Efeito do tratamento crônico com imipramina sobre a neurogênese e sobre a memória de ratos submetidos à isquemia cerebral global e transitória

Abstract

Transient global cerebral ischemia (TGCI) as well as chronic antidepressant treatment stimulate the proliferation of precursor cells in the dentate gyrus (DG) of the hippocampus. This study was aimed to determine whether imipramine further promotes the neurogenesis induced by TGCI in the rat dentate gyrus. The 8-arm aversive radial maze (AvRM) was used to address the effects of imipramine on ischemia-induced memory impairment. Rats were trained for 12 days in the AvRM and subjected to TGCI one day later. After that, the animals were administered imipramine (20 mg/kg, i.p.) or saline (1 ml/kg, i.p.) during 14 days. 5-bromo-2'-deoxyuridine-5'-monophosphate (BrdU, 200 mg/kg, i.p.) was injected 24 h after the last imipramine or saline injection to label proliferating cells. Retention of cognition was assessed weekly on days 16, 23 and 30 post-ischemia and measured by i) the latency to find the goal box, ii) the number of reference memory errors, and c) the number of working memory errors. Cell proliferation was examined 24 h after the last BrdU and neurogenesis was evaluated 15 and 31 days after ischemia by DCX-immunohistochemistry. The rate of cell proliferation increases 7 days after TGCI but returns to basal levels after 15 days. Concomitantly, there was an increase in the number of new neurons in the DG 15 days after ischemia. Imipramine chronic treatment increased the expression of BrdU and DCX-labeled cells in DG of ischemic rats, although it produced no effect on ischemia-induced memory disruption in the AvRM task. In conclusion, the present study shows that imipramine can promote the neurogenic response to cerebral ischemia, an effect that was not accompanied by recovery of cognitive function. Additional studies are needed to evaluate whether imipramine treatment for longer time than that used presently would be able to improve both acquisition (learning) and retention (memory) performance after TGCI, and its relationship with neurogenesis.