Full Text:   <1626>

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CLC number: R338.64

On-line Access: 2019-03-01

Received: 2018-06-19

Revision Accepted: 2018-10-04

Crosschecked: 2019-01-10

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Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Jariya Umka Welbat

https://orcid.org/0000-0002-2872-1542

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Journal of Zhejiang University SCIENCE B 2019 Vol.20 No.3 P.253-263

http://doi.org/10.1631/jzus.B1800340


Valproic acid withdrawal ameliorates impairments of hippocampal-spatial working memory and neurogenesis


Author(s):  Wanassanun Pannangrong, Apiwat Sirichoat, Trai Wongsiri, Peter Wigmore, Jariya Umka Welbat

Affiliation(s):  Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; more

Corresponding email(s):   jariya@kku.ac.th

Key Words:  Hippocampus, Neurogenesis, Spatial memory, Valproic acid


Wanassanun Pannangrong, Apiwat Sirichoat, Trai Wongsiri, Peter Wigmore, Jariya Umka Welbat. Valproic acid withdrawal ameliorates impairments of hippocampal-spatial working memory and neurogenesis[J]. Journal of Zhejiang University Science B, 2019, 20(3): 253-263.

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author="Wanassanun Pannangrong, Apiwat Sirichoat, Trai Wongsiri, Peter Wigmore, Jariya Umka Welbat",
journal="Journal of Zhejiang University Science B",
volume="20",
number="3",
pages="253-263",
year="2019",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B1800340"
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%0 Journal Article
%T Valproic acid withdrawal ameliorates impairments of hippocampal-spatial working memory and neurogenesis
%A Wanassanun Pannangrong
%A Apiwat Sirichoat
%A Trai Wongsiri
%A Peter Wigmore
%A Jariya Umka Welbat
%J Journal of Zhejiang University SCIENCE B
%V 20
%N 3
%P 253-263
%@ 1673-1581
%D 2019
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1800340

TY - JOUR
T1 - Valproic acid withdrawal ameliorates impairments of hippocampal-spatial working memory and neurogenesis
A1 - Wanassanun Pannangrong
A1 - Apiwat Sirichoat
A1 - Trai Wongsiri
A1 - Peter Wigmore
A1 - Jariya Umka Welbat
J0 - Journal of Zhejiang University Science B
VL - 20
IS - 3
SP - 253
EP - 263
%@ 1673-1581
Y1 - 2019
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1800340


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.

停用丙戊酸对海马-空间工作记忆和神经发生损伤的改善作用

目的:丙戊酸是一种用于治疗癫痫发作的药物,可引起成人和儿童的空间记忆障碍.海马的神经发生与学习能力密切相关,而丙戊酸可抑制该区域的神经发生,从而导致空间记忆障碍.我们已有动物模型证明丙戊酸能显著损害海马-空间工作记忆,并抑制齿状回亚颗粒区域中的神经元生成.既往临床病例报道指出患者在停用丙戊酸治疗后记忆能力有所改善.因此,本实验研究停用丙戊酸治疗后两个时间点的空间记忆和海马神经发生的恢复情况.
创新点:研究了停用丙戊酸后的空间记忆恢复的时间进程以及与海马神经发生变化之间的关系.
方法:雄性Wistar大鼠每天两次腹膜内注射0.9%生理盐水或丙戊酸(300 mg/kg),持续10天.在药物治疗结束后第1、30或45天,使用新物体位置(NOL)测试来检查空间记忆;使用Ki67免疫组织化学计数海马细胞分裂情况;并使用免疫印迹法(western immunoblotting)测量脑源性神经营养因子(BDNF)和Notch1的水平.
结论:药物治疗结束后第1天和第30天大鼠的空间工作记忆有受损,但在第45天时,恢复到正常水平.细胞增殖在第30天和第45天时增加至正常水平.神经发生的两种标志物(BDNF和Notch1)在第45天时恢复到正常水平.这些结果表明了记忆能力的恢复发生在停用丙戊酸6周内,并且该种效应发生在海马神经发生恢复至正常水平后.

关键词:海马;神经发生;空间记忆;丙戊酸

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