration often occurs in the elderly. With the progression of the disease and identification of biological targets at different states of the disease, the strategy of neuroprotection can be changed.

Taken together, neuroprotection receives increasing attention from different approaches in different states of neurodegenerative diseases, acute neurological disorders, and even mental disorders. Even in disease progression, neuroprotection can prevent the spread of neuronal damage or neuronal loss from one region to other regions. This book will give insights to scientists in the field to stimulate their research, medical professionals to review their clinical practices, and others who would like to learn more about different neuroprotective approaches.

#### **Raymond Chuen-Chung Chang, PhD**

Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong

#### **Yuen-Shan Ho, PhD**

**1**

Section 1

Neurotransmitter

Receptor as Target for

Neuroprotection

School of Nursing, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong Section 1

Neurotransmitter Receptor as Target for Neuroprotection

**3**

**Chapter 1**

Perspective

even stop progressive neurodegeneration.

**1. Introduction**

neuroprotection.

genetic approaches (**Figure 1**).

Introductory Chapter: Concept

Neuroprotection is an approach to preserve neurons so that neurons cannot be hurt by different pathological factors in neurodegenerative diseases. It can be an approach before the onset of the disease so that neurons cannot be affected by any risk factors. It can also be an approach during the progression of the disease to prevent spreading of injury from one neuron to neighboring neurons. Therefore, neuroprotection can also be one approach as "disease-modifying agent" to delay and

The concept of neuroprotection has long been confined to intervene neurotransmitter receptors via agonists and antagonists. A very well-known example is the neuroprotective effect of caffeine via adenosine receptor, because caffeine is an A2 receptor antagonist. Caffeine can exert neuroprotection via adenosine A2 receptor to protect dopaminergic neurons in an experimental model of Parkinson's disease (PD) by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a toxin agent [1]. Therefore, drinking coffee has been considered to be neuroprotection. Apart from adenosine receptor on neurons, it is now known that microglial cells also express A2 receptor, and A2 receptor antagonist or caffeine can reduce activation of microglial cells [2]. Since caffeine or A2 receptor antagonists can protect neurons and minimize activation of microglial cells, research is still very active in this direction. Indeed, investigation of other neurotransmitter receptor antagonists, agonists, blockers, or even partial blockers is still a very active research area in

While it is exciting to reveal differential neuroprotective effects via modulating receptors for different neurotransmitters, we should not restrict ourselves to this perspective only. In fact, a wider scope of neuroprotection has been evolved. The concept of neuroprotection can now be categorized into three groups: (A) pharmacological intervention, (B) non-pharmacological intervention, and (C) cellular and

In group A neuroprotective approaches, pharmacological intervention includes modulation of neurotransmitter receptors (as introduced above), anti-oxidative stress, and anti-inflammatory responses [3]. These are classical pharmacological approaches. These methods have been explored for decades and can be used for both neuroprotection and as disease-modifying agents. Their effects can be target-specific for one single protein (e.g., receptor for neurotransmitter or one type of cytokines) or pathway-specific (anti-oxidative responses using nuclear factor erythroid 2-related factor 2, Nrf2). Since single biological target may limit the beneficial effects and may not be able to intervene the complexity of the disease

of Neuroprotection - A New

*Raymond Chuen-Chung Chang and Yuen-Shan Ho*

#### **Chapter 1**

## Introductory Chapter: Concept of Neuroprotection - A New Perspective

*Raymond Chuen-Chung Chang and Yuen-Shan Ho*

#### **1. Introduction**

Neuroprotection is an approach to preserve neurons so that neurons cannot be hurt by different pathological factors in neurodegenerative diseases. It can be an approach before the onset of the disease so that neurons cannot be affected by any risk factors. It can also be an approach during the progression of the disease to prevent spreading of injury from one neuron to neighboring neurons. Therefore, neuroprotection can also be one approach as "disease-modifying agent" to delay and even stop progressive neurodegeneration.

The concept of neuroprotection has long been confined to intervene neurotransmitter receptors via agonists and antagonists. A very well-known example is the neuroprotective effect of caffeine via adenosine receptor, because caffeine is an A2 receptor antagonist. Caffeine can exert neuroprotection via adenosine A2 receptor to protect dopaminergic neurons in an experimental model of Parkinson's disease (PD) by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a toxin agent [1]. Therefore, drinking coffee has been considered to be neuroprotection. Apart from adenosine receptor on neurons, it is now known that microglial cells also express A2 receptor, and A2 receptor antagonist or caffeine can reduce activation of microglial cells [2]. Since caffeine or A2 receptor antagonists can protect neurons and minimize activation of microglial cells, research is still very active in this direction. Indeed, investigation of other neurotransmitter receptor antagonists, agonists, blockers, or even partial blockers is still a very active research area in neuroprotection.

While it is exciting to reveal differential neuroprotective effects via modulating receptors for different neurotransmitters, we should not restrict ourselves to this perspective only. In fact, a wider scope of neuroprotection has been evolved. The concept of neuroprotection can now be categorized into three groups: (A) pharmacological intervention, (B) non-pharmacological intervention, and (C) cellular and genetic approaches (**Figure 1**).

In group A neuroprotective approaches, pharmacological intervention includes modulation of neurotransmitter receptors (as introduced above), anti-oxidative stress, and anti-inflammatory responses [3]. These are classical pharmacological approaches. These methods have been explored for decades and can be used for both neuroprotection and as disease-modifying agents. Their effects can be target-specific for one single protein (e.g., receptor for neurotransmitter or one type of cytokines) or pathway-specific (anti-oxidative responses using nuclear factor erythroid 2-related factor 2, Nrf2). Since single biological target may limit the beneficial effects and may not be able to intervene the complexity of the disease

#### **Figure 1.**

*A summary of different neuroprotective approaches.*

progression, neuroprotective effects from herbal medicine or natural products receive increasing attention in scientific research because of their multiple effects on different biological targets [4–6]. For example, it has been shown that triterpenoids extracted from *Prunella vulgaris* has anti-inflammatory effects [7]. We have proved that polysaccharide part of *Prunella vulgaris* can modulate the immune responses of microglia and macrophages [8, 9]. Therefore, *Prunella vulgaris* exerts neuroprotection toward neurodegenerative diseases against neuroinflammation.

In group B neuroprotective approaches, non-pharmacological approaches receive increasing attention. Since it is quite difficult to ask a healthy adult or even elderly to constantly take medicine even though it is herbal, non-pharmacological approaches to earn neuroprotection are most welcome. Among these different methods, exercise is the best to prevent nearly all kinds of diseases. Exercise can be further divided into aerobic and resistance exercises, in which aerobic exercise is suitable for motor-healthy adults or elderly. However, there is a large population of elderly who have difficulty in their motor functions. Resistance exercise becomes an excellent tool for them. Both aerobic and resistance exercises can affect the metabolisms of the body and induce trophic factors like myokines, released from muscles and liver [10, 11]. Since body metabolism is important, diet control is also important to reduce any risk factors leading to the development of neurodegenerative diseases, such as diabetes, hyperlipidemia, or hypercholesterolemia. All of these risk factors are related to vascular components, which may further add on vascular dementia [12–14]. Apart from exercise, it is well-known that, maintaining social activity is essential to keep our brain healthy [15]. In addition, sleeping can promote clearing of pathological factors, such as β-amyloid (Aβ) peptide and phosphorylated tau protein [16, 17]. Also, it has been recently shown that learning second language or bilingualism can be neuroprotective [18]. Furthermore, increasing lines of evidence have shown that acupuncture can help adjusting the body metabolism and immunity [18, 19]. Therefore, acupuncture can also be considered to be one method in non-pharmacological approaches. One key point should be noticed that all these neuroprotective approaches are multiple targets. This may be why they are so effective in minimizing neurodegeneration to preserve neurons.

Neuroprotective approaches in group C are the new extension of multiple effects from trophic factors secreted by genetically engineered cells or viral vector. Alternatively, stimulating the proliferation and differentiation of endogenous stem

**5**

*Introductory Chapter: Concept of Neuroprotection - A New Perspective*

cells, application of induced pluripotent stem cells (iPSC), or mesenchymal stem cells are popular trends in scientific research to prevent neurodegeneration and

**2. Neuroprotective effects of herbal medicine and natural products**

we have investigated polysaccharides extracted from different herbs [23].

more potent antioxidants are required to provide neuroprotection.

In experimental PD using 6-hydroxydopamine (6-OHDA) as toxin agent, we employed oxyresveratrol, which is a natural product but a structural analog of resveratrol, and found that it can attenuate neurodegeneration [35, 36]. For this kind of neurodegenerative disease requiring high levels and high capacity of antioxidant, another method is to employ pro-drug approach so that oxidant cleave the precursor and the product becomes potent antioxidant. Interestingly, polyphenol (-)-epigallocatechin-3-gallate (EGCG) from green tea falls in this category [37]. The advantages of using herbal medicine or natural products are to make use of their multiple effects. In neurodegenerative diseases, a wide array of stress responses is stimulated because of free radicals or accumulation of misfolded or

We have first found that polysaccharides from *Nerium indicum* exert neuroprotective effects against β-amyloid (Aβ) neurotoxicity cultured neurons [24, 25]. Then, we also found that neuroprotective effects of *Verbena officinalis* and *Ganoderma lucidum* [26, 27]. Having investigated different herbal medicine, we found that the polysaccharides from *Lycium barbarum* (Wolfberry) are potent [28, 29]. Polysaccharides can be extracted in hot water or from alkaline condition and elicit neuroprotection [30]. It should be noted that not all polysaccharides, but only some sub-fractions provide neuroprotective effects. Apart from neurons in the brain, polysaccharides from wolfberry can also protect the retina against experimental glaucoma and stroke [31–33]. As harvesting and planting processes have good agricultural practice and the extraction can be done under stringent control of good manufacturing practice, we choose wolfberry as our long-term study. Wolfberry is indeed an anti-aging Chinese herbal medicine. We would like to understand the concept of "anti-aging." Therefore, we have investigated its application in different aging-associated neurodegenerative diseases [34]. In fact, not all aging-associated neurodegenerative diseases can be attenuated by the polysaccharide fraction of Wolfberry. In Parkinson's disease (PD),

Since there are several chapters about the effects of neurotransmitter receptors, we will focus on some neuroprotective approaches only, as this is an introductory

This direction of neuroprotection is the most controversial approach among different pharmacological tools. This is because most of the herbal medicine or natural products have a wide array of effects. If we use traditional way of thinking to target a specific protein or signaling pathway, herbal medicine fails to do so. However, if we are aware of neurodegenerative diseases that are usually multifactorial, we can then accept that herbal medicine should be the direction to prevent neuronal loss and spreading of neurodegeneration. Our group has long been working on discovering herbal medicine as neuroprotective agents and investigating their underlying mechanisms. Since most of the herbal medicines are in decoction form, for oral consumption, the effective components in different herbs are not limited to one single chemical. The small molecules being extracted from one herb can also be found from other herbs. There are many laboratories investigating those small molecules and have Research and Development (R&D) to be commercial products. In contrast, big molecules such as polysaccharides have been an unexplored area. In fact, a large portion of components from herbs is polysaccharides. When we use hot water to prepare decoction, what we can easily absorb is polysaccharides. Therefore,

*DOI: http://dx.doi.org/10.5772/intechopen.85631*

neuronal loss [20–22].

chapter.

*Neuroprotection*

**Figure 1.**

*A summary of different neuroprotective approaches.*

progression, neuroprotective effects from herbal medicine or natural products receive increasing attention in scientific research because of their multiple effects on different biological targets [4–6]. For example, it has been shown that triterpenoids extracted from *Prunella vulgaris* has anti-inflammatory effects [7]. We have proved that polysaccharide part of *Prunella vulgaris* can modulate the immune responses of microglia and macrophages [8, 9]. Therefore, *Prunella vulgaris* exerts neuroprotection toward neurodegenerative diseases against neuroinflammation. In group B neuroprotective approaches, non-pharmacological approaches receive increasing attention. Since it is quite difficult to ask a healthy adult or even elderly to constantly take medicine even though it is herbal, non-pharmacological approaches to earn neuroprotection are most welcome. Among these different methods, exercise is the best to prevent nearly all kinds of diseases. Exercise can be further divided into aerobic and resistance exercises, in which aerobic exercise is suitable for motor-healthy adults or elderly. However, there is a large population of elderly who have difficulty in their motor functions. Resistance exercise becomes an excellent tool for them. Both aerobic and resistance exercises can affect the metabolisms of the body and induce trophic factors like myokines, released from muscles and liver [10, 11]. Since body metabolism is important, diet control is also important to reduce any risk factors leading to the development of neurodegenerative diseases, such as diabetes, hyperlipidemia, or hypercholesterolemia. All of these risk factors are related to vascular components, which may further add on vascular dementia [12–14]. Apart from exercise, it is well-known that, maintaining social activity is essential to keep our brain healthy [15]. In addition, sleeping can promote clearing of pathological factors, such as β-amyloid (Aβ) peptide and phosphorylated tau protein [16, 17]. Also, it has been recently shown that learning second language or bilingualism can be neuroprotective [18]. Furthermore, increasing lines of evidence have shown that acupuncture can help adjusting the body metabolism and immunity [18, 19]. Therefore, acupuncture can also be considered to be one method in non-pharmacological approaches. One key point should be noticed that all these neuroprotective approaches are multiple targets. This may be why they are

so effective in minimizing neurodegeneration to preserve neurons.

Neuroprotective approaches in group C are the new extension of multiple effects from trophic factors secreted by genetically engineered cells or viral vector. Alternatively, stimulating the proliferation and differentiation of endogenous stem

**4**

cells, application of induced pluripotent stem cells (iPSC), or mesenchymal stem cells are popular trends in scientific research to prevent neurodegeneration and neuronal loss [20–22].

Since there are several chapters about the effects of neurotransmitter receptors, we will focus on some neuroprotective approaches only, as this is an introductory chapter.

#### **2. Neuroprotective effects of herbal medicine and natural products**

This direction of neuroprotection is the most controversial approach among different pharmacological tools. This is because most of the herbal medicine or natural products have a wide array of effects. If we use traditional way of thinking to target a specific protein or signaling pathway, herbal medicine fails to do so. However, if we are aware of neurodegenerative diseases that are usually multifactorial, we can then accept that herbal medicine should be the direction to prevent neuronal loss and spreading of neurodegeneration. Our group has long been working on discovering herbal medicine as neuroprotective agents and investigating their underlying mechanisms. Since most of the herbal medicines are in decoction form, for oral consumption, the effective components in different herbs are not limited to one single chemical. The small molecules being extracted from one herb can also be found from other herbs. There are many laboratories investigating those small molecules and have Research and Development (R&D) to be commercial products. In contrast, big molecules such as polysaccharides have been an unexplored area. In fact, a large portion of components from herbs is polysaccharides. When we use hot water to prepare decoction, what we can easily absorb is polysaccharides. Therefore, we have investigated polysaccharides extracted from different herbs [23].

We have first found that polysaccharides from *Nerium indicum* exert neuroprotective effects against β-amyloid (Aβ) neurotoxicity cultured neurons [24, 25]. Then, we also found that neuroprotective effects of *Verbena officinalis* and *Ganoderma lucidum* [26, 27]. Having investigated different herbal medicine, we found that the polysaccharides from *Lycium barbarum* (Wolfberry) are potent [28, 29]. Polysaccharides can be extracted in hot water or from alkaline condition and elicit neuroprotection [30]. It should be noted that not all polysaccharides, but only some sub-fractions provide neuroprotective effects. Apart from neurons in the brain, polysaccharides from wolfberry can also protect the retina against experimental glaucoma and stroke [31–33]. As harvesting and planting processes have good agricultural practice and the extraction can be done under stringent control of good manufacturing practice, we choose wolfberry as our long-term study. Wolfberry is indeed an anti-aging Chinese herbal medicine. We would like to understand the concept of "anti-aging." Therefore, we have investigated its application in different aging-associated neurodegenerative diseases [34]. In fact, not all aging-associated neurodegenerative diseases can be attenuated by the polysaccharide fraction of Wolfberry. In Parkinson's disease (PD), more potent antioxidants are required to provide neuroprotection.

In experimental PD using 6-hydroxydopamine (6-OHDA) as toxin agent, we employed oxyresveratrol, which is a natural product but a structural analog of resveratrol, and found that it can attenuate neurodegeneration [35, 36]. For this kind of neurodegenerative disease requiring high levels and high capacity of antioxidant, another method is to employ pro-drug approach so that oxidant cleave the precursor and the product becomes potent antioxidant. Interestingly, polyphenol (-)-epigallocatechin-3-gallate (EGCG) from green tea falls in this category [37].

The advantages of using herbal medicine or natural products are to make use of their multiple effects. In neurodegenerative diseases, a wide array of stress responses is stimulated because of free radicals or accumulation of misfolded or

badly folded proteins. Most of the herbal medicine and natural products attenuate many stress kinases. They may not be a good candidate to clear accumulation of bad proteins; however, they can inhibit the cascades of stress responses (e.g., activation of c-Jun-N-terminal kinase, JNK; endoplasmic reticulum stress pathways), which usually lead to neuronal apoptosis. Some of the herbal medicine or natural products can even strengthen the survival signaling pathways such as mTOR or Akt pathways.

In addition to their direct effects on neurons, there are many herbal medicine or natural products that can modulate body immune responses. For example, polysaccharides fraction from *Prunella vulgaris* L. can modulate innate immune responses of macrophages [8, 9]. It has been increasingly aware that activation of body (systemic) immune responses are the origin of our sickness responses leading to low appetites and even fever [38]. Long-term effects of systemic immune responses can even result in psychological depression or acute delirium [39]. Experimentally, we have shown that infection in the body or immune responses triggered by surgery (laparotomy) can modulate cognitive functions because of stimulation of neuroimmune responses [40, 41]. Therefore, modulation of body immunity can be a powerful method to minimize neuroimmune responses and then reduce cognitive dysfunctions.

#### **3. Aerobic and resistance exercises**

As emphasized above, the advantages of herbal medicine and natural products are their multiples and wide array effects. Similarly, exercise is another method to achieve this goal. Exercise can stimulate production of different trophic/growth factors, e.g., vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), peroxisome proliferatoractivated receptor gamma coactivator-1α (PGC-1α)/neuronal fibronectin type III domain-containing protein 5 (FNDC5). Some trophic factors can be secreted by muscles or liver, which is collectively called myokines. It has been shown that muscle cells can produce PGC-1α, irisin, cathepsin B, myostatin (growth differentiation factor 8), fibroblast growth factor 21 (FGF-21), IL-6, IL-15, myonectin, and SPARC (osteonectin) as novel brain-beneficial myokines [10, 42]. Some of them, such as FGF21, can also be secreted by the liver or even in the brain upon exercise [43]. They all can affect muscle, liver, adipose tissues, and brain cells, leading to preservation of cognitive functions, modulating the lipid metabolism, and immune responses [44]. This kind of myokine can pass through the blood-brain barrier.

For motor-healthy subject, aerobic exercise is beneficial to majority of people. As discussed above, myokines can be induced so that they provide neuroprotective effects to the brain and attenuate any systemic immune responses. While aerobic exercise is known to be good, a great number of elderly and demented patients could not enjoy the benefit of aerobic exercise. Those patients may have prior knee replacement or fall down hurting the legs. They may be lying down on the bed. No matter how we advocate the beneficial effects of aerobic exercise, this will not be beneficial to this group of patients. Does it mean that they will not have any beneficial effects of exercise? This question leads us to investigate the beneficial effects of resistance exercise.

In a systematic review, aerobic exercise shows beneficial effects on cognitive functions and executive functions, which is better than that from resistance exercise [45]. Furthermore, aerobic exercise seems to elicit strong anti-inflammatory effect than that of resistance exercise [46]. However, resistance exercise seems to particularly increase the volume of hippocampus [47]. A study in laboratory animal

**7**

**Author details**

provided the original work is properly cited.

Hong Kong, Pokfulam, Hong Kong SAR

Raymond Chuen-Chung Chang1,2\* and Yuen-Shan Ho3

the way for our effective neuroprotective strategies.

University of Hong Kong, Pokfulam, Hong Kong SAR

Polytechnic University, Kowloon, Hong Kong SAR

\*Address all correspondence to: rccchang@hku.hk

*Introductory Chapter: Concept of Neuroprotection - A New Perspective*

has shown that aerobic exercise can markedly increase BDNF; whereas, resistance exercise can significantly increase IGF-1 [48]. Although resistance exercise may have some limitations, this is still a good choice for those elderly and dementia patients to have this form of exercise. IGF-1 can still elicit multiple functions in the

Since this is an introductory chapter, we do not intend to discuss every single method of neuroprotection in detail. We should keep in mind that neurodegenerative diseases are multiple-hit processes. Therefore, no single biological target can afford all neuroprotective needs. Approaches in using herbal medicine and natural products remind us that multiple biological targets may be the way to exert effective neuroprotection. Therefore, any non-pharmacological approaches including exercise and even the new stem cell approaches exert multiple effects. This can be

*DOI: http://dx.doi.org/10.5772/intechopen.85631*

brain to preserve neurons.

**4. Concluding remarks**

© 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,

1 Laboratory of Neurodegenerative Diseases, LKS Faculty of Medicine, The

2 State Key Laboratory of Brain and Cognitive Sciences, The University of

3 Faculty of Health and Social Sciences, School of Nursing, The Hong Kong

*Introductory Chapter: Concept of Neuroprotection - A New Perspective DOI: http://dx.doi.org/10.5772/intechopen.85631*

has shown that aerobic exercise can markedly increase BDNF; whereas, resistance exercise can significantly increase IGF-1 [48]. Although resistance exercise may have some limitations, this is still a good choice for those elderly and dementia patients to have this form of exercise. IGF-1 can still elicit multiple functions in the brain to preserve neurons.

#### **4. Concluding remarks**

*Neuroprotection*

pathways.

dysfunctions.

**3. Aerobic and resistance exercises**

badly folded proteins. Most of the herbal medicine and natural products attenuate many stress kinases. They may not be a good candidate to clear accumulation of bad proteins; however, they can inhibit the cascades of stress responses (e.g., activation of c-Jun-N-terminal kinase, JNK; endoplasmic reticulum stress pathways), which usually lead to neuronal apoptosis. Some of the herbal medicine or natural products can even strengthen the survival signaling pathways such as mTOR or Akt

In addition to their direct effects on neurons, there are many herbal medicine or natural products that can modulate body immune responses. For example, polysaccharides fraction from *Prunella vulgaris* L. can modulate innate immune responses of macrophages [8, 9]. It has been increasingly aware that activation of body

(systemic) immune responses are the origin of our sickness responses leading to low appetites and even fever [38]. Long-term effects of systemic immune responses can even result in psychological depression or acute delirium [39]. Experimentally, we have shown that infection in the body or immune responses triggered by surgery (laparotomy) can modulate cognitive functions because of stimulation of neuroimmune responses [40, 41]. Therefore, modulation of body immunity can be a powerful method to minimize neuroimmune responses and then reduce cognitive

As emphasized above, the advantages of herbal medicine and natural products are their multiples and wide array effects. Similarly, exercise is another method to achieve this goal. Exercise can stimulate production of different trophic/growth factors, e.g., vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), peroxisome proliferatoractivated receptor gamma coactivator-1α (PGC-1α)/neuronal fibronectin type III domain-containing protein 5 (FNDC5). Some trophic factors can be secreted by muscles or liver, which is collectively called myokines. It has been shown that muscle cells can produce PGC-1α, irisin, cathepsin B, myostatin (growth differentiation factor 8), fibroblast growth factor 21 (FGF-21), IL-6, IL-15, myonectin, and SPARC (osteonectin) as novel brain-beneficial myokines [10, 42]. Some of them, such as FGF21, can also be secreted by the liver or even in the brain upon exercise [43]. They all can affect muscle, liver, adipose tissues, and brain cells, leading to preservation of cognitive functions, modulating the lipid metabolism, and immune responses [44]. This kind of myokine can pass through the blood-brain barrier. For motor-healthy subject, aerobic exercise is beneficial to majority of people. As discussed above, myokines can be induced so that they provide neuroprotective effects to the brain and attenuate any systemic immune responses. While aerobic exercise is known to be good, a great number of elderly and demented patients could not enjoy the benefit of aerobic exercise. Those patients may have prior knee replacement or fall down hurting the legs. They may be lying down on the bed. No matter how we advocate the beneficial effects of aerobic exercise, this will not be beneficial to this group of patients. Does it mean that they will not have any beneficial effects of exercise? This question leads us to investigate the beneficial effects of

In a systematic review, aerobic exercise shows beneficial effects on cognitive functions and executive functions, which is better than that from resistance exercise [45]. Furthermore, aerobic exercise seems to elicit strong anti-inflammatory effect than that of resistance exercise [46]. However, resistance exercise seems to particularly increase the volume of hippocampus [47]. A study in laboratory animal

**6**

resistance exercise.

Since this is an introductory chapter, we do not intend to discuss every single method of neuroprotection in detail. We should keep in mind that neurodegenerative diseases are multiple-hit processes. Therefore, no single biological target can afford all neuroprotective needs. Approaches in using herbal medicine and natural products remind us that multiple biological targets may be the way to exert effective neuroprotection. Therefore, any non-pharmacological approaches including exercise and even the new stem cell approaches exert multiple effects. This can be the way for our effective neuroprotective strategies.

#### **Author details**

Raymond Chuen-Chung Chang1,2\* and Yuen-Shan Ho3

1 Laboratory of Neurodegenerative Diseases, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR

2 State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR

3 Faculty of Health and Social Sciences, School of Nursing, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR

\*Address all correspondence to: rccchang@hku.hk

© 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.

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[17] Cox SR, Bak TH, Allerhand M, Redmond P, Starr JM, Deary IJ, et al. Bilingualism, social cognition and executive functions: A tale of chickens and eggs. Neuropsychologia. 2016;**91**:299-306

[18] Cao Y, Zhang LW, Wang J, Du SQ, Xiao LY, Tu JF, et al. Mechanisms of acupuncture effect on Alzheimer's disease in animal based researches. Current Topics in Medicinal Chemistry. 2016;**16**:574-578

[19] Leung MC, Yip KK, Ho YS, Siu FK, Li WC, Garner B. Mechanisms underlying the effect of acupuncture on cognitive improvement: A systematic review of animal studies. Journal of Neuroimmune Pharmacology. 2014;**9**:492-507

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[23] Ho YS, Poon DCH, Chan TF, Chang RCC. From small to big molecules: How do we prevent and delay progression of aging-related neurodegeneration? Current Pharmaceutical Design. 2012;**18**:15-26

[24] Yu MS, Lai SW, Lin KF, Fang JN, Yuen WH, Chang RCC. Characterization of polysaccharides from the flowers of *Nerium indicum* and their neuroprotective effects. International Journal of Molecular Medicine. 2004;**14**:917-924

[25] Yu MS, Wong AYY, So KF, Fang JN, Yuen WH, Chang RCC. New polysaccharide from *Nerium indicum* protects neurons via stress kinase signaling pathway. Brain Research. 2007;**1153**:221-230

[26] Lai SW, Yu MS, Yuen WH, Chang RCC. Novel neuroprotective effects of the aqueous extracts from *Verbena officinalis Linn*. Neuropharmacology. 2006;**50**:641-650

[27] Lai CSW, Yu MS, Yuen WH, So KF, Zee SY, Chang RCC. Neuroprotective effects of anti-aging fungus *Gandoderma lucdium*. Brain Research. 2008;**1190**:215-224

[28] Yu MS, Leung SKY, Che CM, Zee SY, So KF, Yuen WH, et al. Neuroprotective effects of an anti-aging Chinese medicine *Lycium barbarum* against β-amyloid peptide neurotoxicity. Experimental Gerontology. 2005;**40**:716-727

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**8**

*Neuroprotection*

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*DOI: http://dx.doi.org/10.5772/intechopen.85631*

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*Neuroprotection*

2007;**203**:269-273

2010;**110**:311-320

2011;**6**:e16380

2008;**28**:643-652

2008;**45**:1019-1026

2010;**21**:482-489

Chinese herbal medicine in protecting retinal ganglion cells in an ocular hypertension model of glaucoma. Experimental Neurology.

[32] Chiu K, Zhou Y, Yeung SC, Lok CKM, Chan OOC, Chang RCC, et al. Up-regulation of crystallins is involved in neuroprotective effects of wolfberry on survival of retinal ganglion cells in rat ocular hypertension model. Journal of Cellular Biochemistry.

[38] Poon DCH, Ho YS, Chiu K, Chang RCC. Cytokines: How important are they in mediating sickness? Neuroscience and Biobehavioral

[39] Poon CH, Ho YS, Chiu K, Wong HL, Chang RCC. Sickness: From the focus on cytokines, prostaglandins, and complement factors to the perspectives

[40] Poon DCH, Ho YS, You R, Tse J, Chu K, Chang RCC. PKR deficiency alters E. Coli-induced sickness behaviors but does not exacerbate neuroimmune responses or bacterial load. Journal of Neuroinflammation. 2015;**12**:212. DOI:

of neurons. Neuroscience and Biobehavioral Reviews. 2015;**57**:30-45

10.1186/s12974-015-0433-2

s12974-018-1163-z

fphys.2019.00042

phy2.12828

2016;**78**:223-241

[41] Huang CX, Irwin MG, Wong GTC, Chang RCC. Evidence of the impact of systemic inflammation on neuroinflammation from a nonbacterial endotoxin animal model. Journal of Neuroinflammation. 2018;**15**:147. DOI: 10.1186/

[42] Lee JH, Jun HS. Role of myokines

[43] Tanimura Y, Aoi W, Takanami Y, Kawai Y, Mizushima K, Naito Y, et al. Acute exercise increases fibroblast growth factor 21 in metabolic organs and circulation. Physiological Reports.

in regulating skeletal muscle mass and function. Frontiers in Physiology. 2018;**10**:42. DOI: 10.3389/

2016;**4**:e12828. DOI: 10.14814/

[44] Fisher FM, Maratos-Flier E. Understanding the physiology of FGF21. Annual Review of Physiology.

[45] Barha CK, Davis JC, Falck RS, Nagamatsu LS, Liu-Ambrose T. Sex differences in exercise efficacy to improve cognition: A systematic review

Reviews. 2013;**37**:1-10

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[34] Chang RCC, So KF. Use of anti-aging herbal medicine, *Lycium barbarum*, against aging-associated diseases. What do we know so far? Cellular and Molecular Neurobiology.

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[37] Chao J, Lau KW, Huie MJ, Ho YS, Yu MS, Lai CSW, et al. A prodrug of the green tea polyphenol (−)-epigallocatechin-3-gallate (EGCG) prevents differentiated SH-SY5Y cells from toxicity induced by 6-hydroxydopamine. Neuroscience

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**10**

[46] King DE, Carek P, Mainous AG 3rd, Pearson WS. Inflammatory markers and exercise: Differences related to exercise type. Medicine & Science in Sports & Exercise. 2003;**35**:575-581

[47] Kim YS, Shin SK, Hong SB, Kim HJ. The effects of strength exercise on hippocampus volume and functional fitness of older women. Experimental Gerontology. 2017;**97**:22-28

[48] Cassilhas RC, Lee KS, Fernandes J, Oliveira MG, Tufik S, Meeusen R, et al. Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms. Neuroscience. 2012;**202**:309-317

Chapter 2

Abstract

Current Therapeutic Approaches

Liliana Mititelu-Tartau, Maria Bogdan, Victor Gheorman,

Liliana Foia, Ancuta Goriuc, Gabriela Rusu, Beatrice Buca,

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.

Increase in life expectancy has led to aging of the population and consequently

to an expansion of the prevalence of neurodegenerative diseases (NDDs) [1].

Keywords: neuroprotection, neurodegenerative diseases, ischemic stroke,

Liliana Pavel, Ana Cristofor, Cosmin-Gabriel Tartau

from Imidazoline and Opioid

Receptors Modulators in

Neuroprotection

and Gratiela Eliza Popa

imidazoline, opioids, nitric oxide

1. Introduction

13

#### Chapter 2
