Neurotoxicity neuroinflammation

DOM treatment also rapidly decreases cellular GSH, which precedes neurotoxicity. This decrease is primarily due to DOM-mediated GSH efflux. DOM also induces an increase in oxidative stress as indicated by increases in ROS and lipid peroxidation products, which follow GSH efflux. Astrocytes from both genotypes are resistant to DOM-mediated neurotoxicity and present a diminished Ca2+ response to DOM-mediated toxicity (Walser et al., 2006). Exposure of neonatal rat microglia to DOM triggers the release of TNF-a and matrix metalloproteinase-9 (MMP-9) (Mayer et al., 2001). These molecules are involved in the modulation of neuroinflammation in brain (Farooqui et al., 2007). Collective evidence suggests that DOM-mediated neurodegeneration involves changes in cellular redox, oxidative stress, and increased expression of cytokines, nitric oxide synthase, NADPH diaphorase, and matrix metalloproteinase-9 (Walser et al., 2006 Chandrasekaran et al., 2004 Ananth et al., 2003a,b Mayer et al., 2001). 

Microglial-mediated neuroinflammation and neurotoxicity are involved in the pathogenesis of AD. Regulation of microglial activation and suppression of neurotoxic proinflammatory molecules may provide a potential therapeutic approach for the treatment of... 

It is unclear at this point if increased levels of neurotoxic metabolites (QUIN and 3-HK) and a reduction in KYNA, the neuroprotective metabolite, may be a direct cause for some of these diseases. Alternatively, kynurenines may simply play a secondary role in disease progression after focal physical injury and in a state of neuroinflammation, the cerebral KP is stimulated, through activation of brain microglial cells or infiltration of macrophages. Under those conditions, KP metabolites can be increased substantially over a longer period and may thus prolong and exacerbate disease symptoms. 

Thus, IKK activation may modulate mutant huntingtin neurotoxicity depending on the cell s ability to degrade the modified species (Thompson et al., 2009). Increased expression of several key inflammatory mediators, such as CCL2 and IL-10, specifically in the striatum occurs in HD patients. In addition, an upregulation of IL-6, IL-8, and MMP9 is found in the cortex and notably in the cerebellum. These observations suggest that neuroinflammation may be a prominent feature associated with HD. 

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