Etazolate, a phosphodiesterase 4 inhibitor reverses chronic unpredictable mild stress-induced depression-like behavior and brain oxidative damage

Abstract

Etazolate, a pyrazolopyridine class compound is selective inhibitor of type 4 phosphodiesterase (PDE4). Previous study in our laboratory has demonstrated that etazolate produced antidepressant-like effect in rodent models of behavioral despair. The present study was designed to investigate whether etazolate could affect the chronic unpredictable mild stress (CUMS)-induced depression in mice. The effect of etazolate on CUMS-induced depression was examined by measuring behavioral parameters and oxidant/antioxidant status of brain tissue. Mice were subjected to different stress paradigms daily for a period of 28 days to induce depressive-like behavior. The results showed that CUMS caused depression-like behavior in mice, as indicated by significant (p < 0.05) decrease in sucrose consumption and increase in duration of immobility. Moreover, CUMS also significantly (p < 0.05) increased the oxidative stress markers and decreased the antioxidant enzymes activity. Chronic administration of etazolate (0.5 and 1 mg/kg., p.o.) and fluoxetine (20 mg/kg., p.o.) significantly (p < 0.05) inhibited the CUMS-induced behavioral (decreased sucrose consumption and increased duration of immobility) and biochemical (increased lipid peroxidation and nitrite level; decreased glutathione, superoxide dismutase and catalase activity) changes. No alteration was observed in locomotor activity. Additionally, in the present study, the efficacy of etazolate (1 mg/kg., p.o.) on the behavioral and biochemical paradigms was found comparable to that of fluoxetine, used as standard antidepressant. In conclusion, the results of the present study suggested that etazolate alleviated the CUMS-induced depression in mice, which is at least in part mediated by modulating oxidative–nitrosative stress status in mice brain.