Valproic acid withdrawal ameliorates impairments of hippocampal-spatial working memory and neurogenesis
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Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) ISSN 1673-1581 (Print); ISSN 1862-1783 (Online) www.jzus.zju.edu.cn; www.springerlink.com E-mail: [email protected]
Valproic acid withdrawal ameliorates impairments of hippocampal-spatial working memory and neurogenesis* Wanassanun PANNANGRONG1, Apiwat SIRICHOAT1, Trai WONGSIRI3, Peter WIGMORE4, Jariya Umka WELBAT†‡1,2 1 2
3 4
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 Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
School of Life Sciences, Medical School, Queen’s Medical Centre, Nottingham University, Nottingham NG7 2UH, UK †
E-mail: [email protected]
Received June 19, 2018; Revision accepted Oct. 4, 2018; Crosschecked Jan. 10, 2019
Abstract: Valproic acid (VPA), an agent that is used to treat epileptic seizures, can cause spatial memory impairment in adults and children. This effect is thought to be due to the ability of VPA to inhibit neurogenesis in the hippocampus, which is required for learning. We have previously used an animal model to show that VPA significantly impairs hippocampal-spatial working memory and inhibits neuronal generation in the sub-granular zone of the dentate gyrus. As there are patient reports of improvements in memory after discontinuing VPA treatment, the present study investigated the recovery of both spatial memory and hippocampal neurogenesis at two time points after withdrawal of VPA. Male Wistar rats were given intraperitoneal injections of 0.9% normal saline or VPA (300 mg/kg) twice a day for 10 d. At 1, 30, or 45 d after the drug treatment, the novel object location (NOL) test was used to examine spatial memory; hippocampal cell division was counted using Ki67 immunohistochemistry, and levels of brain-derived neurotrophic factor (BDNF) and Notch1 were measured using western immunoblotting. Spatial working memory was impaired 1 and 30 d after the final administration, but was restored to control levels by 45 d. Cell proliferation had increased to control levels at 30 and 45 d. Both markers of neurogenesis (BDNF and Notch1 levels) had returned to control levels at 45 d. These results demonstrate that memory recovery occurs over a period of six weeks after discontinuing VPA treatment and is preceded by a return of hippocampal neurogenesis to control levels. Key words: Hippocampus; Neurogenesis; Spatial memory; Valproic acid https://doi.org/10.1631/jzus.B1800340 CLC number: R338.64
1 Introduction Valproic acid (VPA) is commonly used to treat patients for seizures (epilepsy) and mood disorders (bipolar disorder) (Henry, 2003; Buckley, 2008). It is also used as a medication for certain cancer and hu‡
Corresponding author Project supported by the Invitation Research of the Faculty of Medicine, Neuroscience Research and Development Group, Khon Kaen University, Thailand (No. I54119) ORCID: Jariya Umka WELBAT, https://orcid
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