College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China.
Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia.
ACS Infect Dis. 2020 Apr 10;6(4):715-724. doi: 10.1021/acsinfecdis.9b00341. Epub 2020 Feb 20.
Peripheral neurotoxicity often occurs in patients receiving parenteral polymyxin therapy (i.e., colistin methanesulfonate or polymyxin B). The present study aimed to investigate the protective effect of curcumin on colistin-induced peripheral neurotoxicity using a murine model. Female C57BL/6 mice ( = 10 in each group) were randomly divided into the following: (1) control group (saline), (2) curcumin only group (200 mg/kg/day; orally), (3) colistin only group (18 mg/kg/day; i.p.), (4) colistin (18 mg/kg/day) plus curcumin 50 mg/kg/day group, (5) colistin (18 mg/kg/day) plus curcumin 100 mg/kg/day group, (6) colistin (18 mg/kg/day) plus curcumin 200 mg/kg/day group; all mice were treated for 7 days. Orally applied curcumin was detected in the brain, cerebellum, and sciatic nerve. Co-administration of oral curcumin markedly improved colistin-induced impaired sensory and motor dysfunctions in a dose-dependent manner. Curcumin supplementation at 100 and 200 mg/kg significantly decreased lipid peroxidation and upregulated catalase (CAT) and superoxide dismutase (SOD) activities, ATP levels, and Na/K-ATPase activity in sciatic nerve tissue, compared to the colistin alone group. Curcumin supplementation at 200 mg/kg upregulated the levels of AKT, NGF, mTOR, Nrf2, and HO-1 mRNA and concomitantly downregulated Bax, caspases-3, and -9 mRNA; it also decreased caspase-3 and caspase-9 activity. In summary, for the first time, our study reveals that the protective effect of oral curcumin on colistin induced peripheral neurotoxicity is associated with the activation of NGF/Akt and Nrf2/HO-1 pathways and inhibition of oxidative stress. This study highlights the potential clinical application of curcumin as an oral neuroprotective agent coadministered during colistin therapy.
周围神经毒性常发生于接受肠外多黏菌素治疗的患者（即黏菌素甲磺酸盐或黏菌素 B）。本研究旨在通过建立一个小鼠模型来探究姜黄素对黏菌素诱导的周围神经毒性的保护作用。将 10 只雌性 C57BL/6 小鼠（每组 10 只）随机分为以下几组：（1）对照组（生理盐水）；（2）姜黄素组（200mg/kg/天，口服）；（3）黏菌素组（18mg/kg/天，腹腔注射）；（4）黏菌素（18mg/kg/天）+50mg/kg/天姜黄素组；（5）黏菌素（18mg/kg/天）+100mg/kg/天姜黄素组；（6）黏菌素（18mg/kg/天）+200mg/kg/天姜黄素组；所有小鼠均治疗 7 天。姜黄素的脑、小脑和坐骨神经中的口服给药情况。姜黄素的口服给药显著改善了黏菌素诱导的感觉和运动功能障碍，且呈剂量依赖性。与单独使用黏菌素相比，姜黄素补充 100 和 200mg/kg 显著降低了脂质过氧化作用，并上调了坐骨神经组织中的过氧化氢酶（CAT）和超氧化物歧化酶（SOD）活性、三磷酸腺苷（ATP）水平和 Na/K-ATP 酶活性。姜黄素补充 200mg/kg 还上调了 AKT、NGF、mTOR、Nrf2 和 HO-1mRNA 的水平，同时下调了 Bax、caspase-3 和 caspase-9mRNA 的水平；还降低了 caspase-3 和 caspase-9 的活性。总之，本研究首次揭示，姜黄素的口服保护作用对黏菌素诱导的周围神经毒性的作用与 NGF/Akt 和 Nrf2/HO-1 途径的激活以及氧化应激的抑制有关。本研究强调了姜黄素作为黏菌素治疗时的口服神经保护剂的潜在临床应用。
