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 (10mg/kg) by oral gavage for 21days. Some rats were co-administered with VPA (300mg/kg, twice daily i.p. injections) for 14days 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 Notch1, 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 Notch1 and BDNF but not DCX compared to control animals. These changes in behavior, cell proliferation and Notch1 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.
Department of Anatomy, Faculty of medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Neuroscience Research and Development Group, Khon Kaen University, Khon Kaen 40002, Thailand; Center for Research and Development of Herbal Health Products, Khon Kaen University, Khon Kaen 40002, Thailand. Electronic address: jariya@kku.ac.th.
Jariya Umka
JU
Welbat
Department of Anatomy, Faculty of medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Preeyanuch
P
Sangrich
Department of Anatomy, Faculty of medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Apiwat
A
Sirichoat
Department of Anatomy, Faculty of medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Pornthip
P
Chaisawang
Department of Anatomy, Faculty of medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Wunnee
W
Chaijaroonkhanarak
Department of Anatomy, Faculty of medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
Parichat
P
Prachaney
Department of Anatomy, Faculty of medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Center for Research and Development of Herbal Health Products, Khon Kaen University, Khon Kaen 40002, Thailand.
Wanassanun
W
Pannangrong
School of Life Sciences, Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Peter
P
Wigmore
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D000089662:Doublecortin Protein; D005473:Fluoxetine / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D065852:Spatial Memory / Q000187:drug effects; D014635:Valproic Acid
D000089662:Doublecortin Protein; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors; D014635:Valproic Acid; C000714848:Dcx protein, rat
Fluoxetine; Hippocampal neurogenesis; Spatial memory; Valproic acid