Protection against MPP⁺ neurotoxicity in cerebellar granule cells by antioxidants

Abstract

The neuropathology associated with Parkinson's disease (PD) is thought to involve excessive production of free radicals, dopamine autoxidation, defects in glutathione peroxidase expression, attenuated levels of reduced glutathione, altered calcium homeostasis, excitotoxicity and genetic defects in mitochondrial complex I activity. While the neurotoxic mechanisms are vastly different for excitotoxins and 1-methyl-4-phenylpyridinium ion (MPP(+)), both are thought to involve free radical production, compromised mitochondrial activity and excessive lipid peroxidation. We show here that the levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) increased significantly after treatment of cultured cerebellar granule cells (CGCs) with 50 microM MPP(+). Co-treatment with antioxidants such as ascorbate (ASC), catalase, alpha-tocopherol (alpha-TOH), coenzyme Q(10) (CoQ(10)) or superoxide dismutase (SOD) rescued the cells from MPP(+)-induced death. MPP(+)-induced cell death was also abolished by co-treatment with nitric oxide synthase (NOS) inhibitors such as 7-nitroindazole (7-NI), 2-ethyl-2-thiopseudourea hydrobromide (EPTU) or S-methylisothiourea sulphate (MPTU). We also tested the protective effects of an iron chelator (deferoxamine mesylate, DFx) and a peroxynitrite scavenger (FeTTPS) and the results lend further support to the view that the free radical cytotoxicity plays an essential role in MPP(+)-induced death in primary cultures of CGC.

Involvement of Interferon-γ in Microglial-Mediated Loss of Dopaminergic Neurons

“…This is an interesting observation that suggests that microglial activation, although important, is not the only mechanisms by which dopaminergic neuron damage occurs. This notion is supported by the fact that MPTP (MPP ϩ metabolite) can directly target mitochondria in neurons and lead to increased ROS and damage (Liberatore et al, 1999;Dehmer et al, 2000;Gonzalez-Polo et al, 2004;Chen et al, 2006).…”

Nitric Oxide Modulates Sodium Vitamin C Transporter 2 (SVCT-2) Protein Expression via Protein Kinase G (PKG) and Nuclear Factor-κB (NF-κB)

“…However, ascorbate within neuronal cells avoids ␣-tocopherol oxidation; increases the viability of SH-SY5Y cells when these cells are challenged with peroxide (44) or ␤-amyloid (45); inhibits MPP(ϩ)-induced cerebellar granule cells death (46); decreases ferricyanide-induced lipid peroxidation (47); and decreases H 2 O 2 -induced cell swelling in rat brain slices (48). Moreover, here we show a NO-induced regulation of ascorbate content to retinal cells and, specifically in the chicken retina, NO has been demonstrated to display a protective role against medium refeeding-induced neuronal cell death (21).…”

A Macrophage−Nanozyme Delivery System for Parkinson's Disease

“…Catalase catalyzes the conversion of hydrogen peroxide, a known ROS, to water and molecular oxygen with one of the highest turnover rates for all known enzymes. In an in Vitro model of PD, catalase was shown to rescue primary cultured cerebellar granule cells from ROS toxic effects (13,28). Furthermore, a low molecular mass catalase activator, rasagiline, induced neuroprotection in a mouse model of PD (29).…”