Article

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

ABSTRACT

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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    • "Systemic injections of MPTP result in a rapid onset of neuroinflammatory responses in the SN as well as in the CPu. These astroglia-and microglia-mediated responses are triggered by the impairment of mDA neuron function and maintenance, making the MPTP model suitable to analyse the associated neuroinflammatory changes[37]. Due to its lipophilic nature and the ability to cross the BBB, the MPTP model has the advantage that microglia are not activated by direct injections or by mechanical manipulations of the central nervous system (CNS). "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disease characterised by histopathological and biochemical manifestations such as loss of midbrain dopaminergic (DA) neurons and decrease in dopamine levels accompanied by a concomitant neuroinflammatory response in the affected brain regions. Over the past decades, the use of toxin-based animal models has been crucial to elucidate disease pathophysiology, and to develop therapeutic approaches aimed to alleviate its motor symptoms. Analyses of transgenic mice deficient for cytokines, chemokine as well as neurotrophic factors and their respective receptors in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have broadened the current knowledge of neuroinflammation and neurotrophic support. Here, we provide a comprehensive review that summarises the contribution of microglia-mediated neuroinflammation in MPTP-induced neurodegeneration. Moreover, we highlight the contribution of neurotrophic factors as endogenous and/or exogenous molecules to slow the progression of midbrain dopaminergic (mDA) neurons and further discuss the potential of combined therapeutic approaches employing neuroinflammation modifying agents and neurotrophic factors.
    Full-text · Article · Jan 2016 · International Journal of Molecular Sciences
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    • "Microglia—the resident immune cells of the central nervous system (CNS)—are involved in a plethora of neurodegenerative pathologies (Prinz and Priller, 2014) and interestingly, show a higher density in the SN and CPu as compared to other brain areas (Lawson et al., 1990; Sharaf et al., 2013). In human PD cases, microglia reactivity has been extensively described (McGeer and McGeer, 2008). Moreover, due to their unique origin (Prinz and Priller, 2014), microglia undergo ageing and are believed to become senescent, a phenomenon which is likely to impair their normal functions (Streit, 2006). "
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    ABSTRACT: Parkinson´s disease (PD) is a neurodegenerative disorder that is characterised by loss of midbrain dopaminergic (mDA) neurons in the substantia nigra (SN). Microglia-mediated neuroinflammation has been described as a common hallmark of PD and is believed to further trigger the progression of neurodegenerative events. Injections of 6-hydroxydopamine (6-OHDA) are widely used to induce degeneration of mDA neurons in rodents as an attempt to mimic PD and to study neurodegeneration, neuroinflammation as well as potential therapeutic approaches. In the present study, we addressed microglia and astroglia reactivity in the SN and the caudatoputamen (CPu) after 6-OHDA injections into the medial forebrain bundle (MFB), and further analysed the temporal and spatial expression patterns of pro-inflammatory and anti-inflammatory markers in this mouse model of PD. We provide evidence that activated microglia as well as neurons in the lesioned SN and CPu express Tgfβ1, which overlaps with the downregulation of pro-inflammatory markers Tnfα, and iNos, and upregulation of anti-inflammatory markers Ym1 and Arg1. Taken together, the data presented in this study suggest an important role for Tgfβ1 as a lesion-associated factor that might be involved in regulating microglia activation states in the 6-OHDA mouse model of PD in order to prevent degeneration of uninjured neurons by microglia-mediated release of neurotoxic factors such as Tnfα and nitric oxide (NO).
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    • "There have been several attempts to improve cell culture-based test systems for clinical predictivity by a transition from rodent to human cells, and by incorporation of glial cells to neuronal cultures (McNaught and Jenner, 1999; Liu et al., 2009). For co-culture systems, the major focus has been on microglia as the second cell type apart from neurons (McGeer and McGeer, 2008), but astrocytes have been used, for example, with motor neurons or in order to stabilize stem cell-derived neurons (Reinhardt et al., 2013; Zhang et al., 2013). Concerning the transition to human cells, tumour cell lines have often been used as surrogates for neurons (Zhao et al., 2013; Chong et al., 2014). "
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    ABSTRACT: Few neuropharmacological model systems are based on human neurons. Moreover, available test systems rarely reflect functional roles of co-cultured glial cells. The generation of a human in vitro counterpart of the widely-used 1-methyl-4-phenyl-tetrahydropyridine (MPTP) mouse model has therefore remained a challenge in drug discovery technology. We addressed this by successfully growing an intricate network of human dopaminergic (DA) neurons on top of a dense layer of astrocytes. In these co-cultures, MPTP was metabolized to 1-methyl-4-phenyl-pyridinium (MPP(+) ) by the glial cells, and the toxic metabolite was taken up through the dopamine transporter into neurons. For initial model characterization, we studied the activation of poly-(ADP-ribose)-polymerase (PARP). Similar to mouse models, MPTP exposure lead to (poly-ADP-ribose) synthesis, and neurodegeneration was blocked by PARP inhibitors. A panel of different putative neuroprotectants was then compared in monocultures and co-cultures. Rho kinase inhibitors worked in both models; CEP1347, ascorbic acid or a caspase inhibitor protected in monocultures form MPP(+) toxicity, but did not show any protection in co-cultures, when used alone or in combinations. Application of oxidized glutathione (GSSG) prevented degeneration in co-cultures, but not in monocultures. The surprisingly different pharmacological profiles of the models suggest that the presence of glial cells, and the in vivo-like generation of the toxic metabolite MPP(+) within the layered cultures played an important role for predictions of neuroprotection. The novel model system is closer to the situation in human brain tissue than conventional cultures, and its use for screening of candidate neuroprotectants may increase the predictiveness of a test battery. This article is protected by copyright. All rights reserved.
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