Glial cell response: A pathogenic factor in Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of these neurons is associated with a glial response composed mainly of activated microglial cells and, to a lesser extent, of reactive astrocytes. This glial response may be the source of trophic factors and can protect against reactive oxygen species and glutamate. Alternatively, this glial response can also mediate a variety of deleterious events related to the production of pro-oxidant reactive species, proinflammatory prostaglandin, and cytokines. In this review, the authors discuss the potential protective and deleterious effects of glial cells in the SNpc of PD and examine how these factors may contribute to the pathogenesis of this disease.     

The role of glial cells in Parkinson's disease

Parkinson's disease is a common neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta. The loss of these neurons is associated with a glial response composed mainly of activated microglial cells and, to a lesser extent, of reactive astrocytes. This glial response may be the source of trophic factors and can protect against reactive oxygen species and glutamate. Aside from these beneficial effects, the glial response can mediate a variety of deleterious events related to the production of reactive species, and pro-inflammatory prostaglandin and cytokines. This article reviews the potential protective and deleterious effects of glial cells in the substantia nigra pars compacta of Parkinson's disease.     

Tribute to Pasquale Montagna, 1950–2010

Dopaminergic neurons are selectively vulnerable to oxidative stress and inflammatory attack. The neuronal cell loss in the substantia nigra is associated with a glial response composed markedly of activated microglia and, to a lesser extent, of reactive astrocytes although these glial responses may be the source of neurotrophic factors and can protect against oxidative stress such as reactive oxygen species and reactive nitrogen species. However, the glial response can also mediate a variety of deleterious events related to the production of pro-inflammatory, pro-oxidant reactive species, prostaglandins, cytokines, and so on. In this review, we discuss the possible protective and deleterious effects of glial cells in the neurodegenerative diseases and examine how these factors may contribute to the pathogenesis of Parkinson’s disease. This review suggests that further investigation concerning glial reaction in Parkinson’s disease may lead to disease-modifying therapeutic approaches and may contribute to the pathogenesis of this disease.     

Neurodegeneration and inflammation in Parkinson's disease

Parkinson's disease (PD) is characterized by the progressive degeneration of dopamine (DA) neurons of the substantia nigra pars compacta (SNpc) accompanied by a buildup of proteinaceous aggregates termed Lewy bodies (LB). In addition to protein aggregation and the loss of DA signaling, PD is also characterized by an active immune response. T-cell infiltration accompanies activated microglial and astrocytic accumulation in and around the SNpc. Although potentially beneficial, microglial activation is most likely responsible for furthering disease pathology and DA neuron degeneration through the release of harmful substances such as pro-inflammatory cytokines, reactive oxidative species and reactive nitrogen species. Activation of the NF-κB death pathway has been shown to occur following microglial activation related release of Cox-2, IL-1β, and Toll-like receptor activation, resulting in increased degeneration of DA neurons of the SNpc. Blockade of microglial activation can lead to DA neuron protection in animal models of PD; however, clinical application of anti-inflammatory drugs has not yielded similar benefits. Future therapeutic designs must take into account the multifactorial nature of PD, including the varied roles of the adaptive and innate immune responses.     

Estrogen down-regulates glial activation in male mice following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication

Emerging evidence suggests beneficial effect of estrogen for Parkinson's disease (PD), yet the exact mechanisms implicated remain obscured. Activated glia observed in MPTP mouse model and in PD may participate in the cascade of deleterious events that ultimately leads to dopaminergic nigral neuronal death. In vitro studies demonstrate that estrogen can modify the microglial and astroglial expression of inflammatory mediator, such as cytokines and chemokines implicated in neuroinflammation and neurodegeneration. To determine whether estrogen-elicited neuroprotection in PD is mediated through glia, adult male C57Bl/6 mice were treated with 17beta-estradiol (E2) for a total of 11 days. Following 5 days of pretreatment with E2, they were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the sixth day. The brains were collected on day 11. Immunohistochemistry and quantitative study were used to assess the number of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantia nigra pars compacta (SNpc) and that of activated astrocytes and activated microglia in the SNpc and the striatum. Pretreatment with E2 decreased the loss of TH-IR nigral neurons and diminished the deficit of TH-IR striatal fibers triggered by MPTP. The neuroprotective effect of E2 was coincident with an attenuation of a glial response within the nigra and the striatum. These findings suggest that the neuroprotective effects of E2 evidenced in MPTP mouse model might mediate through an inhibition of reactive glia. However, direct neuroprotective effects of E2 upon TH-IR neurons cannot be excluded.     

The 6‐hydroxydopamine‐induced nigrostriatal neurodegeneration produces microglia‐like NG2 glial cells in the rat substantia nigra

Neuron/glial 2 (NG2)‐expressing cells are often referred to as oligodendrocyte precursor cells. NG2‐expressing cells have also been identified as multipotent progenitor cells. However, microglia‐like NG2 glial cells have not been fully examined in neurodegenerative disorders such as Parkinson's disease (PD). In the present study, we chose two rat models of PD, i.e., intranigral or intrastriatal injection of 6‐hydroxydopamine (6‐OHDA), since the cell bodies of dopamine (DA) neurons, which form a nigrostriatal pathway, are in the substantia nigra pars compacta (SNpc) while their nerve terminals are in the striatum. In the nigral 6‐OHDA‐injected model, activated NG2‐positive cells were detected in the SNpc but not in the striatum. In contrast, in the striatal 6‐OHDA‐injected model, these cells were detected in both the SNpc and the striatum. In both models, activated NG2‐positive cells were located close to surviving tyrosine hydroxylase (TH)‐positive neurons in the SNpc. In addition, activated NG2‐positive cells in the SNpc coexpressed ionized calcium‐binding adaptor molecule 1 (Iba1), a microglia/macrophage marker. Interestingly, these double‐positive glial cells coexpressed glial cell line‐derived neurotrophic factor (GDNF). These results suggest that microglia‐like NG2 glial cells may help protect DA neurons and may lead to new therapeutic targets in PD. © 2010 Wiley‐Liss, Inc.     

Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra

Brain-derived neurotrophic factor (BDNF) has potent effects on survival and morphology of dopaminergic neurons and thus its loss could contribute to death of these cells in Parkinson's disease (PD). In situ hybridization revealed that BDNF mRNA is strongly expressed by dopaminergic neurons in control substantia nigra pars compacta (SNpc). In clinically and neuropathologically typical PD, SNpc BDNF mRNA expression is reduced by 70% (P = 0.001). This reduction is due, in part, to loss of dopaminergic neurons which express BDNF. However, surviving dopaminergic neurons in the PD SNpc also expressed less BDNF mRNA (20%, P = 0.02) than their normal counterparts. Moreover, while 15% of control neurons had BDNF mRNA expression >1 SD below the control mean, twice as many (28%) of the surviving PD SNpc dopaminergic neurons had BDNF mRNA expression below this value. This 13% difference in proportions (95% CI 8-17%, P < or = 0.000001) indicates the presence of a subset of neurons in PD with particularly low BDNF mRNA expression. Moreover, both control and PD neurons displayed a direct relationship between the density of BDNF mRNA expression per square micrometer of cell surface and neuronal size (r(2) = 0.93, P 相似文献   

Role of Fcgamma receptors in nigral cell injury induced by Parkinson disease immunoglobulin injection into mouse substantia nigra

Immune/inflammatory factors have been implicated in the pathogenesis of Parkinson's disease (PD). Immunoglobulin G (IgG) from patients with PD can induce injury of dopaminergic neurons following stereotaxic injection into rat substantia nigra (SN). The PD IgG can be demonstrated in vitro to activate microglia via the Fcgamma receptor (Fcgamma R) and induce dopaminergic cell injury. To confirm the involvement of microglia and their Fcgamma R in IgG-induced lesions of SN in vivo we analyzed the tyrosine hydroxylase (TH)-positive cell loss in SN par compacta (SNpc) in mice lacking Fcgamma receptors (Fcgamma R(-/-)) and wild type (Fcgamma R(+/+)). At 1 day after stereotaxic injection of PD IgG into the SN of Fcgamma R(+/+) mice there was a 27% increase in the number of CD11b-positive microglial cells and no significant loss of TH-positive cells. At 14 days after the stereotaxic injection, the number of microglial cells was increased by 42%, accompanied by a 40% loss of TH-positive neurons in the SNpc. PD IgG injection in Fcgamma R(-/-) mice resulted in no significant increase of microglia and no loss of TH-positive cells in the SNpc at any time point. The injection of F(ab')(2) fragments of PD IgG was able to induce TH-positive neuronal loss in the SNpc only when the injected animals raised antibodies against the injected human IgG fragments, which confirmed the importance of the Fcgamma R in microglial activation and nigral injury.     

Low numbers and no loss of melanized nigral neurons with increasing age in normal human brains from India

The prevalence of Parkinson's disease (PD) is higher in whites than in nonwhites and it increases with advancing age. The pathological hallmarks of PD are loss of pigmented neurons in the substantia nigra pars compacta (SNpc) and presence of Lewy bodies. With increasing age, a similar loss of pigmented neurons in the SNpc has been reported. Hence, age and race possibly play a role in the pathogenesis of PD. The objectives of this study were to count the number of melanized neurons in the SNpc in normal human brains from India and study the change in neuronal count with advancing age and to compare the neuronal counts from this Indian population with counts reported in normal brains from the United Kingdom. Melanized neurons in the SNpc were counted in 84 normal human brains (age range, 5–84 years) in a single 7-μm section at the level of emergence of the oculomotor nerve. In the brains from India, there was no loss of melanized nigral neurons with advancing age. The absolute number of these melanized neurons was about 40% lower than the brains from UK. Despite a low number of melanized nigral neurons in the brains from India, individuals function normally and have dopamine levels comparable with their Western counterparts, suggesting that it is not the absolute number of melanized nigral neurons but the percent loss of nigral neurons that results in dopaminergic deficiency in PD. There is no significant loss of pigmented nigral neurons with age, suggesting that the loss seen in PD is exclusively due to the disease process itself. Indians have a lower prevalence of PD despite having a low count of melanized nigral neurons, suggesting that better protective mechanisms may be present in the Indians to prevent the loss of nigral neurons.     

Curcumin protects nigrostriatal dopaminergic neurons and reduces glial activation in 6-hydroxydopamine hemiparkinsonian mice model

This study investigated the effects of curcumin on nigrostriatal dopaminergic (DA) neurons and glial response in 6-hydroxydopamine (6-OHDA) hemiparkinsonian mice. Following unilateral intrastriatal 6-OHDA injection, mice were daily injected with curcumin for seven days, beginning on the day of lesion. Seven days after 6-OHDA lesioning, sections from the striatum and the substantia nigra pars compacta (SNpc) were collected and immunohistochemically stained for DA neurons and reactive glia. Curcumin decreased 6-OHDA-induced loss of nigral tyrosine hydroxylase-immunoreactive (TH-IR) neurons and striatal TH-IR fibers. The neuroprotection was coincided with a significant attenuation of microglial and astroglial reaction in the SNpc and the striatum. These results suggest that the neuroprotective effects of curcumin in 6-OHDA-lesioned mice may be mediated through its anti-inflammatory properties or direct protection on nigral DA neurons, thereby reducing neuronal injury-induced glial activation.     

Glial cells and Parkinson’s disease

Parkinson’s disease is a neurodegenerative disease characterised by a massive loss of dopaminergic neurons in the substantia nigra. Yet glial cells may also participate in the pathophysiology of the disease. Indeed, glial cells can produce trophic factors which may stimulate neuronal survival or, alternatively, they could produce toxic compounds which may be involved in neuronal degeneration. This paper reviews the potentially protective or deleterious effects of glial cells in the substantia nigra of patients with Parkinson’s disease.

     

The parkinsonian toxin MPTP: action and mechanism

MPTP causes damage to substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons as seen in Parkinson's disease (PD). After sys-temic administration of MPTP, its active metabolite, MPP +, accumulates within SNpc DA neurons, where it inhibits ATP production and stim-ulates superoxide radical formation. The produced superoxide radicals react with nitric oxide (NO) to produce peroxynitrite, a highly reactive tissue-damaging species that damages proteins by oxidation and nitration. Only selected proteins appear nitrated, and among these, is found tyrosine hydroxylase (TH), the rate limiting enzyme in DA synthesis. The process of nitration inactivates TH and, consequently dopamine pro-duction. Peroxynitrite also nicks DNA, which, in turn, activates poly(ADP-ribose) polymerase (PARP). PARP activation consumes ATP, and thus acutely depletes cell energy stores. This latter event aggravates the preexisting energy failure due to MPP + -induced mitochondrial respira-tion blockade and precipitates cell death. Altogether, these findings support the view that MPTP's deleterious cascade of events include mito-chondrial respiration deficit, oxidative stress, and energy failure. Because of the similarity between the MPTP mouse model and PD, it is tempting to propose that a similar scenario applies to the pathogenesis of PD.     

Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention

Parkinson's disease (PD) is the second most common neurodegenerative disease, after Alzheimer's disease. The potential causes of PD remain uncertain, but recent studies suggest neuroinflammation and microglia activation play important roles in PD pathogenesis. Major unanswered questions include whether protein aggregates cause the selective loss of dopaminergic neurons in the substantia nigra that underlies the clinical symptoms and whether neuroinflammation is a consequence or a cause of nigral cell loss. Within the microenvironment of the brain, glial cells play a critical role in homeostatic mechanisms that promote neuronal survival. Microglia have a specialized immune surveillance role and mediate innate immune responses to invading pathogens by secreting a myriad of factors that include, cytokines, chemokines, prostaglandins, reactive oxygen and nitrogen species, and growth factors. Some of these factors have neuroprotective and trophic activities and aid in brain repair processes; while others enhance oxidative stress and trigger apoptotic cascades in neurons. Therefore, pro- and anti-inflammatory responses must be in balance to prevent the potential detrimental effects of prolonged or unregulated inflammation-induced oxidative stress on vulnerable neuronal populations. In this review, we discuss potential triggers of neuroinflammation and review the strongest direct evidence that chronic neuroinflammation may have a more important role to play in PD versus other neurodegenerative diseases. Alternatively, we propose that genetic deficiency is not the only way to reduce protective factors in the brain which may function to keep microglial responses in check or regulate the sensitivity of DA neurons. If chronic inflammation can be shown to decrease the levels of neuroprotective factors in the midbrain, in essence genetic haploinsufficiency of protective factors such as Parkin or RGS10 may result from purely environmental triggers (aging, chronic systemic disease, etc.), increasing the vulnerability to inflammation-induced nigral DA neuron death and predisposing an individual to development of PD. Lastly, we review the latest epidemiological and experimental evidence supporting the potential use of anti-inflammatory and immunomodulatory drugs as neuroprotective agents to delay the progressive nigrostriatal degeneration that leads to motor dysfunction in PD.     

Pathogenesis of nigral cell death in Parkinson's disease

Parkinson's disease (PD) is primarily a sporadic condition which results mainly from the death of dopaminergic neurons in the substantia nigra. Its etiology remains enigmatic while its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. As of yet, most insights into PD pathogenesis are derived from toxic models of PD and show that the earlier cellular perturbations arising in dopaminergic neurons include oxidative stress and energy crisis. These alterations, rather than killing neurons, trigger subsequent death-related molecular pathways including elements of apoptosis. The fate of dopaminergic neurons in PD may also be influenced by additional factors such as excitotoxicity, emanating from the increased glutamatergic input from the subthalamic nucleus to the substantia nigra, and the glial response that arises in the striatum and the substantia nigra. In rare instances, PD can be familial, and those genetic forms have also provided clues to the pathogenesis of nigrostriatal dopaminergic neuron death including abnormalities in the mechanisms of protein folding and degradation as well as mitochondrial function. Although more remains to be elucidated about the pathogenic cascade in PD, the compilation of all of the aforementioned alterations starts to shed light on why and how nigral dopaminergic neurons may degenerate in this prominent disease, that is PD.     

Motor and non-motor features of Parkinson's disease - a review of clinical and experimental studies

Classically, Parkinson's disease (PD) is considered to be a motor system affliction and its diagnosis is based on the presence of a set of cardinal motor signs (e.g. rigidity, bradykinesia, rest tremor and postural reflex disturbance). However, there is considerable evidence showing that non-motor alterations (e.g. anxiety, depression, sleep, gastrointestinal and cognitive functions) precede the classical motor symptoms seen in PD. The management of these nonmotor symptoms remains a challenge. A pattern of regional neurodegeneration that varies considerably depending upon the neuronal population affected may explain the different symptoms. In fact, differential mechanisms of neuronal vulnerability within the substantia nigra pars compacta (SNpc) suggests that factors other than location contribute to the susceptibility of these neurons. In this review we discuss how these factors interact to ultimately target the SNpc. Remarkably, this region consists of approximately 95% of the tyrosine hydroxylase (TH)-immunoreactive neurons in both human and rat brains, and consequently this implicates elevated levels of dopamine metabolites, free radicals and other hazard species in these neurons. An understanding of how these factors promote neuronal death may be useful for the development of novel neuroprotective and/or neurorestorative strategies for PD.     

Differential modification of dopamine transporter and tyrosine hydroxylase mRNAs in midbrain of subjects with parkinson's,alzheimer's with parkinsonism,and alzheimer's disease

The molecular characteristics of midbrain dopamine (DA) neurons have been extensively studied in Parkinson's disease (PD). No such studies of the characteristics of midbrain DA neurons in Alzheimer's disease (AD) or Alzheimer's disease with parkinsonism (AD/Park) have been published. We examined the levels of tyrosine hydroxylase (TH) protein, and the expression of TH and dopamine transporter (DAT) mRNAs, in midbrain neurons of PD, AD, and AD/Park cases. In PD, the loss of TH protein in the ventral tier of the substantia nigra pars compacta (SNpc) of the PD group is accompanied by severe losses in the number of neurons that express TH mRNA and DAT mRNA (74% loss). Remaining neurons show a shift to higher concentrations of TH mRNA but a shift to lower concentrations of DAT mRNA per cell. Hence, there is evidence that compensation in the remaining neurons can elevate concentrations of TH mRNA and lower DAT mRNA. Alternatively, there may be a predilection for a loss of neurons with high levels of DAT mRNA and low TH mRNA levels within the SNpc of PD cases. There was no change in TH protein but an elevation of TH mRNA concentrations per neuron without any change in concentrations of DAT mRNA in the AD group. The AD/Park group did not exhibit changes in the level of TH protein, but showed a small loss (26%) of neurons in the SNpc and a greater loss in other regions of the midbrain (43–53%). Remaining DA neurons showed a marked shift to lower concentrations of DAT mRNA per neuron and a nonsignificant shift in cellular concentration of TH mRNA to higher levels. This is consistent with our previous work showing that with AD/Park there is a significant reduction in the number of DAT sites located on DA terminals in the striatum, but the midbrain neurons have not died. Our results indicate that the differential regulation of mRNAs encoding TH and DAT is similar in the parkinsonian disorders (PD and AD/Park) even though the degree of cell death is very different. This might suggest that compensatory events occur in these DA neurons in AD/Park that are similar to those in PD and that result in differential effects on mRNAs encoding TH and DAT proteins.     

Single section and disector counts in evaluating neuronal loss from the substantia nigra in patients with Parkinson's disease

In order to investigate the correlation between single section (SS) and disector (DS) counts for estimating the pigmented neurons in the pars compacta of the substantia nigra (SNpc), 12 patients with Parkinson's disease (PD) and seven controls were studied. The SS counts were obtained at the level of the exit of the third cranial nerve in the SNpc. The DS counts were made from the whole volume of the SNpc. There was a significant correlation between SS and DS counts (r=0.94, P<0.001), suggesting that the methods closely agree. Comparison of SS and DS counts in controls and PD patients showed that the pigmented neurons in PD were decreased by 75% (P<0.001) and 55% (P<0.001) in the SS and DS counts, respectively. This study suggests that loss of pigmented neurons from the SNpc in PD can be estimated by either method.     

Loss of aromatase cytochrome P450 function as a risk factor for Parkinson's disease?

The final step in the physiological synthesis of 17β estradiol (E₂) is aromatization of precursor testosterone by a CYP19 gene product, cytochrome P450 estrogen aromatase in the C19 steroid metabolic pathway. Within the central nervous system (CNS) the presence, distribution, and activity of aromatase have been well characterized. Developmental stage and injury are known modulators of brain enzyme activity, where both neurons and glial cells reportedly have the capability to synthesize this key estrogenic enzyme. The gonadal steroid E₂ is a critical survival, neurotrophic and neuroprotective factor for dopaminergic neurons of the substantia nigra pars compacta (SNpc), the cells that degenerate in Parkinson's disease (PD). In previous studies we underlined a crucial role for the estrogenic status at the time of injury in dictating vulnerability to the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our ongoing studies address the contribution of brain aromatase and extragonadal E₂ as vulnerability factors for PD pathology in female brain, by exposing aromatase knockout (ArKO, −/−) female mice which are unable to synthesize estrogens to MPTP. Our initial results indicate that aromatase deficiency from early embryonic life significantly impairs the functional integrity of SNpc tyrosine hydroxylase-positive neurons and dopamine transporter innervation of the caudate–putamen in adulthood. In addition, ArKO females exhibited a far greater vulnerability to MPTP-induced nigrostriatal damage as compared to their Wt type gonadally intact and gonadectomized counterparts. Characterization of this novel implication of P450 aromatase as determining factor for PD vulnerability may unravel new avenues for the understanding and development of novel therapeutic approaches for Parkinson's disease.     

MPTP: a review of its mechanisms of neurotoxicity

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes damage to substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons as seen in Parkinson's disease (PD). After systemic administration of MPTP, its active metabolite, MPP⁺, accumulates within SNpc DA neurons, where it inhibits ATP production and stimulates superoxide radical formation. The produced superoxide radicals react with nitric oxide (NO) to produce peroxynitrite, a highly reactive tissue-damaging species that damages proteins by oxidation and nitration. Only selected proteins appear nitrated, and among these is found tyrosine hydroxylase (TH), the rate limiting enzyme in DA synthesis, and the pre-synaptic protein α-synuclein. Peroxynitrite also nicks DNA, which, in turn, activates poly(ADP-ribose) polymerase (PARP). PARP activation consumes ATP, and thus acutely depletes the cell energy stores. This latter event aggravates the preexisting energy failure due to MPP⁺-induced mitochondrial respiration blockade and precipitates cell death. On the other hand, MPP⁺ also activates highly regulated cell death-associated molecular pathways that participate in the relentless demise of neurons in PD. Altogether, these findings support the view that MPTP's deleterious cascade of events include mitochondrial respiration deficit, oxidative stress, energy failure and activation of apoptotic genetic programs. Because of the similarity between the MPTP mouse model and PD, it is tempting to propose that a similar scenario applies to the pathogenesis of PD.