Mechanisms of Neuroprotective Action of Imipramine against Dexamethasone Neurotoxicity

Abstract

Imbalances in the corticosteroid millieu have been implicated in several neuropsychiatric disorders and neuronal damage. Administration of the high therapeutic doses of the glucocorticoids also induces neuronal damage. We investigated the early electrophysiological manifestations of neurotoxic action of the glucocorticoids. Administration of the toxic doses of dexamethasone (7 and 20 mg/kg) per 24 hours before the electrophysiological studies of rats hippocampal slices induced a dose-dependent decrease of reactivity of the glutamatergic synapses in CA1 pyramidal and granular neurons of dentate gyrus. This neurotoxic action of dexamethasone (at the dose of 7 mg/kg) was reinforced by a co-agonist of NMDA receptors glycine (50 mg/kg) and a administration of single dose of antidepressant imipramine (25 mg/kg). The neurotoxic effect of studied glucocorticoid was decreased by a noncompetitive blocker of the NMDA receptors ketamine (30 mg/kg), an inhibitor of tyrosine phosphoprotein phosphatases sodium ortovanadate (15 mg/kg) and chronic over two weeks administration of imipramine (25 mg/kg). It can be supposed that dexamethasone neurotoxicity is a result of the glutamate accumulation in brain extracellular spaces and intensive activation of NMDA receptors as well as of the inhibiton of providing survival of the neurons tyrosine phosphorilation of the neuronal protein substrates, which produced by the different activators of tyrosine protein kinases. Chronic administration of imipramine probably decreases the both components of dexamethasone neurotoxicity.