title: Valproic acid reduces spatial working memory and cell proliferation in the hippocampus.
abstract: Valproic acid (VPA) is widely used clinically, as an anticonvulsant and mood stabilizer but is, however, also known to block cell proliferation through its ability to inhibit histone deacetylase enzymes. There have been a number of reports of cognitive impairments in patients taking VPA. In this investigation we examined the relationship between cognition and changes in cell proliferation within the hippocampus, a brain region where continued formation of new neurons is associated with learning and memory. Treatment of rats by i.p. injection of VPA, reduced cell proliferation in the sub granular zone of the dentate gyrus within the hippocampus. This was linked to a significant impairment in their ability to perform a hippocampus-dependent spatial memory test (novel object location). In addition, drug treatment caused a significant reduction in brain-derived neurotrophic factor (BDNF) and Notch 1 but not doublecortin levels within the hippocampus. These results support the idea that VPA may cause cognitive impairment and provide a possible mechanism for this by reducing neurogenesis within the hippocampus.
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Center, Nottingham NG7 2UH, UK. mbxju@nottingham.ac.uk
authors.forename: J
authors.initials: J
authors.lastname: Umka
authors.forename: S
authors.initials: S
authors.lastname: Mustafa
authors.forename: M
authors.initials: M
authors.lastname: ElBeltagy
authors.forename: A
authors.initials: A
authors.lastname: Thorpe
authors.forename: L
authors.initials: L
authors.lastname: Latif
authors.forename: G
authors.initials: G
authors.lastname: Bennett
authors.forename: P M
authors.initials: PM
authors.lastname: Wigmore
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced* / Q000503:physiopathology; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced* / Q000503:physiopathology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009483:Neuropsychological Tests; D051381:Rats; D051881:Receptor, Notch1 / Q000187:drug effects / Q000378:metabolism; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D019208:Brain-Derived Neurotrophic Factor; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; D014635:Valproic Acid