Neurotoxic Effect of Dexamethasone: Weakening upon the Action of Antidepressants

Abstract

Dose-dependent neurotoxic effects (decrease in the amplitude of field potentials generated by neurons of the СА1 area, dentate gyrus, and dorsal striatum, but not by neurons of layers ІІ and ІІІ of the parietal cortex, recorded in slices of the rat brain) were observed 24 h after i.p. injection оf dexamethasone in doses of 7 and 20 mg/kg. Dexamethasone-induced decreases in the reactivity of glutamatergic synapses in the studied cerebral structures were weakened by a noncompetitive blocker of NMDA receptors, ketamine (30 mg/kg), and an inhibitor of tyrosine protein phosphatases, sodium vanadate (15 mg/kg), if the latter agent was injected 6 h after dexamethasone administration. The neurotoxic effect of dexamethasone was intensified by a coagonist of NMDA receptors, glycine (50 mg/kg), as well as in the case where injections of dexamethasone were combined with single injections of the antidepressant fluoxetine (20 mg/kg) but not when another antidepressant, pyrazidol, was injected in the same dose. Chronic (two weeks) injections of fluoxetine and pyrazidol weakened manifestations of dexamethasone neurotoxicity. On-regulation of NMDA receptors and suppression of expression of neurotrophins are considered probable mechanisms underlying neurotoxicity of this hormone. The effect of chronic injections of antidepressants on the respective processes is discussed.