Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 17, Pages -Publisher
MDPI
DOI: 10.3390/ijms21176026
Keywords
global cerebral ischemia; N-acetyl-l-cysteine; transient receptor potential melastatin 2; zinc; neurodegeneration
Funding
- National Research Foundation of Korea (NRF) [NRF-2019R1A6A3A13093671, NRF-2019R1A2C4004912]
- Brain Research Program through the NRF - Ministry of Science, Information and Communication Technology and Future Planning [NRF-2017M3C7A1028937, 2018R1A4A1020922, 2020R1A2C2008480]
- National Research Foundation of Korea [2020R1A2C2008480, 2018R1A4A1020922] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 withN-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.
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