fluvoxamine and Brain-Ischemia

Poststroke depression is one of the major symptoms observed in the chronic stage of brain stroke such as cerebral ischemia. Its pathophysiological mechanisms, however, are not well understood. Using the transient right middle cerebral artery occlusion- (MCAO-, 90 min) operated rats as an ischemia model in this study, we first observed that aggravation of anhedonia spontaneously occurred especially after 20 weeks of MCAO, and it was prevented by chronic antidepressants treatment (imipramine or fluvoxamine). The anhedonia specifically associated with loss of the granular neurons in the ipsilateral side of hippocampal dentate gyrus and was also prevented by an antidepressant imipramine. Immunohistochemical analysis showed increased apoptosis inside the granular cell layer prior to and associated with the neuronal loss, and imipramine seemed to recover the survival signal rather than suppressing the death signal to prevent neurons from apoptosis. Proliferation and development of the neural stem cells were increased transiently in the subgranular zone of both ipsi- and contralateral hippocampus within one week after MCAO and then decreased and almost ceased after 6 weeks of MCAO, while chronic imipramine treatment prevented them partially. Overall, our study suggests new insights for the mechanistic correlation between poststroke depression and the delayed neurodegenerative changes in the hippocampal dentate gyrus with effective use of antidepressants on them.

Topics: Anhedonia; Animals; Antidepressive Agents; Brain Ischemia; Cell Proliferation; Dentate Gyrus; Disease Models, Animal; Fluvoxamine; Imipramine; Male; Nerve Degeneration; Neurons; Rats; Rats, Sprague-Dawley

The aim of this study was to examine the psychopharmacological effects of antidepressants on post-ischemic rats. Global transient cerebral ischemia was performing with the four-vessels occlusion method. Locomotor activity, neurological scores and activity during the 20 min forced swimming test (FST) session were comparatively evaluated in sham-operated and ischemic animals. Three doses of four antidepressants or saline were then intraperitoneally administered 23.5, 5 and 1h before the 5 min FST session, and 0.5h before the elevated plus-maze (EPM). Histological quantification of neuronal loss was performed at the end of the experiments. Results show that before treatment, ischemic animals present significantly greater spontaneous motor activity, a neurological score and an immobility time in the 20 min FST lower than sham-operated animals. After treatment, compared to the saline group, we show an antidepressant-like activity in the FST with all the molecules, except with the fluvoxamine, and an anxiolytic-like effect in the EPM, with at least one dose of each compounds. The observed effect is very similar according to whether or not the animals were ischemic, with a tendency to react more important for ischemic animals versus sham-operated. This difference is significant in the FST for the immobility time and in the EPM for the ratio of distance, of time, of number of entrances and non-protected head dips with the 45 mg dose of milnacipran. These results demonstrate that even though global transient cerebral ischemia induces important cerebral lesions, it modifies little the effects of the different antidepressants, whatever their primary pharmacological target, with a particular effectiveness with the dual serotonin and norepinephrine reuptake inhibitor milnacipran.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Anxiety Disorders; Behavior, Animal; Brain Ischemia; Cyclopropanes; Depressive Disorder; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Fluvoxamine; Hippocampus; Imipramine; Immobility Response, Tonic; Male; Milnacipran; Motor Activity; Rats; Rats, Wistar