Cytokines In Noninfectious Central Nervous System Disease

The Parkinson's-Reversing Breakthrough

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4.1. Multiple Sclerosis

MS is the most common neurological disorder of young adults. The majority of patients are diagnosed with MS during their third or fourth decade of life and thus suffer the effects of the disease for most of their adult life. Most patients with MS initially exhibit periods of disease exacerbations mixed with periods of disease remission (termed relapsing-remitting MS); however, over time, most patients enter a period of increased disability that is characterized by chronic inflammation without periods of significant disease remission (termed secondary progressive MS). Progressive disability in MS may be associated with axonal pathology that is likely initiated following acute inflammatory events during the early course of disease. It should be noted that approx 15% of MS patients exhibit a progressive course of disease without remissions from the onset. This is termed primary progressive MS and is generally characterized by less acute inflammation, as determined by MRI, and an escalated rate of development of disability (280,281). The cause of MS is unknown although epidemiological studies, as well as studies examining identical twins, suggest that both genetics and environment, particularly viral infection, may have a role in pathogenesis (282-284). T cells that are autoreactive to CNS antigens are believed to initiate MS. These autoreactive T cells may be activated in the periphery by microbial antigens exhibiting cross-reactivity to CNS antigens in a process termed molecular mimicry (285,286). An autoimmune etiology of MS is further supported by the observation that MS is characterized by perivascular mononuclear cell inflammatory infiltrates and demyelination, features also characteristic of EAE, an established T-cell-mediated autoimmune disorder (described in detail in Section 4.1.1) (282,287,288). Activated T cells are capable of extravasating through the BBB into the CNS. These activated T cells elicit a variety of cytokines and chemokines capable of activating resident brain microglia and astrocytes, as well as stimulating the migration of both CNS glia and peripheral macrophages to sites of CNS inflammation. Activated leukocytes, as well as resident glia, are believed to contribute to the demyelination characteristic of MS. The Food and Drug Administration has recently approved multiple drugs for use in the treatment of MS (289,290). These drugs include IFN-P and glatiramer acetate that possess potent immunomodulatory activities and are preferable to previous MS therapies, including the immunosuppressive corticosteroids. IFN-P and glatiramer acetate likely modulate MS disease activity in part by modulating cytokine production by peripheral immune cells, as well as by resident CNS cells. It should be noted that because these new therapeutic agents do not cure disease, better treatment strategies for MS need development.

4.1.1 Cytokine Modulation of T-Cell Phenotype

EAE is an autoimmune disorder characterized by CNS inflammation, demyelination, and remittent paralysis, features consistent with MS (282). During recent years, the understanding of immunologic mechanisms involved in demyelination has advanced greatly through the investigation of EAE, which can be induced either by active immunization of susceptible animals with components of myelin or by adoptive transfer of CD4+ T cells specific for myelin antigens into syngeneic recipients (291,292). The adoptive transfer experiments have clearly established that EAE is a T-cell-mediated autoimmune disease. CD4+ T cells exhibit two distinct patterns of cytokine production and are designated Th1 and Th2 cells, both of which are believed to derive from a common precursor. Th1 cells produce IL-2, IFN-y, TNF-a, andTNF-p/lymphotoxin. Th1 responses are associated with cell-mediated immunity and are responsible for delayed-type hypersensitivity. Th2 cells are characterized by the production of IL-4, -5, -6, -10, and -13. Th2 responses are associated with humoral immunity, enhanced antibody production by

B cells, and induction of the allergic response (293). The cytokines IL-12 and IFN-y are critical for the differentiation of Th1 cells, whereas IL-4 is pivotal for the differentiation of Th2 cells (293). In EAE, Th1 cells are believed to be encephalitogenic, whereas Th2 cells may be protective (294-297). In this section, we discuss the importance of four cytokines (IL-12, -18, -10, and -4) that have an important role in dictating Th1 vs Th2 responses in the context of MS and EAE.

IL-12 is an important mediator of EAE and MS. In the CNS, IL-12 is produced by microglia (298-300) and possibly at low levels in astrocytes (301). The presence of IL-12 p40 RNA early in disease suggests a role for IL-12 in the initiation of MS (302). In addition, IL-12 levels also appear to correlate with MS disease progression (303,304). The functional importance of IL-12 in EAE was revealed by studies demonstrating that the administration of exogenous cytokine increases disease severity (305) and that IL-12 antibodies inhibit the development of EAE (306). Similarly, EAE does not develop in IL-12-p40-deficient mice (307). The role of IL-12 in the pathogenesis of EAE is likely to involve the generation of encephalogenic Th1 cells. Indeed, IL-12 triggers Th1 differentiation in vitro (308,309) and in vivo (310). The cytokine also induces T-cell proliferation and IFN-y production (311,312). Several studies have revealed that IL-12 and IFN-y cooperate in stimulating the development of Th1 cells. This likely represents an important mechanism for the generation of encephalogenic Th1 cells in MS and EAE, since both cytokines are present in the inflamed CNS. The importance of IL-12 in regulating IFN-y production is supported by studies in mice lacking IL-12 or signal transducers and activators of transcription (STAT-4) (which is responsible for IL-12 signaling) that exhibit impaired IFN-y production (313315). IFN-y stimulates monocytes to produce IL-12 (316,317) and T cells to express IL-12R (318). Therefore, the interplay between IL-12 and IFN-y in regulating Th1 development suggests that these cytokines are pivotal in dictating the pathogenesis of MS and EAE. It should be noted that some of the actions attributed to IL-12 in modulating MS and EAE may actually be due to IL-23 because these cytokines both function as heterodimers and share a common p40 subunit. IL-12 consists of a p40/p35 heterodimer, whereas IL-23 exists as a heterodimer containing p40 and p19. The observation that p35-deficient mice are susceptible to EAE, whereas p40-deficient mice are not susceptible may suggest that IL-23 plays a more important role than IL-12 in modulating EAE (reviewed in ref. 318a).

Another cytokine that has been implicated in the development of EAE and MS is IL-18. In the CNS, IL-18 is produced by microglia and possibly by astrocytes (143,319). Increased levels of IL-18 RNA were observed in the brains of rodents with EAE (320), and IL-18 protein is expressed in demyelinating brain lesions in MS (321). Furthermore, the level of Casp-1, the protein responsible for the activational cleavage of IL-18, correlates with the severity of EAE (322) and MS (323). In EAE, IL-18-neutralizing antibodies blocked the disorder, suggesting that this occurred because of a shift in the Th1/Th2 balance toward Th2 cells (324). The effects of IL-18 in MS and EAE are likely mediated by its ability to influence Th1 development. For example, IL-18 alone does not induce the formation of Th1 cells, but it greatly potentiates Th1 development in response to IL-12 (325). Similar to the cooperative effects of IL-12 and IFN-y, IL-18 has also been shown to associate with these cytokines to influence T-cell activation. For example, IL-18, together with IL-12, synergistically induces T cells to produce IFN-y (326-328). In addition, IL-12 induces the expression of IL-18R on Th1 cells, whereas IL-18 stimulates IL-12R expression (329,330). Thus, the synergistic induction of IFN-y by Th1 cells in response to IL-12 and IL-18 may result in part from this reciprocal induction of their corresponding receptors, although the synergistic induction of IFN-y by IL-12 and IL-18 may occur through alternative mechanisms. For example, IL-12 signals are transduced by STAT-4 (331), and IL-18 activates NF-kB (332). The IFN-y-gene promoter contains binding elements for these transcription factors (333), suggesting that these proteins may synergistically induce transcription of the IFN-y gene. The complex interactions between IL-18, IL-12, and IFN-y likely dictate the nature and extent of encephalogenic Th1 development in MS and EAE.

IL-10 is a cytokine that may function to limit the extent of inflammation in MS and EAE. IL-10 is principally produced by Th2 cells that are considered protective in these diseases. Other cells, including antigen-presenting macrophages and B cells, also produce this cytokine (334,335). In the CNS, microglia and astrocytes are both capable of producing IL-10 (336-341). Because IL-10 levels appear to inversely correlate with symptoms in patients with MS, the cytokine may have a protective role in disease (342-344). Numerous studies indicating that IL-10 suppresses disease directly support its protective role in EAE (345-348). IL-10 may regulate the extent of neuroinflammation in MS and EAE through its ability to repress IFN-y production by Th1 cells, which favors Th2 differentiation (349). In turn, IFN-y can also inhibit monocytes from expressing IL-10 (350,351), which favors development of Th1 cells. Thus, IFN-y and IL-10 cross-regulate each other's expression in monocytes and differentially affect T-cell phenotype. Based on IL-10's reported ability to attenuate disease severity in EAE, therapies designed to augment its expression in the CNS may have beneficial effects on the progression of MS.

IL-4 is a cytokine produced by Th2 cells that also has a critical role in their differentiation. This cytokine is also produced by eosinophils, mast cells, and NK cells. Administration of IL-4 has been demonstrated to suppress EAE (352,353). Although some reports have indicated that IL-4 KO mice are more susceptible than WT controls to the development of EAE (354), other studies indicate that IL-4-deficient mice do not develop more severe disease (346,355,356). Thus, the role of IL-4 in the pathogenesis of EAE is somewhat controversial. Relevant to its reported protective effects in EAE, one of the principle functions of IL-4 involves the polarization of CD4+ T cells toward a Th2 phenotype. IL-4 also skews T cells toward a Th2 phenotype by suppressing the production of IFN-y-producing Th1 cells (357). IL-4 likely stimulates Th2 differentiation through activation of STAT-6 following receptor binding, which is supported by studies indicating that STAT-6 knockout mice have impaired Th2-cell differentiation and that activation of STAT-6 is sufficient to trigger Th2 differentiation (358,359). In response to IL-4, STAT-6 mediates the induction of the transcription factor GATA-3 (359,360). GATA-3 has a critical role in Th2 differentiation, and the expression of this protein is elevated during Th2 differentiation and decreased during Th1 differentiation (361,362). GATA-3 stimulates Th2 differentiation, at least in part, by inhibiting IFN-y (363). Future studies are needed to clarify the exact role of IL-4 in modulating the course of EAE.

4.1.2. Role of Innate Immune Cytokines in MS and EAE

In addition to autoreactive T cells, activated glia participate in the pathology associated with MS that is thought to result in part from the excessive production of TNF-a, IL-1P, and NO (58,364). NO is a gaseous molecule that performs a variety of cellular functions. It is produced by a series of enzymes termed NO synthases. Inducible NOS (iNOS) was first demonstrated in monocytes but is now known to be expressed in a variety of cells, including microglia and astrocytes. Expression of iNOS is stimulated by a variety of inflammatory cytokines (e.g, IFN-y, TNF-a, and IL-1P, which are elevated in patients with MS) and bacterial products, including lipopolysac-charide (LPS) (365). Although molecules including NO, TNF-a, and IL-1P may be toxic to pathogens, these agents can also be toxic to CNS cells, including myelin-producing oligodendrocytes (58), which are compromised in MS (366). These molecules may also be toxic to neurons and thus may contribute to axonal degeneration characteristic of MS (75), although there is also compelling evidence that NO, TNF-a, and IL-1P may contribute to the resolution of CNS inflammatory conditions, particularly in vivo (22,367). These issues are discussed in detail in the following paragraphs.

In vitro, activated glia can produce molecules, including NO, TNF-a, and IL-1p. The vast majority of studies indicate that these molecules are toxic to oligodendrocytes in vitro, suggesting that they may contribute to the pathogenesis of MS. Specifically, TNF-a and IL-1P are reportedly toxic to oligodendrocytes and oligodendrocyte-precursor cell lines (68-74,77). Likewise, NO has also been demonstrated to be toxic to these cells (368-370). Interestingly, a few studies indicate that NO can exert either toxic or protective effects on oligodendrocytes, depending on the intracellular redox state of the cells (371,372).

In vivo studies have suggested that NO and proinflammatory cytokines may suppress or alternatively contribute to CNS inflammation and degeneration. A potential dual role for numerous proin-flammatory mediators in the context of CNS inflammatory diseases is a theme that is just beginning to be appreciated. For example, inhibition of NO synthesis has been reported to block development of EAE (373-375). Furthermore, NO reacts with superoxide to form peroxynitrite, which is a strong lipid-peroxidizing agent capable of altering myelin integrity (376). Peroxynitrite has been detected in the CNS in both EAE and MS (377,378), suggesting it may contribute to NO-stimulated oligodendrocyte death. These findings indicate that agents that inhibit NO synthesis may be effective in the treatment of MS. Contrary to these studies, mice genetically deficient in iNOS are susceptible to the development of EAE. In fact, these animals exhibit earlier onset of disease and increased disability than do WT mice (379,380). Increased severity of EAE in iNOS KO mice may be explained in part by studies indicating that NO has a critical role in the resolution of EAE by inhibiting T-cell proliferation in established disease (381). A dual role for NO in the inductive vs resolution phases of EAE is supported by studies in Lewis rats that generally exhibit monophasic disease on active immunization with myelin basic protein (MBP) in the presence of CFA. For example, treatment of recovered rats with the NO-synthase inhibitor ^-methyl-L-arginine acetate precipitated a second episode of disease (382). Administration of the selective iNOS inhibitor aminoguanidine indicated that NO is a pathogenic factor in the inductive phase and has an inhibitory role in the progressive phase of EAE (383). Inhibition of iNOS production using antisense oligonucleotides immediately following the transfer of myelin-specific T cells further supports the conclusion that NO is pathogenic in the inductive phase of EAE (375). Collectively, these studies indicate that the role of NO in EAE and MS is complex and is likely dictated by the timing of its expression during disease and/or the local concentrations achieved within the CNS microenvironment.

The role of TNF-a in vivo in modulating EAE is also controversial. Many studies indicate that genetic deficiency of TNF-a results in the development of EAE that is not significantly different or is less severe than in WT animals (384-386). Neutralization of TNF-a activity also reportedly results in less severe EAE (387,388). This reduction in disease severity may result primarily from decreased movement of leukocytes into the CNS parenchyma (389). Studies demonstrating that MBP-specific T-cells retrovirally transduced to express TNF-a increased the severity of EAE, support the idea that this cytokine has a pathogenic role in the disease (390). Conversely, other studies demonstrate that TNF-a-deficient mice develop more severe EAE and that TNF-a treatment reduces the severity of their disease (391,392). Elucidation of the role of TNF-a in EAE has been complicated by the fact that both lymphotoxin and TNF receptors can also influence the initiation and clinical course of EAE (393-397).

IL-1 likely contributes to pathogenesis in EAE, as reflected by studies demonstrating that IL-1 administration increases disease severity (398). In addition, targeted disruption of the IL-1RI gene and IL-1-receptor antagonist studies indicate that IL-1 receptors are critical for the development of EAE (399-401); however, priming with IL-1P can suppress the development of EAE, likely through effects on the hypothalamus-pituitary-adrenal axis (402). Therefore, further studies must be conducted to clarify the role of IL-1 and IL-1 receptors in EAE and MS.

Recent studies have begun to clarify the apparently disparate roles of NO, TNF-a, and IL-1P in demyelinating disorders using a cuprizone model of demyelination. Although it is acknowledged that the mechanisms of remyelination in the cuprizone model may be distinct from EAE, the cuprizone system offers advantages, such as the ability to control remyelination temporally, which is very difficult to achieve in the EAE model. In the cuprizone model, the genetic deficiency of either TNF-a and IL-1P resulted in the failure to remyelinate, likely the result of the inability of oligodendrocyte precursors to differentiate into mature oligodendrocytes (76,78). Inducible NOS KO mice also exhibited an inability to remyelinate following cuprizone administration that was coincident with the depletion of mature oligodendrocytes (403). Additional studies indicated that TNFR2, and not TNFR1, is critical to oligodendrocyte regeneration (403). Interestingly, previous studies in the EAE model suggested that TNFR1, and not TNFR2, may contribute to the initial exacerbation of disease because of increased demyelination (70,391,399). Collectively, these studies suggest that NO, TNF-a, and IL-1P likely contribute to the inductive phase of EAE but also are critical for remyelination and resolution of existing disease. The studies also suggest that the efficacy of therapies designed to alter the expression or function of NO, TNF-a, and IL-1P may depend on the timing of drug administration.

In summary, cytokines are critical mediators of MS and EAE. IFN-y and IL-12 have a pivotal role in Th1 differentiation, which is associated with the development of these disorders, whereas IL-4 is critical in Th2-cell differentiation, which protects against the diseases. Cytokines elicited by T cells also control the responses of innate immune cells, including peripheral macrophages and CNS-derived microglia and astrocytes. On activation, these cells produce cytokines, including TNF-a and IL-1P, as well as NO. These molecules are required for the resolution of microbial infections; however, in the context of noninfectious neuroinflammatory disorders, such as MS and EAE, these mediators may also be toxic to oligodendrocytes and neurons. Interestingly, these same molecules appear to facilitate remyelination and thus may facilitate recovery from disease. Therefore, future therapies designed to regulate the expression of these molecules must consider their dual role in exacerbating and resolving disease. Experimentally, it is difficult to assess the role of specific cytokines in modulating EAE because of the redundant activities of these mediators. Future studies involving the conditional knock-in and knock-out of genes encoding these cytokines will be useful in determining the role of the cytokines in modulating disease.

4.2. Alzheimer's Disease

AD is the most common form of dementia. The disease is characterized by progressive neurodegeneration associated with impairment of memory, deterioration of language skills, altered judgment, confusion, and restlessness. The incidence of AD increases with age, and the probability of developing the disease approximately doubles every 5 yr beyond the age of 65. Concerns exist that the personal and societal costs of AD may become staggering as life expectancy increases in developing countries. The causes of AD are not completely understood. Approximately 5 to 10% of AD cases are familial and linked to gene mutations, whereas the majority of cases are sporadic in nature. AD is characterized by brain atrophy resulting from loss of neurons and the presence of neurofibrillary tangles as well as amyloid plaques containing P-amyloid peptide (P-AP). This peptide has a tendency to aggregate and is highly insoluble (404,405).

Several lines of evidence suggest that inflammation contributes to the neuropathology associated with AD. For example, many clinical studies have indicated that anti-inflammatory drugs, including nonsteroidal anti-inflammatory drugs, protect against the development of AD (406-408). In addition, large numbers of activated microglia and astrocytes are observed in the brains of patients with AD (409-411). Activated microglia (and possibly astrocytes) may contribute to AD pathology, likely through the production of neurotoxic molecules, including inflammatory cytokines. In addition to CNS parenchymal cells, a limited number of T cells can be observed near postcapillary venules in areas of severe inflammation in the brains of patients with AD (412), although cell-mediated immunity is not believed to take place in AD. It is possible however, that these limited T cells may contribute to AD pathology through the production of IFN-y, which potently stimulates the production of inflammatory cytokines by microglia and astrocytes. The localization of activated glia near amyloid plaques supports the hypothesis that these cells contribute to neurodegeneration. For example, active amyloid plaques that contain degenerating neuritic processes (designated neuritic plaques) are associated with activated microglia. Activated astrocytes are also observed at the periphery of these neuritic plaques; however, end stage burnt out plaques are devoid of injured neuritic processes as well as activated glia

(413,414). Finally, a tremendous variety of proinflammatory mediators are observed in the brains of patients with AD. These include cytokines, chemokines, complement proteins, acute phase reactants, and oxidative stress molecules (415). As mentioned previously, AD is characterized by the presence of neurofibrillary tangles and plaques associated with the highly insoluble P-AP. Although inflammation is not likely to initiate disease, it is highly probable that inflammation perpetuates neurodegeneration through the production of proinflammatory and neurotoxic molecules by activated glia in response to insoluble P-AP. The following sections focus on the role of cytokines in mediating AD pathogenesis.

A variety of cytokines are associated with AD plaques, including IL-1a, IL-1P, IL-6, TNF-a, and TGF-P (413,415-422). These cytokines are produced by activated glia and some (IL-1P and TNF-a) are capable of perpetuating glial activation, leading to a cycle of overproduction of these potentially neurotoxic molecules. It should be noted, however, that these same cytokines at low concentrations may be neuroprotective. Microglia isolated post-mortem from AD patients have been shown to either constitutively express cytokines, including IL-1P, IL-6, and TNF-a, or produce these cytokines in response to P-AP (423). Likewise, P-AP and other amyloid-associated proteins are capable of stimulating the production of these same cytokines by rodent glia (415,423-425). Polymorphisms in the regulatory regions of the genes that encode these cytokines have been demonstrated to affect the risk of developing AD (426-433). The probability of developing AD is increased in individuals who exhibit more than one of these high-risk cytokine alleles.

As mentioned previously, a variety of cytokines, including IL-1, IL-6, TNF-a, and TGF-P, are expressed in the brains of AD patients. Each of these cytokines may contribute to or alternatively protect against neuropathology associated with neuroinflammatory disorders, including AD. The strongest evidence for cytokine involvement in the pathology of AD originates from studies of IL-1. Griffin et al. (416) first described IL-1 overexpression in AD. IL-1 is primarily associated with microglia surrounding AD plaques (434). Importantly, microglial expression of IL-1 correlates with the transformation of AD plaques. For example, diffuse non-neuritic pre-amyloid deposits contain microglia expressing relatively low levels of IL-1, whereas neuritic plaques are associated with microglia expressing high levels of this cytokine. Finally, end-stage burnt out plaques devoid of neuritic structures also lack IL-1-expressing microglia (413). These studies suggest that IL-1 contributes to neuron loss in AD (435).

IL-1 may stimulate neuron death in AD through a number of mechanisms. First, IL-1 stimulates the synthesis (436,437) and processing of P-amyloid precursor protein (PAPP), thus promoting the release of amyloid proteins. Furthermore, IL-1 activates glia (438-440), which perpetuates the continued release of neurotoxic molecules by these cells. IL-1 also stimulates the release of S-100B by astrocytes (420). This molecule contributes to the pathology associated with AD by promoting neuritic growth (441) and stimulating increased intracellular calcium levels in neurons, which may lead to cell death (442). Additional support for the role of IL-1 in AD pathogenesis comes from studies indicating that polymorphisms in the genes encoding IL-1a and IL-1P can increase the risk of developing disease (428,429). These polymorphisms are associated with increased production of IL-1 a and IL-1P, which supports the role of these cytokines in the pathogenesis of disease (443,444).

In summary, additional studies demonstrating the functional involvement of cytokines in the pathogenesis of AD are needed to begin to understand the role of these mediators in dementia; however, these types of studies have been limited to date by the lack of available animal models of AD in cytokine KO mice. The generation of cytokine transgenic or KO mice in Alzheimer's-susceptible strains would facilitate the establishment of the role of individual mediators in disease pathogenesis.

4.3. Parkinson's Disease

Parkinson's disease (PD) is a common progressive neurodegenerative disorder characterized by motor system dysfunction. Patients commonly exhibit tremor, rigidity, bradykinesia or slowness of movement, and postural instability or impaired balance and coordination. PD is distinguished neu-ropathologically by the selective loss of dopaminergic neurons of the substantia nigra and in related brainstem nuclei. Loss of the neurotransmitter dopamine results in uncontrolled firing of spared neurons, resulting in movement disorders in patients. The causes of PD as well as the mechanisms that result in neurodegeneration are largely unknown. Inheritance contributes to the development of familial forms of the disease, which represent only about 10% of all cases of PD. Most forms of PD are sporadic in nature and are not inherited. Oxidative stress and mitochondrial dysfunction have been suggested to have roles in PD (445). Metabolism of dopamine results in increased production of free radicals that may be toxic to dopaminergic neurons. Increased lipid peroxidation and iron levels and decreased glutathione transferase observed in the substantia nigra of patients with PD supports a hypothesis that reactive oxygen formation may contribute to pathology (446). The finding that complex I of the mitochondrial respiratory chain is defective in some patients with PD, in addition to the identification of missense mutations in mitochondrial complex I genes (447), supports mitochondrial dysfunction as a contributor to the development of disease (448,449).

There are several lines of evidence to suggest that neuroinflammation plays a role in the degeneration of dopaminergic neurons in PD. Seminal studies by McGeer demonstrated elevated levels of human leukocyte antigen-DR positive microglial cells in the substantia nigra of patients with PD (450). These findings are supported by studies of a cohort of patients who developed parkinsonian syndrome following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication during drug use (451). Postmortem neuropathology studies of these individuals demonstrated that years following MPTP intoxication, reactive gliosis and activated microglia clustered around dopaminergic neurons were still evident in the CNS. These studies suggest that following an initiating event, reactive glia may perpetuate neurodegeneration in parkinsonian syndromes. Although the initiating event in these studies was MPTP intoxication, the initiating event in the development of most cases of PD is unknown. Animal models of PD support the hypothesis that activated glia contribute to neurodegeneration. In vitro studies demonstrate that LPS, a potent activator of glia, is capable of killing dopaminergic neurons in culture and that loss of neurons is more profound in neuron-glial mixed cultures. This suggests that products of activated glia contribute to neuron death (452). Furthermore, agents including methylphenylpyridinium or 6-hydroxydopamine were shown to be directly toxic to dopaminer-gic neurons, which was enhanced when the cells were co-cultured with activated astrocytes (453). In vivo studies demonstrated that LPS injected into rats damaged dopaminergic neurons in the substantia nigra without damaging GABAergic and serotoninergic neurons (454,455). Interestingly, dexamethasone, a potent immunosuppressive agent, inhibited microglial/ macrophage activation and protected dopaminergic neurons in this in vivo model (456). Collectively, these studies suggest that activated glia contribute to the loss of dopaminergic neurons observed in PD.

A variety of cytokines are expressed at higher levels in the substantia nigra, striatum, and/or CSF of patients with PD relative to control subjects. These include TNF-a, IL-ip, IL-6, and TGF-P that are known to be produced by glia, and IL-2, IL-4, and IFN-y produced primarily by T and/or NK cells (457). The potential role of these cytokines in mediating PD has not been elucidated; however, as previously mentioned, TNF-a and IL-ip elicited by activated glia may be directly toxic to neurons. TGF-P is an anti-inflammatory cytokine capable of suppressing glial activation and thus may aid in the resolution of inflammation associated with PD. CD4+ and CD8+ T cells have been shown to infiltrate the CNS of MPTP-intoxicated rodents (458). In addition, CD8+ T cells have been identified in the substantia nigra of patients with PD, although the abundance of T cells in the CNS in these disorders is relatively low and their potential role in modulating PD has not been defined. It is possible that the limited number of T cells present in the CNS in parkinsonian disorders may affect the viability of dopaminergic neurons by eliciting cytokines, such as IFN-y and IL-4 that control the activation state of glia. This possibility is supported by the fact that both IL-4 and IFN-y have been detected in the brain tissue and CSF of patients with PD.

Hunet et al. (459) present two hypotheses that may explain how cytokines could cause neurodegeneration in PD. They suggest that proinflammatory cytokines, including IFN-y, TNF-a, and IL-1P, may stimulate production of NO by glial cells. Although NO can protect neurons under some circumstances, in profound inflammatory conditions, NO likely contributes to neuron cell death, possibly through lipid peroxidation. In support of this hypothesis, glia expressing iNOS have been identified in the substantia nigra of patients with PD (460) and NO has been observed in the CSF of these patients (461). Hunet et al. further hypothesize that TNF-a produced by activated glia may stimulate the death of TNFR1-expressing dopaminergic neurons by activating the TNFR1 signaling pathway, which, under certain conditions, is capable of inducing apoptosis.

Studies demonstrating that anti-inflammatory drugs are capable of suppressing neurodegeneration in animal models of PD support the notion that inflammation contributes to disease. These anti-inflammatory drugs likely suppress disease, at least in part, by modulating the expression of both pro- and anti-inflammatory cytokines. In general, modification of a single inflammatory pathway has not proved effective in protecting dopaminergic neurons in these model systems (462). Inhibition of apoptotic pathways using Casp inhibitors have also proved largely ineffective in preventing neurodegeneration (463). Agents with a broader spectrum of anti-inflammatory actions have been more effective in protecting dopaminergic neurons in these models. For example, the peroxisome proliferator-activated receptor-y agonist pioglitazone blocked glial activation and protected dopaminergic neurons in the substantia nigra of MPTP-treated mice (464), although pioglitazone neither suppressed glial activation nor protected neurons in the striatum. These and other studies suggest that the mechanisms that regulate glial cell activation and neuron viability may be different in the terminals relative to cell bodies of dopaminergic neurons. Minocycline, a tetracycline derivative, has been demonstrated to block glial cell activation and protect neurons in the entire stratoni-gral system in MPTP and in 6-hydroxydopamine-treated rats (465-467). This suggests the intriguing possibility that minocycline or other broad-spectrum anti-inflammatory agents may be effective in delaying the progression of PD.

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