Neuroinflammation and oxidative stress: Co-conspirators in the pathology of Parkinson’s disease

Abstract

Parkinson's disease (PD) is a complex disease, with genetics and environment contributing to the disease onset. Recent studies of causative PD genes have confirmed the involvement of cellular mechanisms engaged in mitochondrial and UPS dysfunction, oxidative stress and apoptosis in the progressive degeneration of the dopaminergic neurons in PD. In addition, clinical, epidemiological and experimental evidence has implicated neuroinflammation in the disease progression. This review will discuss neuroinflammation in PD, with particular focus on the genetic and toxin-based models of the disease. These studies have confirmed elevated oxidative stress and the pro-inflammatory response occurs early in the disease and these processes contribute to and/or exacerbate the nigro-striatal degeneration. In addition, the experimental models discussed here have also provided strong evidence that these pathways are an important link between the familial and sporadic causes of PD. The potential application of anti-inflammatory interventions in limiting the dopaminergic neuronal cell death in these models is discussed with evidence suggesting that the further investigation of their use as part of multi-targeted clinical trials is warranted.

Inhibition of Neuronal Cell Mitochondrial Complex I with Rotenone Increases Lipid β-Oxidation, Supporting Acetyl-Coenzyme A Levels

“…In particular, the complex I inhibitory effects of rotenone have been tied to the onset of a parkinsonian phenotype in both animal models and human studies (2-4). Although much focus has been placed on oxida- tive stress and the role it may play in the pathogenesis of neurodegeneration in PD (9,(32)(33)(34), there is substantial evidence to suggest that mitochondrial dysfunction may also contribute to this process (35,36).…”

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

“…A link between inflammation and PD was first described in a postmortem study by McGeer et al in 1988, where activated microglia was found in the SN of PD patients [34]. Furthermore, several clinical studies have confirmed this association by reporting increased microglial activation and elevated pro-inflammatory cytokines in post-mortem brains and CSF [35][36][37] (Figure 2). These data have been also reproduced by experimental studies in animal models of the disease [23,38,39], where neuroinflammation has been shown to be an important contributor to PD progression.…”

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“…In postmortem brains from PD victims markers of lipid peroxidation are found 6 . Malodyaldhyde (MDA) is a specific marker of lipid peroxidation, which is largely a result of the peroxidation of polyunsaturated fatty acids with more than two double bonds 18 .…”

“…The main mechanisms proposed to explain the events culminating in neuronal death in PD are associated with mitochondrial changes, apoptosis and elevated levels of oxidative stress 5 . There is also a neuroinflammatory process with activation of glial cells and release of cytokines and nitric oxide 6 . Therefore, the process of degeneration is multifactorial.…”