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Sci Rep. 2018 Nov 7;8(1):16457. doi: 10.1038/s41598-018-34915-5.

Valproate reduces neuroinflammation and neuronal death in a rat chronic constriction injury model.

Chen JY1,2, Chu LW3,4, Cheng KI5,6, Hsieh SL7, Juan YS8,9, Wu BN10,11.

Author information

1
Division of Neurosurgery, Fooyin University Hospital, Pingtung, Taiwan.
2
School of Nursing, Fooyin University, Kaohsiung, Taiwan.
3
Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
4
Yuh-Ing Junior College of Health Care and Management, Kaohsiung, Taiwan.
5
Department of Anesthesiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
6
Department of Anesthesiology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
7
Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
8
Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
9
Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
10
Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. binnan@kmu.edu.tw.
11
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. binnan@kmu.edu.tw.

Abstract

Valproate (VPA) is a well-known drug for treating epilepsy and mania, but its action in neuropathic pain is unclear. We used a chronic constriction injury (CCI) model to explore whether VPA prevents neuropathic pain-mediated inflammation and neuronal death. Rats were treated with or without VPA. CCI + VPA rats were intraperitoneally injected with VPA (300 mg/kg/day) from postoperative day (POD) 1 to 14. We measured paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) 1 day before surgery and 1, 3, 7, 14 days after CCI and harvested the sciatic nerves (SN), spinal cord (SC) and dorsal root ganglia (DRG) on POD 3, 7, and 14. PWL and PWT were reduced in CCI rats, but increased in CCI + VPA rats on POD 7 and POD 14. VPA lowered CCI-induced inflammatory proteins (pNFκB, iNOS and COX-2), pro-apoptotic proteins (pAKT/AKT and pGSK-3β/GSK-3β), proinflammatory cytokines (TNF-α and IL-1β) and nuclear pNFκB activation in the SN, DRG and SC in CCI rats. COX-2 and pGSK-3 proteins were decreased by VPA on immunofluorescence analysis. VPA attenuated CCI-induced thermal and mechanical pain behaviors in rats in correlation with anti-neuroinflammation action involving reduction of pNFκB/iNOS/COX-2 activation and inhibition of pAKT/pGSK-3β-mediated neuronal death from injury to peripheral nerves.

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