Fluoxetine prevents the memory deficits and reduction in hippocampal cell proliferation caused by valproic acid

Valproic acid (VPA), a commonly used antiepileptic drug, has been reported to cause cognitive impairments in patients. In a previous study, using a rodent model, we showed that VPA treatment impaired cognition which was associated with a reduction in the cell proliferation required for hippocampal neurogenesis. The antidepressant fluoxetine has been shown to increase hippocampal neurogenesis and to reverse the memory deficits found in a number of pathological conditions. In the present study we investigated the protective effects of fluoxetine treatment against the impairments in memory and hippocampal cell proliferation produced by VPA. Male Sprague Dawley rats received daily treatment with fluoxetine (10 mg/kg) by oral gavage for 21 days. Some rats were co-administered with VPA (300 mg/kg, twice daily i.p. injections) for 14 days from day 8 to day 21 of the fluoxetine treatment. Spatial memory was tested using the novel object location (NOL) test. The number of proliferating cells present in the sub granular zone of the dentate gyrus was quantified using Ki67 immunohistochemistry at the end of the experiment. Levels of the receptor Notchl, the neurotrophic factor BDNF and the neural differentiation marker DCX were determined by Western blotting. VPA-treated rats showed memory deficits, a decrease in the number of proliferating cells in the sub granular zone and decreases in the levels of Notchl and BDNF but not DCX compared to control animals. These changes in behavior, cell proliferation and Notchl and BDNF were prevented in animals which had received both VPA and fluoxetine. Rats receiving fluoxetine alone did not show a significant difference in the number of proliferating cells or behavior compared to controls. These results demonstrated that the spatial memory deficits and reduction of cell proliferation produced by VPA can be ameliorated by the simultaneous administration of the antidepressant fluoxetine. Crown Copyright (C) 2016 Published by Elsevier B.V. All rights reserved.