Endothelin Confers Protection against High Glucose-Induced Neurotoxicity via Alleviation of Oxidative Stress.
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.
Department of Pharmacology, Brody School of Medicine, East Carolina University, North Carolina.
Mohamed A
MA
Fouda
Department of Pharmacology, Brody School of Medicine, East Carolina University, North Carolina abdelrahmana@ecu.edu.
Abdel A
AA
Abdel-Rahman
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D019334:Endothelin-3 / Q000494:pharmacology*; D005947:Glucose / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D051381:Rats
D019332:Endothelin-1; D019334:Endothelin-3; D018696:Neuroprotective Agents; D005947:Glucose