Activation of large-conductance Ca2+-activated K+ channels inhibits glutamate-induced oxidative stress through attenuating ER stress and mitochondrial dysfunction

作者：Yan, Xiao-Hua; Guo, Xiang-Yang; Jiao, Fu-Yong; Liu, Xuan; Liu, Yong^*

来源：Neurochemistry International, 2015, 90: 28-35.

DOI：10.1016/j.neuint.2015.07.004

• BK channels
• Oxidative stress
• Neuroprotection
• Mitochondrial dysfunction
• ER stress

Large-conductance Ca2+-activated K+ channels (BK channels) are widely expressed throughout the vertebrate nervous system, and are involved in the regulation of neurotransmitter release and neuronal excitability. Here, the neuroprotective effects of NS11021, a selective and chemically unrelated BK channel activator, and potential molecular mechanism involved have been studied in rat cortical neurons exposed to glutamate in vitro. Pretreatment with NS11021 significantly inhibited the loss of neuronal viability, LDH release and neuronal apoptosis in a dose-dependent manner. All these protective effects were fully antagonized by the BK-channel inhibitor paxilline. NS11021-induced neuroprotection was associated with reduced oxidative stress, as evidenced by decreased reactive oxygen species (ROS) generation, lipid peroxidation and preserved activity of antioxidant enzymes. Moreover, NS11021 significantly attenuated the glutamate-induced endoplasmic reticulum (ER) calcium release and activation of ER stress markers, including glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and caspase-12. Pretreatment with NS11021 also mitigated the mitochondrial membrane potential (MMP) collapse, cytochrome c release, and preserved mitochondrial Ca2+ buffering capacity and ATP synthesis after glutamate exposure, Taken together, these results suggest that activation of BK channels via NS11021 protects cortical neurons against glutamate-induced excitatory damage, which may be dependent on the inhibition of ER stress and preservation of mitochondrial dysfunction.

• 出版日期2015-11
• 单位陕西省人民医院; 西安交通大学