RT Journal Article
SR Electronic
T1 Endothelin Confers Protection against High Glucose-Induced Neurotoxicity via Alleviation of Oxidative Stress
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 130
OP 139
DO 10.1124/jpet.116.238659
VO 361
IS 1
A1 Mohamed A. Fouda
A1 Abdel A. Abdel-Rahman
YR 2017
UL http://jpet.aspetjournals.org/content/361/1/130.abstract
AB Recent findings linked the inhibition in the neuromodulator peptide endothelin-1 (ET-1) level to the high glucose-evoked neurotoxicity. However, definitive neuroprotective role for ET-1 and the major neuronal ET (ET-3) against high glucose-evoked toxicity and the implicated neurochemical responses triggered by their ET-A and ET-B receptors remain unknown. Here, we tested the hypothesis that ET-B activation alleviates high glucose-evoked oxidative stress and cell death. High glucose (100 mM for 48 hours)-evoked cell death was associated with elevation in reactive oxygen species, inhibition of catalase activity, and a paradoxical upregulation of hemeoxygenase-1 expression along with ET-A and ET-B receptors were downregulated and upregulated, respectively. ET-1 or ET-3, in concentrations that had no effect on PC12 cell viability in normal glucose medium, alleviated all high glucose-evoked neurochemical responses, except for the reduction in ET-A receptor expression. Prior (4 hours) incubation with a selective ET-A (BQ123) or ET-B (BQ788) receptor blocker abrogated the neuroprotection conferred by ET-1 or ET-3. However, the ET-B receptor played a greater role because BQ788 abrogated the favorable ET-1- or ET-3-mediated reversal of the ERK1/2 phosphorylation and the inhibition in catalase activity caused by high glucose. These findings suggest that endothelin exerts ET-B receptor-dependent favorable redox and neuroprotective effects against high glucose-evoked oxidative damage and neurotoxicity.