The dual role of KCNQ/M channels upon OGD or OGD/R insults in cultured cortical neurons of mice: Timing is crucial in targeting M‐channels against ischemic injuries

Abstract

KCNQ/M potassium channels play a vital role in neuronal excitability; however, it is required to explore their pharmacological modulation on N‐Methyl‐ d‐aspartic acid receptors (NMDARs)‐mediated glutamatergic transmission of neurons upon ischemic insults. In the current study, both presynaptic glutamatergic release and activities of NMDARs were measured by NMDAR‐induced miniature excitatory postsynaptic currents (mEPSCs) in cultured cortical neurons of C57 mice undergoing oxygen and glucose deprivation (OGD) or OGD/reperfusion (OGD/R). The KCNQ/M‐channel opener, retigabine (RTG), suppressed the overactivation of postsynaptic NMDARs induced by OGD and then NO transient; RTG also decreased OGD‐induced neuronal death measured with MTT assay, suggesting the beneficial role of KCNQ/M‐channels for the neurons exposed to ischemic insults. However, when the neurons exposed to the subsequent reperfusion, KCNQ/M‐channels played a differential role from its protective effect. OGD/R increased presynaptic glutamatergic release, which was further augmented by RTG or decreased by KCNQ/M‐channel blocker, XE991. Reactive oxygen species (ROS) were produced partly in a NO‐dependent manner. In addition, XE991 decreased neuronal injuries upon reperfusion measured with DCF and PI staining. Meanwhile, the addition of RTG upon OGD or XE991 upon reperfusion can reverse OGD or OGD/R‐reduced mitochondrial membrane potential. Our present study indicates the dual role of KCNQ/M‐channels in OGD and OGD/R, which will decide the fate of neurons. Provided that activation of KCNQ/M‐channels has differential effects on neuronal injuries during OGD or OGD/R, we propose that therapy targeting KCNQ/M‐channels may be effective for ischemic injuries but the proper timing is so crucial for the corresponding treatment.

Physiology and Therapeutic Potential of SK, H, and M Medium AfterHyperPolarization Ion Channels

“…Increasing SK channel activity by using 1-EBIO (SK channel agonist) increases the effect of Mg 2+ blocking on NMDARs and prevents glutamate-mediated excitotoxic damage ( Allen et al, 2011 ). The use of the HCN blocker ZD7288 and the M channel activator retigabine soon after ischemic damage (within 0–6 h) prevents excessive activation of postsynaptic NMDARs, prevents LTP deficits, and provides neuroprotection against oxygen or glucose deprivation in organotypic hippocampal cultures and in vivo ischemic models ( Boscia et al, 2006 ; He et al, 2014 ; Bierbower et al, 2015 ; Diao et al, 2019 ; Chen et al, 2020 ; Table 2 ). Astrocytes also respond to ischemia to prevent neurotoxicity.…”