Neurological Sciences

, Volume 32, Issue 1, pp 1–7

Role of glial cells in neurotoxin-induced animal models of Parkinson’s disease


  • Hironori Yokoyama
    • Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical SciencesThe University of Tokushima
  • Hiroto Uchida
    • Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical SciencesThe University of Tokushima
  • Hayato Kuroiwa
    • Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical SciencesThe University of Tokushima
    • Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical SciencesThe University of Tokushima
  • Tsutomu Araki
    • Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical SciencesThe University of Tokushima
Review Article

DOI: 10.1007/s10072-010-0424-0

Cite this article as:
Yokoyama, H., Uchida, H., Kuroiwa, H. et al. Neurol Sci (2011) 32: 1. doi:10.1007/s10072-010-0424-0


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.


Parkinson’s diseaseGliaOxidative stressInflammationCytokinesNeurotrophic factorsNeurodegeneration


Clinically, Parkinson’s disease (PD) is a common neurodegenerative disorder characterized mainly by tremor, bradykinesia, rigidity, slowness of movement, and postural instability [1] and associated with dramatic loss of dopaminergic neurons, cytoplasmic inclusion of aggregated proteins such as Lewy bodies and neuroinflammation [24]. The hallmarks of neuroinflammation are the presence of activated microglia and reactive astrocytes in the parenchyma of the central nervous system (CNS) and increased production of chemokines, cytokines, prostaglandins, complement cascade proteins and reactive oxygen species (ROS), and reactive nitrogen species (RNS) which in some case can result in disruption of the blood–brain barrier (BBB) and direct participation of adaptive immune system [5]. PD symptoms first manifest when approximately 60% of the dopaminergic neurons have already died [6] and 70% of dopamine responsiveness disappears [7]. To date, the most effective treatment for PD remains the administration of a precursor of dopamine, levodopa (L-dopa), which by replenishing the brain in dopamine, alleviates almost all PD symptoms. The chronic administration of levodopa, however, often produces motor and psychiatric side effects, which may be as debilitating as PD itself. The administration of levodopa alleviates major symptom of PD patients. However, chronic treatment with levodopa is often complicated by the development of adverse effects. There have been additional anti-parkinsonian agents, such as dopamine receptor agonists and selective inhibitor of monoamine oxidase-B (MAO-B), but the available therapies do not protect against dopaminergic neuronal cell death. The PD patients begin not to respond well to treatment, and start to suffer disabilities which cannot be controlled with existing medical therapies. The prevalence of PD is likely to increase in the coming decades, as the number of elderly people increases. Therefore, it is of utmost importance to develop new drugs or targets that show or halt the rate of progression of PD patients in the world. This review will not cover all these aspects but will concentrate on reactions of astrocytes, microglia and oligodendrocytes in PD.

MPTP-induced Parkinsonism

Previous interesting studies reported the occurrence of an akinetic rigid syndrome responsive to levodopa resembling the clinical features of PD in seven individuals after intravenous injection of an illicit synthetic heroin analog that contained high amounts of the by-product 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [8, 9]. MPTP is a neurotoxin that produces a parkinsonian syndrome in both humans and experimental animals [10, 11]. Its neurotoxic effects also appear to involve energy depletion and free radical generation. MPTP is converted to its metabolite 1-methyl-4-phenyl-pyridinium (MPP+) by MAO-B. MPP+ is selectively accumulated by high affinity dopamine transporters and taken up into the mitochondria of dopaminergic neurons, where it disrupts oxidative phosphorylation by inhibiting complex I of the mitochondrial electron transport chain [12, 13]. This leads to impairment of ATP production, elevated intracellular calcium levels, and free radical generation, thereby exhibiting dopaminergic neurotoxicity [13, 14]. Therefore, MPTP treatments are known to cause a marked depletion of dopamine and nigrostriatal neuronal cell death in a wide variety of animal species, including mice, dogs and nonhuman primates [15]. Although the monkey MPTP model remains the best, most studies have been performed in mice as a good model of PD [1618].

It is known that microglia constitute about 10% of all glial cells. Microglia are evenly distributed throughout the normal brain with their ramified processes being close together but not each other. Gliosis is a prominent neuropathological feature of many diseases of the brain whose sole and unique function has been thought, for many years, to be the removal of cellular debris. Mounting evidence demonstrates that the role played by gliosis in pathological situations may not be restricted to its housekeeping function but may also include actions that markedly and actively contribute the neuronal death, especially in neurodegenerative disorders such as PD. Several lines of evidence suggest that gliosis may actually exert very different effects on the brain disease, depending upon the situation. Therefore, it may mediate either beneficial or harmful events. In normal brains, neither resting astrocytes nor microglia are evenly distributed throughout the brain [19, 20]. Among glial cells, astrocytes are crucial in the normal brain condition for the homeostatic control of the neuronal extracellular environments [21]. Following an injury to the brain, astrocytes and microglia undergo various phenotypic alterations that enable them to both respond to and to play a role in the pathological processes [22, 23]. Especially, microglial activation is characterized by proliferation, increased or de novo expression of marker molecules such as major histocompatibility complex antigen, migration, and eventually transformation into a macrophage-like appearance [24]. In this review, we demonstrate mainly the possible role of glial cells against MPTP neurotoxicity in mice.

Role of astrocytes in Parkinson’s disease and neurotoxin-induced animal models

It is well known that the nigrostriatal pathway is the most affected dopaminergic system in PD. The dopaminergic neurons that form this pathway have their cell bodies in the substantia nigra pars compacta and their nerve terminals in the striatum. In particular, the loss of dopaminergic neurons in post-mortem parkinsonian brains is associated with a significant glial reaction [25, 26]. The function of astrocytes is even less well understood than those of microglia. Astrocytes migrate to a site of injury and develop a hypertrophic morphology (reactive astrocytes). They might be stimulating the microglia while at the same time secreting protective agents to the peripheral surround. Astrocytes are also known to elaborate both pro-inflammatory and anti-inflammatory agents. In fact, astrocytes produce several factors that may be important in the inflammatory reaction that occurs in the substantia nigra in PD. In many cases of PD, a mild increase in the number of astrocytes and immunoreactivity for glial fibrillary acid proteins (GFAP) has been observed, but only in a few cases full-blown reactive astrocytes [25]. The amount of GFAP-positive astrocytes correlates inversely to the amount of dopaminergic cell loss [20]. They respond particularly to pro-inflammatory cytokines, such as IL-1β (interleukin-1β) and TNF-α (tumor necrosis factor-α), and it is believed that these cytokines participate in astrocytic activation after CNS damage [27].

In an MPTP model, astrocytic activation parallels the time course of dopaminergic cell loss in the substantia nigra as well as the striatum and the expression of GFAP remains up-regulated even after MPTP treatment [2830]. These observations suggest that astrocytic activation occurs following neuronal cell death. It is known that PD is caused by apoptosis due to increased levels of cytokines, apoptosis-related proteins, and/or to decreased levels of neurotrophins [3133]. Several postmortem studies of PD patients demonstrated morphological signs of apoptosis in dopaminergic neurons [32, 34, 35]. A previous study with immunohistochemical analysis reported that NF-kappa B (nuclear transcription factor kappa B), as a key factor, in immune-responses and inflammation increased in the nigral dopaminergic region of parkinsonian brain [36]. We recently demonstrated that dopaminergic neuronal loss may be caused by apoptosis due to increased cytokines and apoptosis-related proteins via activation of NF-kappa B in reactive astrocytes of the substantia nigra after MPTP treatment in mice [30]. However, astrocytes have also been shown to secrete a number of neurotrophic factors for dopaminergic neurons. These include glial cell-line-derived neurotrophic factor (GDNF) [37, 38], brain-derived neurotrophic factor (BDNF) [39], mesencephalic astrocyte-derived neurotrophic factor (MANF) [40] and so forth. Furthermore, astrocytes may reduce the oxidative stress by metabolizing dopamine, as they express MAO-B and catechol-O-methyl-transferase (COMT) [41]. Additionally, astrocytes are capable of preventing nitric oxide- (NO) generated neurotoxicity by glutathione-dependent mechanism [42]. These observations support the view that astrocytes might have a neuroprotective role in PD. In this review, therefore, we cannot exclude the possibility that astrocytes may have a neutralizing function in regulating the deleterious action of microglia, as shown in Fig. 1. Further studies are needed to investigate the precise role of astrocytes in PD.
Fig. 1

Schematic representation showing the potential involvement of glial cells in the pathogenesis in an MPTP model of PD. Reactive astrocytes and microglia may contribute to dopaminergic cell loss by releasing cytotoxic compounds such as ROS, cytokines, chemokines, prostaglandins and so on. Reactive astrocytes, on the other hand, may play a key role in regulating microglial activation, oxidative stress, and NO-generated neurotoxicity. Furthermore, reactive astrocytes may secrete a number of neurotrophic factors for dopaminergic neurons

Role of microglia in Parkinson’s disease and neurotoxin-induced animal models

It is known that microglia constitute a significant proportion of cells in the human brain, in the range of 5–20% by various estimates, depending on the region of the brain [43]. The substantia nigra is relatively rich in microglia compared with other brain areas of experimental animals [19, 44]. Reactive microglia have been demonstrated in the basal ganglia and brainstem of PD cases using positron emission tomography (PET) with [11C](R)-PK1195, a marker of peripheral benzodiazepine binding sites that is selectively expressed by activated microglia [45, 46]. Ouchi et al. [45] did a PET study by comparing midbrain PK1195 binding with basal ganglia binding of the dopamine transporter (DAT) marker (11C)CFT. They observed a correction in their PD cases between elevated PK1195 binding, indicative of reactive microglia and reduced CFT binding, indicative of DAT loss. Therefore, they demonstrated that neuroinflammatory responses from intrinsic microglia were contributing significantly to the progressive dopaminergic degeneration in PD patients.

It is known that reactive microglia can cause large amount of ROS, which may well be the major source of the oxidative stress believed to be largely responsible for dopaminergic cell loss in PD [47, 48]. Such oxidative stress may produce the oxidation of dopamine to the quinone products, which are believed to be damaging to neuronal mitochondria [49]. Furthermore, reactive microglia are observed in basal ganglia in the MPTP [50, 51]—6-hydroxydopamine (6-OHDA) [52, 53]—and rotenone [54, 55]-induced experimental animal models of PD, as well as in models of dopaminergic cell death produced in rodents by nigral injection of LPS (lipopolysaccharide), of Fcγ receptor activators such as trisialoganglioside [56], or immunoglobulins [57] from PD patients. Furthermore, systematic LPS injection to mice is known to cause the activation of microglia and dopaminergic cell loss [58]. In addition, dopaminergic neurons in the substantia nigra have a reached level of intracellular glutathione, making them much more susceptible to a variety of insults, including oxidative stress and activated microglia-mediated damage [44]. These findings of elevated levels of pro-inflammatory cytokines and increased oxidative stress-mediated injury in postmortem samples of PD suggest that microglia activation might play a key role in the degenerative process observed in PD patients [59]. Epidemiological studies also indicate a correlation between brain injuries in young age and development of PD later during life, implicating that inflammatory processes and microglia activation might play a deleterious role in the development of PD [60]. These observations suggest that microglia may play a deleterious role in the pathogenesis of PD.

On the other hand, it is known that microglia are capable of mediating protective effects. One way by which microglia may provide neuroprotection is by the release of neurotrophic factors. One of these neurotrophic factors, GDNF, supports the dopaminergic neurons of the substantia nigra in natural development death in post-natal midbrain cultures [61] and can cause sprouting in damaged rodent striatum [62]. Infusion of recombinant GDNF protein as well as delivery by viral vectors resulted in attention of MPTP-mediated dysfunction and was able to boost dopaminergic function of damaged neurons in MPTP-treated monkeys and mice [6365]. Another neurotrophic factor, BDNF, which is released by reactive microglia, supports the survival and process outgrowth of dopaminergic structures in the striatum [62]. In MPTP- and 6-OHDA-induced animal models, BDNF was able to confer a neuroprotective effects on dopaminergic neurons [66, 67], but data on human PD are still lacking. Furthermore, microglia might be neuroprotective by scavenging ROS and/or RNS [68]. Especially, ROS can be detoxified by glutathione, which is present in microglia [69]. Microglia can also take up extracellular glutamate, thus obviating the subthalamic excitotoxic input to the substantia nigra [70], which is hyperactive in PD [71].

Based on these observations, we speculate that microglia may play dual roles in the pathogenesis of PD, as shown in Fig. 1.

Role of oligodendrocytes in Parkinson’s disease and neurotoxin-induced animal models

Glial cells are composed of astrocytes, microglia, and oligodendrocytes. Oligodendrocytes, which are responsible for myelination, have not been implicated in PD [21], but in another parkinsonian disorder, multiple system atrophy (MSA). For oligodendrocytes, there are very important literatures in PD. Previous studies reported that the presence of complement-activated oligodendrocytes in the substantia nigra in PD cases [72] and in several brain areas in two case of Lewy body dementia with greatly decreased dopamine levels [73]. Oligodendrocytes are the cells responsible for myelin synthesis and assembly around axon in CNS. Oligodendrocyte loss and demyelination in the CNS have been reported in a variety of myelin disorders such as multiple sclerosis [74]. Furthermore, it is suggested that the oligodendrocytes are vulnerable to various factors that can easily cause cell death, including inflammatory cytokines, viruses, and BBB disruption. A previous study reported that the myelin-basic protein immunoreactivity in the sciatic nerve was markedly decreased in normal aging [75]. A recent interesting study also suggests that age-related degeneration of oligodendrocytes had occurred in the hippocampus of senescence-accelerated mouse [76]. Moreover, oligodendroglial injury has been shown to occur rapidly in response to ischemia [7779]. Oligodendroglial injury has also been reported to occur in response to cerebral ischemia. Irving et al. [77] observed structural alterations to the oligodendrocyte cytoskeleton within 20 and 40 min of middle cerebral artery occlusion (MCAO) in rats. These changes were assessed by increases in immunoreactivity to the microtubule-associated protein, Tau-1, which has been found to be a sensitive marker for oligodendroglial damage in several studies involving focal cerebral ischemia in rats [78, 80, 81]. The levels of CNPase were also decreased in the patient’s brain in cases of Alzheimer’s disease and Down’s syndrome [82]. Based on these findings, it is conceivable that oligodendrocytes may be damaged after MPTP treatment, as shown in Fig. 2.
Fig. 2

Schematic diagram showing the potential role of reactive astrocytes and microglia in the damage of oligodendrocytes in an MPTP model of PD. Reactive astrocytes and microglia may cause the overexpression of ROS, RNS, cytokines, chemokines, prostaglandins, and glutamate that contribute to the damage of oligodendrocytes

In our laboratory, a significant decrease in the area of CNPase-positive profiles as an oligodendrocyte marker was observed in the striatum 3 and 7 days after MPTP treatment. Furthermore, our Western blot analysis with CNPase protein showed a significant decrease in the striatum 3 and 7 days after MPTP treatment. These findings demonstrate that oligodendrocytes may be damaged by inflammatory cytokines produced by microglial cells after MPTP treatment [83]. However, further investigations concerning glial reaction in PD may lead to disease-modifying therapeutic approaches.


Many transgenic models offer an opportunity to invasively study the mutant human genes or combination of mutant genes and their role in the pathogenesis of PD. In the present condition, however, they do not always provide the evidence to evaluate potential genetic and pharmacological therapies. In this review, therefore, we discuss the protective and deleterious effects of glial cells such as reactive astrocytes and reactive microglia in neurotoxin-induced animal models of PD. In general, dopaminergic neurons are highly vulnerable to oxidative stress and inflammatory attack. Reactive astrocytes and microglia can secrete inflammatory cytokines and other neurotoxic compounds. By contrast, reactive astrocytes may also play a key role in regulating microglial activation, oxidative stress, and NO-generated neurotoxicity for dopaminergic neurons or oligodendrocytes. Furthermore, reactive astrocytes may secrete a number of neurotrophic factors for dopaminergic neurons. Therefore, the role of glial cells against dopaminergic neurons and oligodendrocytes is still obscure. Further studies with the exact relationship among reactive glial cells, neurotoxic products, and neuroprotective compounds may lead to better understanding of PD as well as provide clues to novel targets for therapeutic interventions.


This study was supported in part by a Grant-in-Aid for Scientific Research (22590935) from the Ministry of Science and Education in Japan.

Conflict of interest

All authors have no conflict of interest.

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© Springer-Verlag 2010