Abstract
The activation of group I metabotropic glutamate receptor (group I mGlus) has been shown to produce neuroprotective or neurotoxic effects. In this study, we investigated the effects of N-acetylcysteine (NAC), a precursor of the antioxidant glutathione, on group I mGlus activation in apoptosis of glial C6 and MN9D cell lines, and a rat model of Parkinson's disease (PD). We demonstrated that NAC protected against apoptosis through modulation of group I mGlus activity. In glial C6 cells, NAC promoted phosphorylation of ERK induced by (s)-3,5- dihydroxy-phenylglycine (DHPG), an agonist of group I mGlus. NAC enhanced the group I mGlus-mediated protection from staurosporine (STS)-induced apoptosis following DHPG treatment. Moreover, in rotenone-treated MN9D cells and PD rat model, NAC protected against group I mGlus-induced toxicity by compromising the decrease in phosphorylation of ERK, phosphorylation or expression level of TH. Furthermore, the results showed that NAC prohibited the level of ROS and oxidation of cellular GSH/GSSG (Eh) accompanied by activated group I mGlus in the experimental models. Our results suggest that NAC might act as a regulator of group I mGlus-mediated activities in both neuroprotection and neurotoxicity via reducing the oxidative stress, eventually to protect cell survival. The study also suggests that NAC might be a potential therapeutics targeting for group I mGlus activation in the treatment of PD.
Highlights
Metabotropic glutamate receptors are G-proteincoupled receptors that can be classified into group I receptors, groups II and III, based on their signal transduction pathways and pharmacologic profiles
Recent studies showed that group I Metabotropic glutamate receptors (mGlus) was expressed in C6 glial cells [15] and that activation of these receptors by DHPG led to phosphorylation of extracellular signal-regulated kinase (ERK), which was well characterized in the activity of group I mGlus [16,17]
This study investigated the relationship between group I mGlus activation and NAC in neuroprotection in glial C6 and MN9D cells, and in a rat model of Parkinson’s disease (PD)
Summary
Metabotropic glutamate receptors (mGlus) are G-proteincoupled receptors that can be classified into group I receptors (mGlu and mGlu5), groups II (mGlu and mGlu3) and III (mGlu, mGlu, mGlu and mGlu8), based on their signal transduction pathways and pharmacologic profiles. Increasing evidence has indicated roles for group I metabotropic glutamate receptors (group I mGlus) in a variety of disorders, including Parkinson’s disease (PD), amyotrophic lateral sclerosis, epilepsy, stroke and Alzheimer’s disease [1]. The activation of group I mGlus has been shown to produce neuroprotective or neurotoxic effects in cell viabilty [2]. It is of considerable interest to investigate the regulation of group I mGlus in the context of neuroprotection in more details. The activation of group I mGlus can be neuroprotective or neurotoxic effects depending on different stimuli or the molecular mechanism by which the signaling is achieved. Activation of group I mGlus can either exacerbate neuronal death induced by oxygen-glucose deprivation [3] or attenuate oligodendrocyte excitoxicity by inhibiting the accumulation of reactive oxygen species (ROS) and intracellular glutathione (GSH) loss [4].
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