Abstract
A variety of pathogenic mechanisms, such as cytoplasmic calcium/zinc influx, reactive oxygen species production, and ionic imbalance, have been suggested to play a role in cerebral ischemia induced neurodegeneration. During the ischemic state that occurs after stroke or heart attack, it is observed that vesicular zinc can be released into the synaptic cleft, and then translocated into the cytoplasm via various cation channels. Transient receptor potential melastatin 2 (TRPM2) is highly distributed in the central nervous system and has high sensitivity to oxidative damage. Several previous studies have shown that TRPM2 channel activation contributes to neuroinflammation and neurodegeneration cascades. Therefore, we examined whether anti-oxidant treatment, such as with N-acetyl-l-cysteine (NAC), provides neuroprotection via regulation of TRPM2, following global cerebral ischemia (GCI). Experimental animals were then immediately injected with NAC (150 mg/kg/day) for 3 and 7 days, before sacrifice. We demonstrated that NAC administration reduced activation of GCI-induced neuronal death cascades, such as lipid peroxidation, microglia and astroglia activation, free zinc accumulation, and TRPM2 over-activation. Therefore, modulation of the TRPM2 channel can be a potential therapeutic target to prevent ischemia-induced neuronal death.
Highlights
Recent decades have seen a dramatic increase in the attention and focus on the study of brain disease
We verified whether NAC administration attenuates Global cerebral ischemia (GCI)-induced neuronal death via inhibition of Transient receptor potential melastatin 2 (TRPM2) channels
Our findings indicate that NAC reduces accumulation of intracellular free zinc and TRPM2 over-activation by maintaining a sufficient supply of glutathione production
Summary
Recent decades have seen a dramatic increase in the attention and focus on the study of brain disease. We tested the hypothesis that if ischemia-induced oxidative damage leads to TRPM2 activation, inhibition of this channel may have therapeutic effects through blockade of zinc influx-induced cell damage, which is supported by evidence that NAC administration decreased brain damage in several other neurological diseases [24,34]. Following this logic, we hypothesized that if the TRPM2 level was increased by global cerebral ischemia-induced cell death cascades, regulation of TRPM2 as a potential target for preventing ischemia-induced injury could ameliorate a diverse number of cerebral pathologies associated with ischemia. We used a GCI brain disease model in adult rats and conducted several types of histological evaluations and behavioral assessments
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