Inflammatory Process in Alzheimer’s and Parkinson's Diseases: Central Role of Cytokines

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Current Pharmaceutical Design, 2016, 22, 000-000 1

Inflammatory Process in Alzheimer’s and Parkinson's Diseases: Central Role of Cytokines

Qamre Alam

^1#

, Mohammad Zubair Alam

¹

, Gohar Mushtaq

^2#

, Ghazi A. Damanhouri

¹

, Mahmood Rasool

³

, Mohammad Amjad Kamal

¹

* and Absarul Haque

¹

*

1King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah, Saudi Arabia;

2Department of Biochemistry, College of Science, King Abdulaziz University, Jeddah, Saudi Arabia; ³Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box80216, Jeddah 21589, Saudi Arabia

Abstracts: Alzheimer’s disease (AD) and Parkinson's disease (PD) are the two most widespread neurological disorders (NDs) characterized by degeneration of cognitive and motor functions due to malfunction and loss of neurons in the central nervous system (CNS). Numerous evidences have established the role of neuroinflammation in the AD and PD pathology. The inflammatory components such as microglia, astrocytes, complement system and cytokines are linked to neuroinflammation in the CNS. More specifically, cytokines have been found to play a central role in the neuroinflammation of AD and PD. A number of studies have demonstrated abnormally elevated levels of inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) in AD and PD pa-

tients. Activated microglial cells have been shown to be involved in the secretion of pro-inflammatory cytokines such as IL-1, IL-6, TNF- and transforming growth factor-, thereby contributing towards the progress of NDs. In addition, studies on AD pathogenesis have demonstrated that microglia produce beta-amyloid protein (A), which by itself is pro-inflammatory and causes activation of several inflammatory components. Similarly, chronic inflammation caused by microglial cells is the fundamental process involved in the destruc- tion of neurons associated with dopamine (DA)-production in the brain of PD patients. Hence, there is a need to explore the key inflammatory components in AD and PD pathogenesis in order to fully understand the root cause and establish a substantial link between these two disorders. Such knowledge will help in better management and treatment of AD and PD.

Keywords: Alzheimer's disease, Parkinson's disease, Inflammation, Cytokines, Interleukin-1, Interleukin-6, Tumor Necrosis factor-, Transforming Growth factor-, Microglia.

INTRODUCTION

Alzheimer's disease (AD) and Parkinson’s disease (PD) are prevalent in aged people and have risen at alarming rate due to the increase in longevity of old individuals [1]. Presently, both of the diseases have drawn significant attention of the researchers towards better understanding of the pathophysiology of these disorders along with a need for devising effective management strategies in terms of treatment modalities. German psychiatrist and neuropa- thologist Alois Alzheimer was the first one who coined the term

“senile dementia” more than a century ago and later the disease was given the name “Alzheimer’s disease” in honor of its discoverer [2].

AD is a multifactorial, constantly progressive neurodegenerative disorder characterized by impaired cognitive function, diffused amyloid plaques deposition and neurofibrillary tangles [3, 4]. Clini- cally, AD is defined by degeneration of memory, composite cogni- tion, language, visuospatial skills, emotion and personality [5]. This disease is responsible for the most frequent form of dementia. The incidence and prevalence of AD is age related. AD is more common among older people above the age of 65 and its early onset is less prevalent [6]. Due to its high impact on the social and behav- ioral skills of people affected with this disease, AD is rapidly becoming one of the most noticed healthcare problems globally [7].

Apart from the social impact, AD management also imposes heavy financial burden on patients, families, and the society as a whole.

*Address correspondence to these authors at the King Fahd Medical Re- search Center, King Abdulaziz University, P. O. Box 80216, Jeddah, Saudi Arabia; Tel: +96626401000; Ext: 25185; Fax: +966- 26952076;

E-mail: [email protected]

Tel: +96626401000; Ext: 25185; Fax: +966- 26952076;

E-mail: [email protected]

#Authors contributed equally and considered as first co-authors.

There are nearly more than twenty-four million people affected with dementia worldwide, and this number is expected to reach to forty-two million by the year 2020 and to eighty-one million by 2040 [8]. In the U.S.A. alone, 4.5 million people are affected by AD and the management of those patients could cost $100 billion US dollars annually according to one of the estimates carried out by the National Institutes of Health (NIH) [9].

Parkinson’s disease, just like AD, is another persistent progressive neurological disorder (ND) in the elderly people [10, 11]. First discovered by James Parkinson in 1817, PD is now considered the most frequent neurodegenerative disorder second only to AD [12, 13]. PD is often characterized by neurodegeneration of the nigral striatal trac and, as a result, there is a great reduction in the dopaminergic neurons in the substantia nigra (SN), loss of tyrosine hydroxylase (TH) containing nerve endings in the striatum and dimin- ished striatal dopamine production causing akinesia [14, 15]. Clini- cally, PD patients display a variety of symptoms, but the most common ones include motor function like resting tremor, postural instability, akinesia, bradykinesia and rigidity, while non-motor symptoms comprise of depression, autonomic dysfunction, dementia and visual hallucination [16]. The degenerated dopaminergic neurons in substantia nigra pars compacta (SNpc) are a constant neurochemical defect in PD, hence causing reduction in striatal dopamine (DA) levels. The tyrosine hydroxylase (TH) acts as a catalyst in the formation of L-dihydroxyphenylalanine (L-DOPA), and this is the rate-limiting step in the biosynthesis of DA. There- fore, PD can be regarded as a TH-deficiency syndrome of the striatum [17]. The incidence of PD increases with age with only four percent of people with PD diagnosed before the age of 50. In one recent estimate, 60,000 Americans are diagnosed with PD each year while 7 to 10 million people worldwide are affected with this disease. Studies on death rates and prevalence of NDs have indicated

Absarul Haque

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that the occurrence of PD is found to be less common in women as compared to men [18, 19]. Similar to AD, the socioeconomic burden in the management of PD is very high. The direct and indirect healthcare costs of PD are estimated to be approximately $25 billion per year in the United States alone [20, 21]. Thus, it seems that the high incidences of both AD and PD represent a great socioeconomic burden on the societies globally.

Although the exact cause of AD and PD remains elusive, grow- ing evidence continues to support the involvement of inflammatory process in the development of both the diseases [5]. In this perspective, there exists a continuous need to develop and understand the intricacies of the role of inflammation in NDs mainly in AD and PD. At present, treatment strategies adopted in order to manage neurodegenerative conditions are mainly focused on symptomatic relief. However, better management and permanent cure for AD and PD would necessitate in-depth study of these disorders to reveal the root cause of these diseases. Despite our current understanding of inflammatory pathways being the major players in the pathogenesis of several NDs, still more research is needed in order to establish a substantial link between inflammation and NDs such as PD and AD [22]. It is not a new idea to linking the process of inflammation to dementia and neurodegenerative disorders. For instance, enhancement in the levels of key inflammatory cytokines, namely, IL-1 and TNF-, has been reported to be associated with AD and PD patients [23]. Furthermore, MRI scans of AD patients reveal the presence of inflammatory lesions [22, 23]. Similarly, visualization of activated microglia accumulation in affected and injured parts of the brain is correlated with inflammation, hence forming the basis of involvement of inflammation in the disease progression of PD [24, 25]. The link of inflammation to the development of PD was first established by the finding of stimulated microglia and T-lymphocytes in the SNpc of a post-mortem of PD patient almost twenty years ago [26]. Later studies further sup- ported the idea that the activation of microglia is linked to neuroinflammation, thereby establishing its role in the pathogenesis of PD [27-29]. This is further substantiated by the findings that pro- inflammatory cytokines such as IL-1, TNF- and IL-6 are found to be overexpressed in PD patients as compared with healthy individuals [30, 31].

ROLE OF INFLAMMATION IN COMMON NEUROLOGI- CAL DISEASES

Inflammation is an integral part of immune response in order to protect human body against infection and injuries. The body's white blood cells and chemicals associated with the inflammatory process direct the cells and tissues in order to eliminate harmful stimuli, pathogens, irritants, and necrotic cells [32]. However, it has been found that chronic inflammatory response can lead to undersired injury which may result into continuous eroding of surrounding tissues, eventually becoming detrimental for normal functioning of the body [27]. The brain is susceptible to innate immune responses but has relatively low adaptive immune reactions. Since neurons lack the ability to divide and regenerate in the aftermath of an injury, they are unable able to recover from a neuronal insult. These properties make the neurons extremely vulnerable to auto- destructive immune and inflammatory processes [28, 29, 30]. In NDs, chronic inflamed tissues are characterized by the presence of high count of monocytes as well as monocyte-derived tissue macrophages, parallel to microglia cells in the CNS [25, 26]. It has been experimentally shown that inflammation occurs in pathologi- cally vulnerable areas of the AD brain, with enhanced expression of acute phase proteins and pro-inflammatory cytokines which are otherwise not detectable in the normal brain [33]. In general, cells get activated in response to neurological damage and direct the production of inflammatory mediators such as pro-inflammatory cytokines, chemokines, inflammatory proteins, monocyte, macrophage, thromboxanes, prostaglandins, coagulation factors, chemo- attractant proteins, leukotrienes, protease inhibitors, reactive oxy-

gen species, nitric oxide, pentraxins and C-reactive protein as well as complement factors. [34, 35]. Hence, neuroinflammation is ac- tively involved in neurological diseases and disorders. Neurodegen- eration is characterized by decline in cognitive and motor function due to the uninterrupted malfunction and loss of neurons in the CNS [36]. Apart from AD and PD, neuronal degeneration is also reported in other disorders such as neurotrophic infections, spinal cord and traumatic brain injury, stroke, neuropsychiatric, neoplastic disorders, multiple sclerosis, prion diseases, amyotrophic lateral sclerosis, genetic disorders [37]. Notably, a general association between these diseases is the persistent activation of innate immune responses including those mediated by microglia, the resident CNS macrophages. Such activation can lead to triggering of neurotoxic pathways that eventually become responsible for progressive degeneration. Nevertheless, microglia are also vital for regulating inflammatory processes, and for repair and regeneration [36]. Thus, inflammatory elements associated with neuroinflammation in the brain cells include microglia, astrocytes and neurons and, these are considered to contribute most to the inflammatory reaction in the NDs [38].

INVOLVEMENT OF INFLAMMATORY PROCESS IN AD AND PD

The connection of inflammation in the progression of AD and PD is characterized by an accumulation of activated microglia in damaged regions of the brain [39, 40]. Microglial activation during inflammatory attack occuring in peripheral macrophages was first discovered in the AD brain two decades ago. Notably, microglial cells have been found to be localized in vulnerable regions of AD cortex as well as in the amyloid- peptide (A) deposition areas.

The capability of activated microglia to release toxic inflammatory factors at those pathological vulnerable sites of the brain suggests the pathogenic role of microglial activation in AD [39, 40]. Like- wise, preliminary evidence of microglial role in the pathology of PD had been reported from a post-mortem study over twenty years ago , when researchers found the presence of activated microglia and T-lymphocytes in the substantia nigra pars compacta (SNpc) of a PD patient [41, 42]. So far, numerous studies have demonstrated the link of activated microglia in the pathology of AD and PD. In view of these findings, we would like to elaborate on and establish direct link of microglia as well as cytokines especially IL-1, IL-6, TNF- and transforming growth factor- (TGF)-) in the process of inflammation which is being widely considered as a major cause of AD and PD.

ROLE OF ACTIVATED MICROGLIA IN AD & PD

The microglia are considered immunologically competent de- fense cells which coordinate the endogenous immune response as a part of innate immunity in the brain cells. In general, the microglia helps and protects the neurons against injury in the CNS. However, microglia are also scavenger and phagocytic in nature. Depending on the conditions and cells response, microglia may get activated and generate both neuroprotective as well as neurotoxic effects in the brain cells [43]. The microglia is generally in an inactive state in the normal adult brain but once activated, they stimulate the expression of a variety of new receptors and additional molecules engaged in the inflammatory process and phagocytosis. In addition to activated state, the microglia also engage in the production of huge amounts of superoxide anions and other potential neurotoxins [44]. It is now generally understood that microglia contribute to the neurodegenerative process through discharge of a variety of neurotoxic factors involved in intensifying the degeneration of neurons [45]. There are a variety of pathways known to be associated with the induction of microglial activation, namely, direct neurotoxin, indirect neurotoxin and mixed neurotoxin pathways as shown in Fig 1. In the direct neurotoxins pathway (such as 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6- OHDA)), microglia get activated through a process called reactive

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microgliosis, which leads to an aggravation of the neurotoxicity [46, 47]. On the other hand, indirect neurotoxin pathway (such as bacterial LPS) is also a widely utilized and effective pathway for the activation of microglia. Although LPS does not exert direct toxic effect on neurons, its involvement in the activation of microglia leads to the release of neurotoxic factors to induce neuronal cell death [48-50]. In addition to direct and indirect toxins discharge through microglial activation, there is another group of agents that are recognized to be associated with various neurodegenerative diseases, displaying a “mixed mode” mechanism of neurotoxicity.

These agents include -amyloid, prion protein-derived peptides, HIV coat protein gp120, and the pesticide rotenone [51]. Activated microglial cells, such as macrophages, go through a transforma- tional state leading to an increase in their microbicidal effectiveness and their capability to modulate the inflammatory immune response [52]. These changes in microglial cells are considered crucial in terms of enhancing their phagocytic ability, antigen presentation, microbial killing, and inflammatory mediator production [53]. It is well established that pro-inflammatory cytokines like IL-1, IL-6, TNF- and TGF- get secreted by the activated microglial cells [51-54]. In addition to the discharge of nitric oxide (NO), activated microglial cells can also generate respiratory burst activity. The microglial respiratory burst is typified by the release of diverse reactive oxygen species (ROS) such as superoxide radicals and hydrogen peroxide [54]. Interestingly, the microglia has also been found to play a pivotal role in degradation of A by the release of insulin degrading enzyme. Insulin degrading enzyme is a protease that is engaged in the cleavage of a number of proteins having low size such as insulin and glucagon that are susceptible to degradation by A [55, 56].

ROLE OF CYTOKINES IN THE INFLAMMATORY PROC- ESS OF AD AND PD

Cytokines are nonstructural proteins having low molecular weights ranging from 8,000 to 40,000 Da. Cytokines are considered to play an active role in both health and disease, that is, immune responses, inflammation, host responses to infection, trauma, sep- sis, and cancer [57]. A number of different immune cells (e.g. T- lymphocytes, macrophages and natural killer cells) and non- immune cells (e.g., Schwann cells, fibroblasts) are known to produce cytokines that are important in cell signaling [58]. In general, cytokines (including chemokines, interferon, interleukins, lymphokines, tumor necrosis factor etc.) are responsible for inducing many biological effects such as stimulation or inhibition of cell growth and differentiation, cytotoxicity/apoptosis, inflammatory responses, over-expression of surface membrane proteins and anti- viral activity [59]. Moreover, cytokines play a vital role in the inflammatory or anti-inflammatory processes depending on the need of the host environmental condition. Cytokines are categorized into two types on the basis of functional activity: 1) pro-inflammatory cytokines (IL-1, TNF) that are involved in inducing inflammation and 2) anti-inflammatory cytokines (IL-4, IL-10, IL-13 and TGF) that are responsible for the inhibition of pro-inflammatory cytokines activity [60]. In addition to their role in the peripheral system, cytokines also play a pivotal role in both inflammatory and anti- inflammatory processes in many neurological disorders. Various cytokines are secreted by neurons or glia, thereby changing cytokines levels in the brain, blood, and CSF of AD patients [61]. A number of studies have established that IL-1 plays a central role in the initiation of immune response as along with active participation in Fig. (1). Schematic representation showing activation of Microglia and their consequence on AD & PD.

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the progression and advancement of a multifaceted hormonal and cellular inflammatory cascade. Nevertheless, abnormally elevated levels of IL-1 contribute towards neuronal degeneration. As a mat- ter of fact, enhanced IL-1 levels have been reported in CSF and brain parenchyma of both humans and rodents immediately after brain injury [62, 63]. Furthermore, up regulation of IL-1 is the main factor involved in the initiation of inflammatory process, thus start- ing a vicious cycle of several reactions which eventually result in neuronal death. Other notable cytokines associated with neuroinflammation are tumor necrosis factor (TNF)- and IL-6 [61]. In contrast to pro-inflammatory cytokines, there are also cytokines such as IL-1 receptor antagonist (IL-1ra), IL-4, IL-10, and TGF- all of which have been found to be involved in protecting the degeneration of neurons by suppressing pro-inflammatory cytokines production [60].

ROLE OF INTERLEUKIN-1 IN AD & PD

Interleukin-1 belongs to pleiotropic cytokine family having ability to perform and exert many actions in the CNS. Iinterleukin-1 is characterized as a 17 Kilo Dalton (kDa) polypeptide that exists in two distinct isoforms, namely, IL-1 and IL-1, though other mem- bers of the IL-1 family have also been identified in recent times [64]. In spite of the separate genes encoding for IL-1 and IL-1, these two types of interleukins share sequence homology between them and elicit similar biological actions [64]. It is well known that IL-1 act as a pro-inflammatory cytokine that orchestrates host de- fense machinery including inflammatory response in the peripheral system of the body [65]. Normally, IL-1 actions involve activation of T cells (thus indirectly activating the B cells), over expression of adhesion molecules, and induction of the expression of a number of other pro-inflammatory cytokines thus contributing to the cascade of inflammatory response [64, 65]. The expression of IL-1 is consti- tutive in nature and its low levels have been detected in a variety of cell types of healthy adult brain. However, in response to local brain injury or the cerebral damage, IL-1 is found to be over expressed by microglia which are macrophage-equivalent resident cells of CNS [66, 67]. Over expression of IL-1 in the brain of an Alzheimer’s patient was first reported by Griffin et al. in 1989 [58].

Using immunohistochemical method, Griffin’s team demonstrated approximately 6-fold rise in the expression of IL-1 immunoreactive microglia along with presence of high levels of IL-1 in tissues [68].

The over expression of IL-1 by microglia in the brain of AD is often coupled with A plaques, and thus the pattern of sharing of this microglia across brain regions correlates with the distribution of A plaques [69]. Moreover, the patterns of sharing of amyloid plaque within cortical layers reflect the allocation of microglia in normal cerebral cortex [70]. The microglia involved in over expression of IL-1 exhibit reproducible patterns of organization with various types of A plaques, hence, further advocating the role of IL-1 in the initiation and progression of neurotic and neuronal injury in AD [71]. In vitro and in vivo studies have demonstrated that IL-1 is associated with many neurotrophic and gliotrophic actions that are essentially required during progression and development of AD [72]. Neurotrophic IL-1 actions promote the synthesis and processing of the A precursor protein, APP, that is essentially required before the release of amyloid peptide fragments and gliotrophic secreted APP fragments. Moreover, IL-1 increases the expression and functions of neuronal acetylcholinesterase thus suggesting the partial role of cholinergic dysfunction in AD pathogenesis [73, 74].

On the other hand, gliotrophic IL-1 actions exert thier effects through autocrine signaling on microglia in order to fully promote IL-1 activation and expression [75, 76]. The production of IL-1 occurs via activation of microglia thereby leading to activation of the pro-oxidant enzymes like nicotinamide adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase (iNOS), and, consequently the production of reactive oxygen species (ROS) and nitric oxide [77,78]. The production of such molecules generates oxidative stress which is considered detrimental for dopaminergic

neurons due to their vulnerability to oxidative stress as it has been shown that there is selective loss of dopaminergic neurons in the SN in disorders such as PD [79, 80].

INVOLVEMENT OF TUMOR NECROSIS FACTOR- IN AD

& PD

TNF- is a non-glycosylated protein of 157 amino acids with 17 kDa molecular weight that is a member of peptide ligands family involved in the activation of a corresponding set of structurally inter related receptors [81, 82]. The biological response to TNF- is mediated through two structurally distinct receptors: type I and type II.

Both receptors are trans-membrane glycoproteins having multiple cysteine-rich repeats in the extracellular N-terminal domains [83].

In peripheral system, the activated macrophages and T lymphocytes are largely responsible for the production of pro-TNF (molecular weight 26 kDa) protein. The expressed TNF on the plasma membrane is further processed by matrix metalloproteinase, causing the cleavage of the extracellular domain and finally resulting into 17 KDa soluble form of TNF [84-86]. However, a variety of pathological processes such as ischaemia, inflammatory process, traumatic injury and infection can cause the stimulation of microglia and astrocytes in order to produce TNF in the CNS [87].

Originally TNF was considered to be a circulating factor responsible for causing tumor necrosis. However, current findings have confirmed that TNF plays critical and diverse roles in the pathological advancement of numerous chronic inflammatory disorders including neurodegenerative diseases [88, 89]. At normal levels, TNF plays a vital role in brain development and physiology such as synaptic plasticity, sleep, circadian rhythm and normal be- havior [88, 89]. On the other hand, microglial activation in the CNS leads to enhanced expression of TNF- which in turn activates NFK-, an important mediator in the activation of iNOS. iNOS is involved in the generation of NO as well as peroxynitrite known as NO-derived reactive nitrogen species. Hence, enrichment of enor- mous reactive molecules results in the induction of lipid peroxida- tion, tyrosine nitrosylation, oxidative damage to DNA and, finally, the disruption of neurons that are considered potential features associated with the pathology of AD & PD brain [90, 91].

The first evidence of TNF signaling associated with the pathology of AD was reported after the post-mortem analysis where the finding confirmed the deposition of TNF at amyloidogenic plaques in AD brains [92]. This finding served as the basis of further studies aimed to establish a substantial link between AD and TNF and its receptors [93]. On genomic level, efforts have been made to establish a link between TNF receptors (TNFR1 and TNFR2) and AD. Notably, it has been found that TNFR1 and TNFR2 genes are present on chromosome 1p and chromosome 12p, respectively.

Remarkably, those same regions on the chromosomes have been mapped for a genetic linkage to late-onset AD [94]. Further, the firm genetic proof associated with TNF in initiation and progression of PD can be established with the reported -1031C polymorphism in the promoter region of TNF. This polymorphism is linked with enhanced transcriptional activity and, hence, greater production of TNF as compared to normal. In fact, increased levels of TNF have been documented in a cohort of Japanese early-onset PD patients as compared to patients having late-onset of PD and healthy controls [95]. Similarly, another polymorphism in the promoter region of TNF (-308 G/A) has been found to be over-represent in early onset sporadic PD and that is responsible for high TNF levels in the serum [96, 97].

ROLE OF TRANSFORMING GROWTH FACTOR- IN AD

& PD

Transforming growth factor-1 belongs to a member of TGF- super family, consisting of several groups of highly conserved mul- tifunctional cell-cell signaling proteins [98-101]. Within the mammalian TGF- superfamily, TGF-1, 2 and 3 are key modulators of

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cell survival and apoptosis [102]. All three TGF-s are synthesized as homodimeric pro-proteins (pro-TGF ) and derived from three unlinked genetic loci, TGFB1, TGFB2 and TGFB3, which encode three protein isoforms, TGF-1, TGF-2 and TGF-3, respectively, with high degree of structural and functional similarities [102].

However, TGF-1 isoform is known to be high in abundance and its primary sequence is considered as the most conserved during the course of evolution [103]. Moreover, nucleotide sequences as well as related amino acid sequences of human, mouse, pig, cow, ape and chicken demonstrate that mature polypeptide of TGF-1 is conserved 100% across these species with the exception of a single amino acid substitution in the murine peptide [103]. The human TGF-1 gene located on chromosome 19q13 is comprised of seven exons among which exon 5, exon 6, and exon 7 encode for a precursor protein (pro-TGF) of 390 amino acids. This pro-TGF is then processed proteolytically to generate the active mature protein of 112 amino acids, existing as disulphide linked homodimer or heterodimer protein (25 kDa) having diverse biological functions [104,105].

Interestingly, TGF- levels in serum, cerebrospinal fluid (CSF) and plaques are found to be higher in AD patients as compared to elder healthy controls [106-108]. In parallel, increased cerebrovascular amyloid deposition in the transgenic mice having over expressed TGF- in the astrocytes strongly suggest that TGF- in- duces cerebrovascular amyloidosis and causes microvascular degeneration in AD [109]. Likewise, the role of TGF- in the pathology of PD has been evaluated by measuring the content of TGF- in the brain (cerebral cortex, putamen and caudate nucleus) as well as ventricular cerebrospinal fluid (VCSF) from healthy controls and Parkinsonian patients [109]. The ELISA revealed significantly higher concentration of TGF- in the dopaminergic striatal regions in Parkinsonian patients as compared to normal individuals. How- ever, no significant differences were recorded in the cerebral cortex of Parkinsonian and control patients [110-112]. Furthermore, the comparative evaluation of TGF- concentrations in VCSF were carried out and the results suggested that TGF- level is significantly higher in Parkinsonian patients as compared to healthy control. TGF- is known to function as a strong regulator of cell growth, suggesting that it may play an important role as modulator of the neurodegeneration process in PD [113].

ROLE OF INTERLEUKIN-6 IN AD & PD

Interleukin-6 belongs to the neuropoietic cytokine family and plays an essential role in the development, differentiation, degeneration and regeneration of neurons in the central and peripheral nervous system. It is also involved in the stimulation of glial cells [114-116]. The signals of IL-6 rely upon the formation of biologi- cally active IL-6 receptor complex (IL-6RC) [117]. It is an important mediator of fever as well as acute phase response. IL-6 has been reported to be capable of crossing the blood brain barrier and is normally expressed in the nervous system during development.

The levels of IL-6 are normally low in the body but the levels go up in response to certain infections or other pathological conditions [118]. Normally, microglia, astroglia, neurons, and endothelial cells are involved in the synthesis of IL-6 [119,120]. The detection of IL- 6 in significant amounts is usually considered to be harmful and could contribute to pathological effects associated with AD and PD.

However, evidence indicates that IL-6 may also have anti- inflammatory, immunosuppressive and other beneficial properties under restricted conditions and levels of exposure. For instance, when present in low amount, IL-6 plays a key role in regulating neural cells survival and function [121-125]. It has been shown that IL-6 over-expression leads to induction of neural cell death in certain neurodegenerative diseases such as AD and PD [126]. Fur- thermore, IL-6 is involved in increasing leukocyte adhesion and migration, disruption of the blood-brain barrier and enhancement of glial cell activation that could subsequently lead to overproduction of reactive oxygen species. As a result, there is induction of apopto-

sis and specific cytolysis caused by the activation of complement system in the CNS [126]. In addition, overexpression of IL-6 in the brain of transgenic mice has been associated with a variety of neu- ropathologic changes including gliosis and selective disruption of cholinergic neurotransmission in the hippocampus. Hence, these findings establish a direct correlation between the neurotoxicity of IL-6 and ND like AD and PD [125,126].

CONCLUSION

Chronic inflammation as a result of inflammatory process is one of the major factors in the progression and development of both AD and PD [5]. The production and secretion of pro-inflammatory mediators may interact at multiple levels with neurodegeneration.

Hence, pro-inflammatory cytokines may not only contribute to neuronal death but they may also influence classical neurodegenerative pathways such as APP processing and phosphorylation. In parallel, the release of anti-inflammatory mediators may antagonize this action and eventually lead to chronic disease. Further, several studies have concluded that the pro-inflammatory agents lead to the induction of inflammatory process that can result in the degeneration of dopamine-containing neurons which further implicates neuroinflammation as the key contributor to the neuronal damage in PD. Experimental findings have also revealed that inhibition of the inflammatory process is related to reduced neuronal injury, thus supporting the idea that inflammation plays a destructive role in the neurodegeneration in PD. Hence, restricting inflammation may turn into a promising therapeutic intervention for PD. Likewise, microglial activation plays a pivotal role in the initiation and progression of several neurodegenerative diseases including AD and PD. Thus, inhibition of microglial activation would be an effective therapeutic approach to reduce the progression of both diseases. In this en- deavor, naloxone appears to be a useful candidate to treat AD and PD since it is well understood that this drug preferentially inhibits the production of superoxide free radicals in microglia. To sum up, there is a constant need to decipher the role of inflammation in neurodegenerative disorders such as AD and PD. At present, the treatment strategies adopted in order to manage the neurodegenerative conditions are mainly focused upon symptomatic relief. How- ever, better management with permanent solution to cure AD and PD necessitate in-depth clinical studies to reveal the root cause of such diseases.

LIST OF ABBREVIATIONS

6-OHDA = 6-hydroxydopamine

AD = Alzheimer’s disease

A = Beta-amyloid

CNS = Central Nervous System CSF = Cerebro Spinal Fluid

IL = Interleukin

L-DOPA = L-dihydroxyphenylalanine

LPS = Lipopolysaccharide

MPTP = 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine NDs = Neurological Diseases

PD = Parkinson's disease

SN = Substantia Nigra

TGF = transforming growth factor TH = Tyrosine Hydroxylase TNF = Tumor Necrosis Factor CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

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ACKNOWLEDGEMENTS

The authors would like to thank Deanship of Scientific Re- search (DSR), King Abdulaziz University for providing grant, bear- ing number: 424-141-1434 for the establishment of state of the art research facilities at KFMRC.

REFERENCES

[1] Nazem A, Mansoori GA. Nanotechnology solutions for Alz- heimer's disease: advances in research tools, diagnostic methods and therapeutic agents. J Alzheimers Dis 2008; 13: 199-223.

[2] Alam Q, Alam MZ, Karim S, et al. Nanotechnological approach to the management of Alzheimer disease and type 2 diabetes. CNS Neurol Disord Drug Targets 2014; 13: 478-86.

[3] Fia IG, Enciu AM, Stnoiu BP. New insights on Alzheimer's disease diagnostic. Rom J Morphol Embryol 2011; 52: 975-9.

[4] Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297: 353-6.

[5] Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM.

Inflammation and Alzheimer’s disease. Neurobiol Aging 2000; 21:

383-421.

[6] Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M. Global prevalence of dementia: a Delphi consensus study. Lan- cet 2005; 366: 2112-7.

[7] Sloane PD, Zimmerman S, Suchindran C, et al. The public health impact of Alzheimer’s disease, 2000-2050: potential implication of treatment advances, Annu Rev Public Health 2002; 23: 213-31.

[8] Stefanacci RG. The costs of Alzheimer's disease and the value of effective therapies. Am J Manag Care 2011; 17: 356-62.

[9] Stefanacci RG. The costs of Alzheimer's disease and the value of effective therapies. Am J Manag Care 2011; 17: 356-62.

[10] Kawajiri S, Saiki S, Sato S, Hattori N. Genetic mutations and functions of PINK1. Trends Pharmacol Sci 2011 32: 573-80.

[11] Tabrez S, Jabir NR, Shakil S, et al. A synopsis on the role of tyrosine hydroxylase in Parkinson's disease. CNS Neurol Disord Drug Targets 2012; 11: 395-409.

[12] Khan W, Priyadarshini M, Zakai HA, Kamal MA, Alam Q. A brief overview of tyrosine hydroxylase and -synuclein in the Parkin- sonian brain. CNS Neurol Disord Drug Targets 2012; 11: 456-62.

[13] Ruiz PJ, Catalán MJ, Carril JM. Initial motor symptoms of Parkin- son disease. Neurologist 2011; 17: 18-20.

[14] Booij j, Bergmans P, Winogroolzka A, Speelman JD, Wolters EC.

Imaging of dopamine transporters with [123I] Fp-CIT SPECT does not suggest a significant effect of age on the symptomatic threshold of disease in Parkinson’s disease. Synapse 2001; 39: 101-8.

[15] Olsen JH, Friis S, Frederiksen K, McLaughlin JK, Mellemkjaer L, Moller H. Atypical cancer pattern in patients with Parkinson’s disease. Br J Cancer 2005; 92: 201-5.

[16] Stacy MA, Murck H, Kroenke K. Responsiveness of motor and nonmotor symptoms of Parkinson disease to dopaminergic therapy.

Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 57-61.

[17] Hwang DY, Ardayfio P, Kang UJ, Semina EV, Kim KS. Selective loss of dopaminergic neurons in the substantia nigra of Pitx3- deficient aphakia mice. Brain Res Mol Brain Res 2003 114: 123- 31.

[18] Tanner CM, Goldman SM. Epidemiology of Parkinson’s disease. Neurol Clin 1996; 14: 317-35.

[19] Zhang Z, Roman GC. Worldwide occurrence of Parkinson’s disease: an updated review. Neuroepidemiology 1993 12: 195-208.

[20] Nedjadi T, Haque A, Alam Q, et al. Genomic approach towards Molecular Linkage in between Alzheimer’s disease and type 2 Diabetes. CNS Neurol Disord Drug Targets 2014; 13: 203-12.

[21] Ahmed F, Ansari JA, Ansari ZE, et al. Molecular bridge:

Connecting Diabetes type II and Alzheimer’s disease. CNS Neurol Disord Drug Targets 2014; 13: 312-21.

[22] Courtney C, Farrell D, Gray R, et al. AD2000 Collaborative Group long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004; 363:

2105-15.

[23] Chen H, Zhang SM, Hernan MA, et al. Nonsteroidal anti- inflammatory drugs and the risk of Parkinson disease. Arch Neurol 2003; 60: 1059-64.

[24] Gao HM, Hong JS. Why neurodegenerative diseases are progressive: Uncontrolled inflammation drives disease progression. Trends Immunol 2008; 29: 357-65.

[25] Long-Smith CM, Sullivan AM, Nolan YM. The influence of microglia on the pathogenesis of Parkinson's disease. Prog Neurobiol 2009; 89: 277-87.

[26] McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia is positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 1988; 38: 1285-91.

[27] Banati RB, Daniel SE, Blunt SB. Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease. Mov Disord 1998; 13: 221-7.

[28] Hirsch EC, Hunot S. Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol 2009; 8: 382-97.

[29] Imamura K, Hishikawa N, Sawada M, Nagatsu T, Yoshida M, Hashizume Y. Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains. Acta Neuropathol 2003; 106: 518-26.

[30] Boka G, Anglade P, Wallach D, Javoy-Agid F, Agid Y, Hirsch EC.

Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson's disease. Neurosci Lett 1994; 172: 151-4.

[31] Dobbs RJ, Charlett A, Purkiss AG, Dobbs SM, Weller C, Peterson DW. Association of circulating TNF-alpha and IL-6 with ageing and Parkinsonism. Acta Neurol Scand 1999; 100: 34-41.

[32] Finch CE, Morgan TE. Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a position paper. Curr Alzheimer Res 2007; 4: 185-9.

[33] Heneka MT, O’Banion MK. Inflammatory processesin Alzheimer’s disease. J Neuroimmunol 2007; 184: 69-91.

[34] Barger SW, Harmon AD. Microglial activation by alzhelmer amyloid precursor protein and modulation by apolipoprotein E. Nature 1997; 388: 878-1.

[35] Owens T, Babcock AA, Millward JM, ToftHansen H. Cytokine and chemokine inter-regulation in the inflamed or injured CNS. Br Res Rev 2005; 48: 178-84.

[36] Brown GC, Bal-Price A. Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 2003; 27: 325-55.

[37] Puentes F, Topping J, Kuhle J, et al. Immune reactivity to neuro- filament proteins in the clinical staging of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2014; 85: 274-8.

[38] Lindberg C, Hjorth E, Post C, Winblad B, Schultzberg M. Cytokine production by a human microglial cell line: effects of amyloid and -melanocyte-stimulatinghormone. Neurot Res 2005; 8: 267-76.

[39] Nyoman G, Darmadipura S. The Role of Microglia as Prime Com- ponent of CNS Immune System in Acute and Chronic Neuroin- flammation. Folic Med Indonesiana 2007; 43: 54-58.

[40] Long-Smith CM, Sullivan AM, Nolan YM. The influence of microglia on the pathogenesis of Parkinson's disease. Prog Neurobiol 2009; 89: 277-87.

[41] McGeer PL, Itagaki S, Boyes BE, McGeer EG. Reactive microglia is positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 1988; 38: 1285-91.

[42] Mogi M, Harada M, Kondo T, et al. Interleukin-1 beta, interleukin 6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonianpatients. Neurosci Lett 1994a; 180: 147-50.

[43] Streit WJ, Walter SA, Pennell NA. Reactive microgliosis.Prog Neurobiol 1999; 57: 563-81.

[45] Le WD, Rowe DB, Xie W. Activated microglia induce dopaminergic cell injury in vitro. XIII International Congress on Parkinson’s disease. Parkinson Relat Disord Vancouver 1999; 5: 19.

[46] liu B, jau-shyong H. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Therap 2003; 304: 1-7.

[47] Bronstein DM, Perez-Otano I, Sun V, et al. Glia-dependent neurotoxicity and neuroprotection in mesencephalic cultures. Brain Res 1995; 704: 112-6.

[48] Araki E, Forster C, Dubinsky JM, Ross ME, Iadecola C. Cy- clooxygenase-2 inhibitor NS-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity. Stroke 2001; 32: 2370-5.

[49] Itzhak Y, Martin JL, Ali SF. Methamphetamine- and 1-methyl-4- phenyl- 1, 2, 3,6-tetrahydropyridine-induced dopaminergic neurotoxicity in inducible nitric oxide synthase-deficient mice. Synapse 1999; 34: 305-12.

(7)

[50] Liberatore GT, Jackson-Lewis V, Vukosavic S, et al. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 1999; 5: 1403-9.

[51] Dehmer T, Lindenau J, Haid S, Dichgans J, Schulz JB. Deficiency of inducible nitric oxide synthase protects against MPTP toxicity in vivo. J Neurochem 2000; 74: 2213-6.

[52] Qin L, Liu YX, Cooper CL, Liu B, Wilson B, Hong JS. The role of microglia in amyloid (1-42) toxicity to cortical and mesencephalic neurons. J Neurochem 2002; 293: 617-9.

[53] Fujiwara N, Kobayashi K. Macrophages in inXammation. Curr Drug Targets InXamm Allergy 2005; 4: 281-6.

[54] Gordon S. Alternative activation of macrophages. Nat Rev Immu- nol 2003; 3: 23-35.

[55] Qiu WQ, Walsh DM, Ye Z. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 1998; 273: 32730-8.

[56] Chesneau V, Vekrellis K, Rosner MR, Selkoe DJ. Purified recom- binant insulin-degrading enzyme degrades amyloid beta-protein but does not promote its oligomerization. Biochem J 2000; 351: 509- 16.

[57] Sawada M, Imamura K, Nagatsu T. Role of cytokines in inflammatory process in Parkinson's disease. J Neural Transm Suppl 2000;

70: 373-81.

[58] Nagatsu T, Sawada M. Inflammatory process in Parkinson's disease: role for cytokines. Curr Pharm Des 2005; 11: 999-1016.

[59] Griffin WST, Mrak RE. Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alz- heimer's disease. J Leuko Biol 2002; 72: 233-8.

[60] Cacquevel M, Lebeurrier N, Chéenne S, Vivien D. Cytokines in neuroinflammation and Alzheimer's disease. Curr Drug Targets 2004; 5: 529-34.

[61] Dinarello CA. The IL-1 family and inflammatory diseases. Clin Exp Rheumatol 2002; 20: S1-13.

[62] Saito T, Yasukawa K, Suzuki H. Preparation of soluble murine IL- 6 receptor and anti-murine IL-6 receptor antibodies. J Immunol 1991; 147: 168-73.

[63] Satoh T, Nakamura S, Taga T. Induction of neuronal differentiation in PC12 cells by B-cell stimulatory factor 2/interleukin 6. Mol Cell Biol 1988; 8: 3546-9.

[64] Rodney R, Dietert RW. The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neurosci 2008; 29: 1846-54.

[65] Dinarello CA. Biological basis for IL-1 in disease. Blood 1996; 87:

2095-147.

[66] Hetier E, Ayala J, Denefle P, et al. Brain macrophages synthesize interleukin-1, and interleukin- 1 mRNAs in vitro. J Neurosci Res 1988; 21: 391-7.

[67] Vitkovic L, Bockaert J, Jacque C. “Inflammatory” cytokines: neu- romodulators in normal brain? J Neurochem 2000; 74: 457-71.

[68] Griffin WST, Stanley LC, Ling C, et al. Brain interleukin 1, and S- 100 immunoreactivity are elevated in Down syndrome, and Alz- heimer disease. Proc. Natl Acad Sci USA 1989; 86: 7611-5.

[69] Sheng JG, Mrak RE, Griffin WST. Microglial interleukin-1_ expression in brain regions in Alzheimer’sdisease: correlation with neuritic plaque distribution. Neuropathol Appl Neurobiol 1995; 21:

290-301.

[70] Sheng JG, Griffin WST, Royston CM, Mrak RE. Distribution of IL-1-immunoreactive microglia in cerebral cortical layers: implica- tions for neuritic plaque formation in Alzheimer’s disease. Neuro- pathol Appl Neurobiol 1998; 24; 278-83.

[71] Forloni G, Demicheli F, Giorgi S, Bendotti C, Angaretti N. Expres- sion of amyloid precursor protein mRNAs in endothelial, neuronal, and glial cells: modulation by interleukin 1. Brain Res Mol Brain Res 1992; 16: 128-34.

[72] Goldgaber D, Harris HW, Hla T, et al Interleukin 1 regulates synthesis of amyloid _-protein precursor mRNA in human endothelial cells. Proc Natl Acad Sci USA 1989; 86: 7606-10.

[73] Buxbaum JD, Oishi M, Chen HI, et al. Cholinergic agonists, and interleukin 1 regulate processing, and secretion of the Alzheimer A4 amyloid protein precursor. Proc Natl Acad Sci USA 1992; 89:

10075-8.

[74] Barger SW, Harmon AD. Microglial activation by Alzheimer amyloid precursor protein, and modulation by apolipoprotein E. Nature 1997; 388: 878-81.

[75] Lee SC, Liu W, Dickson DW, Brosnan CF, Berman JW. Cytokine production by human fetal microglia, and astrocytes. Differential

induction by lipopolysaccharide and IL1. J Immunol 1993; 150:

2659-67.

[76] Sebire G, Emilie D, Wallon C, et al. In vitro production of IL-6, IL-1, and TNF- by human embryonic microglial, and neural cells.

J Immunol 1993; 150: 1517-23.

[77] Jenner P. Oxidative stress in Parkinson’s disease. Ann Neurol 2003; 53: S26-38.

[78] Gao HM, Zhou H, Hong JS. NADPH oxidases: novel therapeutic targets for neurodegenerative diseases. Trends Pharmacol Sci 2012;

33: 295-303.

[79] Jenner P, Olanow CW. Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 1996; 47: S161-70.

[80] Izumi Y, Sawada H, Yamamoto N, et al. Iron accelerates the con- version of dopamine-oxidized intermediates into melanin and pro- vides protection in SH-SY5Y cells. J Neurosci Res 2005; 82: 126- 37.

[81] Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med 1996; 334: 1717-25.

[82] Idriss HT, Naismith JH. TNF- and the TNF receptor superfamily:

structure-function relationship(s). Microsc Res Tech 2000; 50: 184- 95.

[83] Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104:

487-501.

[84] Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF. A metalloproteinase disintegrin that releases tumournecrosis factor-alpha from cells. Nature 1997; 385: 729-33.

[85] Wang J, Al-Lamki RS, Zhang H, Kirkiles-Smith N, Gaeta ML, Thiru S. Histamine antagonizes tumor necrosis factor(TNF) signalling by stimulating TNF receptor shedding from the cell surface and Golgi storage pool. J Biol Chem 2003; 278: 21751- 60.

[86] Sharma V, Thakur V, Singh SN, Guleria R.Tumor necrosis factor and Alzheimer’s disease: a cause and consequence relationship.

Bull Clin Psychopharmacol 2012; 22: 86-97.

[87] Feuerstein GZ, Liu T, Barone FC. Cytokines, inflammation, and brain injury: role of tumor necrosis factor-alpha. Cerebrovasc Brain Metab Rev 1994; 6: 341-60.

[88] Shohami E, Ginis I, Hallenbeck JM. Dual role of tumor necrosis factor alpha in brain injury. Cytokine Growth Factor Rev 1999; 10:

119-30.

[89] Nawashiro H, Martin D, Hallenbeck JM. Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res 1997;

778: 265-71.

[90] Butterfield DA, Drake J., Pocernich C, Castegna A. Evidence of oxidativedamage in Alzheimer’s disease brain: central role for amyloid betapeptide. Trends Mol Med 2001; 7: 548-54.

[91] Goodwin JL, Uemura E, Cunnick JE. Microglial release of nitric oxide by the synergistic action of-amyloid and IFN-. Brain Res 1995; 692: 207-14.

[92] Beattie EC, Stellwagen D, Morishita W, et al. Control of synaptic strength by glial TNF alpha. Science 2002; 295: 2282-5.

[93] Pickering M, Cumiskey D, O'Connor JJ. Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system.

Exp Physiol 2005; 90: 663-70.

[94] Domonkos A, Udvardy A, Laszlo L, Nagy T, Duda E. Receptor- like properties of the 26 kDa transmembrane form of TNF. Eur Cy- tokine Netw 2001; 12: 411-9.

[95] Nishimura M, Mizuta I, Mizuta E, et al. Tumor necrosis factor gene polymorphisms in patients with sporadic Parkinson's disease.

Neurosci Lett 2001; 311:1-4.

[96] Kruger R, Hardt C, Tschentscher F, et al. Genetic analysis of im- munomodulating factors in sporadic Parkinson's disease. J Neural Transm 2000; 107: 553-62.

[97] Wahner AD, Sinsheimer JS, Bronstein JM, Ritz B. Inflammatory cytokine gene polymorphisms and increased risk of Parkinson disease. Arch Neurol 2007; 64: 836-40.

[98] Dijke PT, Hill CS. New insights into TGF-beta-Smad signalling.

Trends Biochem Sci 2004; 29: 265-73.

[99] Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Trans- forming growth factor- regulation of immune responses. Annu Rev Immunol 2006; 24: 99-146.

[100] Hamaguchi T, Okino S, Sodeyama N, et al. Association of a polymorphism of the transforming growth factor-b1 gene with cerebral amyloid angiopathy. J Neurol Neurosurg Psychiatry 2005; 76: 696- 9.

(8)

[101] Caraci F, Spampinato S, Sortino MA, et al. Dysfunction of TGF-1 signaling in Alzheimer's disease: perspectives for neuroprotection.

Cell Tissue Res 2012; 347: 291-301.

[102] Taipale J, Saharinen J, Keski-Oja J. Extracellular matrixaassociated transforming growth factor-beta: role in cancer cell growth and in- vasion. Adv Cancer Res 1998; 75: 87-134.

[103] Grainger DJ, Heathcote K, Chiano M, et al. Genetic control of the circulating concentration of transforming growth factor type beta1 Hum Mol Genet 1999; 8: 93-97.

[104] Syrris P, Carter ND, Metcalfe JC, et al. Transforming growth factor-1 gene polymorphisms and coronary artery disease. Clin Sci 1998; 5: 659-67.

[105] Awad MR, El-Gamel A, Hasleton P, Turner DM, Sinnott PJ, Hutchinson IV. Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor- beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation 1998; 66: 1014-20.

[106] Chao CC, Hu S, Frey WH, Ala TA, Tourtellotte WW, Peterson PK.

Transforming growth factor beta in Alzheimer’s disease. Clin Diag Lab Immunol 1994; 1: 109-10.

[107] Flanders KC, Lippa CF, Smith TW, Pollen DA, Sporn MB. Altered expression of transforming growth factor-beta in Alzheimer’s disease. Neurology 1995; 45: 1561-9.

[108] Van der Wal EA, Gomez-Pinilla F, Cotman CW. Transforming growth factor-beta 1 is in plaques in Alzheimer and Down patholo- gies. Neuroreport 1993; 4: 69-72.

[109] Masliah E, Ho G, Wyss-Coray T. Functional role of TGFbeta in Alzheimer’s disease microvascular injury: lessons from transgenic mice. Neurochem Int 2001; 39: 393-400.

[110] Mogi M, Harada M, Kondo T, Narabayashi H, Riederer R, Na- gatsu T. Transforming growth factor-l 1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson's disease. Neurosci Lett 1995; 193: 129-32.

[111] Carvey PM, Ptak LR, Nath ST, et al. Striatal extracts from patients with Parkinson's disease promote dopamine neuron growth in mesencephalic cultures. Exp Neurol 1993; 120: 149-52.

[112] Yu SJ, Lo ES, Cochran EJ, et al. Cerebrospinal fluid from patients with Parkinson's disease alters the survival of dopamine neurons in mesencephaiic culture. Exp Neurol 1994; 126: 15-24.

[113] Wyss-Coray T. TGF- Pathway as a Potential Target in Neurode- generation and Alzheimer’s. Curr Alzheimer Res 2006; 3: 191-5.

[114] Sawada M, Imamura K, Nagatsu T. Role of cytokines in inflammatory process in Parkinson’s disease. J Neural Transm Suppl 2006;

70: 373-81.

[115] Gruol DL, Nelson TE. Physiological and pathological roles of interleukin-6 in the central nervous system. Mol Neurobiol 1997;

15: 307-39.

[116] Gadient RA, Otten UH. Interleukin-6 (IL-6)-a molecule with both beneficial and destructive potentials. Prog Neurobiol 1997; 52:

379-90.

[117] O’Hara J, Paul WE. Receptors for B-cell stimulatory factor-1 expressed on cells of hematopoietic lineage. Nature 1987; 325: 537- 40.

[118] Vallieres L, Rivest S. Regulation of the genes encoding IL-6, its receptor, and gp130 in the rat brain in response to the immune acti- vator lipopolysaccharide and the proinflammatory cytokine IL- 1beta. J Neurochem 1997; 69: 1668-83.

[119] Frei K, Malipiero UV, Leist TP, Zinkernagel RM, Schwab ME, Fontana A. On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur J Im- munol 1989; 19: 689 -94.

[120] Marz P, Cheng JG, Gadient RA. Sympathetic neurons can produce and respond to interleukin 6. Proc Natl Acad Sci USA 1998; 95:

3251- 6.

[121] Campbell IL. Transgenic mice and cytokine actions in the brain:

bridging the gap between structural and functional neuropathology.

Brain Res Rev 1998; 26: 327-36.

[122] Gadient RA, Otten UH. IL-6—a molecule with both beneficial and destructive potentials. Prog Neurobiol 1997; 52: 379 -90.

[123] Gruol DL, Nelson TE. Physiological and pathological roles of IL-6 in the central nervous system. Mol Neurobiol 1997; 15: 307-39.

[124] Murphy PG, Altares M, Gauldie J, Richardson PM. IL-6 promotes survival of sensory neurons. Neuroscience 1997; 23: 890.

[125] Rodriguez M, Pavelko KD, McKinney CW, Leibowitz JL. Recom- binant human IL-6 suppresses demyelination in a viral model of multiple sclerosis. J Immunol 1994; 153: 3811-21.

[126] Czlonkowska A, Jastrzebska IK, Cztonkowski A. Immune processes in the pathogenesis of Parkinson’s disease—a potential role for microglia and nitric oxide. Med Sci Monit 2002; 8: 165-77.

Received: October 10, 2015 Accepted: November 24, 2015

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