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Abstract
Dexmedetomidine (DEX) may act as an antioxidant through regulation of TRPM2 and TRPV1 channel activations in the neurons by reducing cerebral ischemia-induced oxidative stress and apoptosis. The neuroprotective roles of DEX were tested on cerebral ischemia (ISC) in the cultures of rat primary hippocampal and DRG neurons. Fifty-six rats were divided into five groups. A placebo was given to control, sham control, and ISC groups, respectively. In the third group, ISC was induced. The DEX and ISC+DEX groups received intraperitoneal DEX (40 μg/kg) 3, 24, and 48 hours after ISC induction. DEX effectively reversed capsaicin and cumene hydroperoxide/ADP-ribose-induced TRPV1 and TRPM2 densities and cytosolic calcium ion accumulation in the neurons, respectively. In addition, DEX completely reduced ISC-induced oxidative toxicity and apoptosis through intracellular reactive oxygen species production and depolarization of mitochondrial membrane. The DEX and ISC+DEX treatments also decreased the expression levels of caspase 3, caspase 9, and poly (ADP-ribose) polymerase in the hippocampus and DRG. In conclusion, the current results are the first to demonstrate the molecular level effects of DEX on TRPM2 and TRPV1 activation. Therefore, DEX can have remarkable neuroprotective impairment effects in the hippocampus and DRG of ISC-induced rats.
Highlights
Cerebral ischemia is a neurodegenerative disease that causes disability and mortality[1,2]
Prevention of apoptotic cascades through inhibition of the TRP melastatin 2 (TRPM2) and TRP vanilloid 1 (TRPV1) in the hippocampal (HIPPO) and dorsal root ganglion (DRG) neurons of rats were more recently reported[5,17]. These later results raised the possibility that HIPPO and DRG neuron apoptosis mediated by the TRPM2 and TRPV1 channels could contribute to cerebral ischemia injuries, as accumulating evidence suggests their involvement in cerebral ischemia and spinal cord injury (SCI), including oxidative stress induced by the TRPM2 and TRPV1 channels[2,5]
The best TRPM2 channel antagonist within nonspecific agonists of the TRPM2 channel is N-(p-amylcinnamoyl) anthranilic acid (ACA)[24] and we used with the potential treatment action of DEX in the ISC-induced HIPPO and DRG neuron injury models through the TRPM2 involved in Ca2+ accumulation
Summary
Cerebral ischemia is a neurodegenerative disease that causes disability and mortality[1,2]. Prevention of apoptotic cascades through inhibition of the TRPM2 and TRPV1 in the hippocampal (HIPPO) and DRG neurons of rats were more recently reported[5,17] These later results raised the possibility that HIPPO and DRG neuron apoptosis mediated by the TRPM2 and TRPV1 channels could contribute to cerebral ischemia injuries, as accumulating evidence suggests their involvement in cerebral ischemia and SCI, including oxidative stress induced by the TRPM2 and TRPV1 channels[2,5]. DEX may reduce the entry of overload Ca2+ via modulation of TRPM2 and TRPV1 channel activations in the HIPPO and DRG neurons of rats with cerebral ischemia, and this effect should be clarified.
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