Glial reactions in Parkinson's disease

Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada.
Movement Disorders (Impact Factor: 5.68). 03/2008; 23(4):474-83. DOI: 10.1002/mds.21751
Source: PubMed


Dopaminergic neurons of the substantia nigra are particularly vulnerable to oxidative and inflammatory attack. Such processes may play a crucial role in the etiology of Parkinson disease (PD). Since glia are the main generators of these processes, the possibility that PD may be caused by glial dysfunction needs to be considered. This review concentrates on glial reactions in PD. Reactive astrocytes and reactive microglia are abundant in the substantia nigra (SN) of PD cases indicating a robust inflammatory state. Glia normally serve neuroprotective roles but, given adverse stimulation, they may contribute to damaging chronic inflammation. Microglia, the phagocytes of brain, may be the main contributors since they can produce large numbers of superoxide anions and other neurotoxins. Their toxicity towards dopaminergic neurons has been demonstrated in tissue culture and various animal models of PD. The MPTP and alpha-synuclein models are of particular interest. Years after exposure to MPTP, inflammation has been observed in the SN. This has established that an acute insult to the SN can result in a sustained local inflammation. The alpha-synuclein model indicates that an endogenous protein can induce inflammation, and, when overexpressed, can lead to autosomal dominant PD. Less is known about the role of astrocytes than microglia, but they are known to secrete both inflammatory and anti-inflammatory molecules and may play a role in modulating microglial activity. Oligodendrocytes do not seem to play a role in promoting inflammation although, like neurons, they may be damaged by inflammatory processes. Further research concerning glial reactions in PD may lead to disease-modifying therapeutic approaches.

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    • "The idea that detrimental microglial activation also contributes to the degeneration of neurons in the substantia nigra in Parkinson’s disease (PD) is firmly embedded in the literature yet much of it is speculative and extrapolated from animal and cell culture models [103–107]. In a thoughtfully delivered discussion, Croisier et al. state unequivocally that “there is no evidence that microglia initiate neurodegeneration” [108], and it would thus be fair to say that microglial involvement in PD remains a controversial and unresolved issue [109,110]. "
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    ABSTRACT: This paper summarizes pathological changes that affect microglial cells in the human brain during aging and in aging-related neurodegenerative diseases, primarily Alzheimer¿s disease (AD). It also provides examples of microglial changes that have been observed in laboratory animals during aging and in some experimentally induced lesions and disease models. Dissimilarities and similarities between humans and rodents are discussed in an attempt to generate a current understanding of microglial pathology and its significance during aging and in the pathogenesis of Alzheimer dementia (AD). The identification of dystrophic (senescent) microglia has created an ostensible conflict with prior work claiming a role for activated microglia and neuroinflammation during normal aging and in AD, and this has raised a basic question: does the brain¿s immune system become hyperactive (inflamed) or does it become weakened (senescent) in elderly and demented people, and what is the impact on neuronal function and cognition? Here we strive to reconcile these seemingly contradictory notions by arguing that both low-grade neuroinflammation and microglial senescence are the result of aging-associated free radical injury. Both processes are damaging for microglia as they synergistically exhaust this essential cell population to the point where the brain¿s immune system is effete and unable to support neuronal function.
    09/2014; 2(1):142. DOI:10.1186/PREACCEPT-1035265697142235
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    • "Opposite to earlier concepts, microglia in the healthy brain are not resting but are highly dynamic cells that carry out homeostatic surveillance of the extracellular environment by the extension and retraction of their protrusions and phagocytosis of tissue debris, which could otherwise cause inflammation [15]. Activated microglia are found in diseased CNS tissue, such as within demyelinated cortical grey matter lesions in the MS brain, surrounding amyloid plaques in Alzheimer brain and in the degenerating substantia nigra in Parkinson's disease [16, 17]. Although the diverse expression profiles of microglia appear to reflect a broad, continuous spectrum of activation states, two activation states at both ends of the spectrum can be recognized corresponding to the M1 and M2 state designated for macrophages [18]. "
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    ABSTRACT: Accumulating evidence suggests that inflammatory mediators secreted by activated resident or infiltrated innate immune cells have a significant impact on the pathogenesis of neurodegenerative diseases. This may imply that patients affected by a neurodegenerative disease may benefit from treatment with selective inhibitors of innate immune activity. Here we review the therapeutic potential of apocynin, an essentially nontoxic phenolic compound isolated from the medicinal plant Jatropha multifida . Apocynin is a selective inhibitor of the phagocyte NADPH oxidase Nox2 that can be applied orally and is remarkably effective at low dose.
    BioMed Research International 07/2014; 2014(5):298020. DOI:10.1155/2014/298020 · 1.58 Impact Factor
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    • "Activated microglia play important roles in the death of DA neurons in PD patients [6, 7] and the MPTP-induced animal model of PD [5]. To determine whether the neuroprotective effect of CS resulted from the inhibition of microglial activation in the SN, we performed immunostaining with anti-CD11b to detect microglia/macrophages in brain sections that were prepared 7 days after the final MPTP injection (Figure 6). "
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    ABSTRACT: Parkinson’s disease (PD) is a neurodegenerative movement disorder that is characterized by the progressive degeneration of the dopaminergic (DA) pathway. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes damage to the DA neurons, and 1-4-methyl-4-phenylpyridinium (MPP + ) causes cell death in differentiated PC12 cells that is similar to the degeneration that occurs in PD. Moreover, MPTP treatment increases the activity of the brain’s immune cells, reactive oxygen species- (ROS-) generating processes, and glutathione peroxidase. We recently reported that Cuscutae Semen (CS), a widely used traditional herbal medicine, increases cell viability in a yeast model of PD. In the present study, we examined the inhibitory effect of CS on the neurotoxicity of MPTP in mice and on the MPP+-induced cell death in differentiated PC12 cells. The MPTP-induced loss of nigral DA neurons was partly inhibited by CS-mediated decreases in ROS generation. The activation of microglia was slightly inhibited by CS, although this effect did not reach statistical significance. Furthermore, CS may reduce the MPP+ toxicity in PC12 cells by suppressing glutathione peroxidase activation. These results suggest that CS may be beneficial for the treatment of neurodegenerative diseases such as PD.
    Evidence-based Complementary and Alternative Medicine 07/2014; 2014(6):150153. DOI:10.1155/2014/150153 · 1.88 Impact Factor
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