当归四逆汤防治奥沙利铂致慢性周围神经病变

Danggui Sini Decoction for Prevention and Treatment of Chronic CIPN Caused by Oxaliplatin

摘要:

目的: 通过观察化疗致周围神经病变(CIPN)大鼠疼痛行为学变化、脊髓N-甲基-D-天冬氨酸受体2B亚基(NR2B)的表达,探讨当归四逆汤对奥沙利铂致CIPN的防治作用。方法: 52只成年Wistar雌性大鼠随机分为5组,正常组、模型组、甲钴胺组(104 μg·kg^-1)、当归四逆汤低、高剂量组(5.59,22.36 g·kg^-1)。造模前预防性给药7 d,当归四逆汤高、低剂量组5 mL·kg^-1ig, 1次／d;甲钴胺组ip,2次／周;造模过程中继续给药,持续50 d。除正常组其余4组按照奥沙利铂4 mg·kg^-12次/周 ip 共8次。给药期间每3日称体重;每周测定机械性缩足阈值(MWT)。给药结束后,处死大鼠,剖取腰段L2~4脊髓、L4~5背根神经节(DRG),实时荧光定量PCR(qRT-PCR)检测L2~4脊髓NR2B mRNA水平。结果: 大鼠体重d₄₀后当归四逆汤低、高剂量组体重均上升,高于模型组及甲钴胺组(P<0.01);模型组与正常组比较,MWT明显下降(P<0.05),当归四逆汤低、高剂量组、甲钴胺组与模型组比较MWT明显增高(P<0.05);模型组NR2B mRNA水平显著高于正常组(P<0.05),当归四逆汤低、高剂量组可显著下调模型大鼠NR2B mRNA水平(P<0.05),甲钴胺组效果不明显。结论: 当归四逆汤组使CIPN大鼠L2~4脊髓NR2B mRNA水平减少,且与行为学表现有明显的相关性,当归四逆汤可能在CIPN的防治中起重要作用。

Abstract:

Objective: To investigated the preventive and therapeutic effects of Danggui Sini decoction (DSD) on oxaliplatin induced chronic chemotherapy induced peripheral neuropathy (CIPN) by observing the pain response of rats, the expression of NR2B mRNA level. Method: Fifty-two adult female Wistar rats were divided randomly into 5 groups:blank control group, model control group, positive control group of mecobalamin (104 μg·kg^-1), DSD group of (5.59,22.36 g·kg^-1). Animal model of chronic CIPN was induced by oxaliplatin (4 mg·kg^-1, ip, twice a week for 8 times), rats were pretreated by DSD (ig, daily) and mecobalamin (ip, twice in a week) from 7 days before making models and continued for 50 days after modeling. The body weight (every three days) and MWT (weekly) of rats were measured. The expression of NR2B mRNA in L2-4 spinal sample was tested by Q-PCR. Result: Rat weights in DSD groups were significantly higher than those in model and positive control group after day 40th (P<0.01). Comparing to the model group, there were significant increasing on MWT in both DSD and mecobalamin groups (P<0.05). The significant decrease of NR2B mRNA and the increase of pNF-H were spotted in tissue samples from DSD group, compared with those in the model group, however, the changes on NR2B and pNF-H was not obvious in mecobalamin group (P<0.05). Conclusion: The chronic CIPN in rats could be alleviated by treatment of DSD by decreasing the expression of NR2B mRNA in L2-4 spine. Hence, treatment of DSD could be a potential alternative therapy for chronic CIPN.