Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
Department of Pharmacology and Toxicology, University of Otago, P.O. Box 913, Dunedin, New Zealand.
Neurotoxicology. 2014 Mar;41:1-8. doi: 10.1016/j.neuro.2013.12.002. Epub 2013 Dec 26.
Vincristine (VCR) peripheral neuropathy is a dose-limiting side effect. Several studies have shown that tropisetron, a 5-HT3 receptor antagonist, exerts anti-inflammatory and immunomodulatory properties. Current study was designed to investigate a suppressive effect of tropisetron on VCR-induced neuropathy and whether this effect exerts through the 5-HT3 receptor or not. Neuropathy was induced in rats by administration of vincristine (0.5mg/kg, 3 intraperitoneal injections on alternate days) and in treatment group, tropisetron (3mg/kg); m-chlorophenylbiguanide (mCPBG), a selective 5-HT3 receptor agonist (15mg/kg); tropisetron (3mg/kg) plus mCPBG (15mg/kg); granisetron, another selective 5-HT3 receptor antagonist (3mg/kg) were administered intraperitoneally 1h prior to vincristine injection. Hot plate, open field tests (total distance moved, mean velocity and percentage of total duration of the movement) and motor nerve conduction velocity (MNCV) were performed to evaluate the sensory and motor neuropathy. Further, plasma levels of tumor necrosis factor-alpha (TNF-α) and interleukin-2 (IL-2) and the level of TNF-α in sciatic nerve were assessed as well as histological examination. In only VCR-treated rats hot plate latencies were significantly increased, total distance moved, mean velocity, total duration of the movement and sciatic MNCV significantly decreased compared with control. In tropisetron and tropisetron plus mCPBG groups, one injection of tropisetron prior to each VCR injection robustly diminished TNF-α and IL-2 levels, and also prevented mixed sensory-motor neuropathy, as indicated by less mortality rate, better general conditions, behavioral and electrophysiological studies. Moreover, pathological evidence confirmed the results obtained from other findings. But granisetron and mCPBG had no significant effect on the mentioned parameters. In conclusion, these studies demonstrate that tropisetron significantly suppressed VCR-induced neuropathy and could be a neuroprotective agent for prevention of VCR-induced neuropathy via a receptor-independent pathway.
长春新碱（VCR）周围神经病是一种剂量限制的副作用。几项研究表明，5-HT3 受体拮抗剂托烷司琼具有抗炎和免疫调节作用。本研究旨在探讨托烷司琼对长春新碱诱导的周围神经病的抑制作用，以及这种作用是否通过 5-HT3 受体发挥作用。长春新碱（0.5mg/kg，3 次腹腔注射，隔日 1 次）诱导大鼠周围神经病，在治疗组中，托烷司琼（3mg/kg）；m-氯苯基大碱（mCPBG），一种选择性 5-HT3 受体激动剂（15mg/kg）；托烷司琼（3mg/kg）加 mCPBG（15mg/kg）；格拉司琼，另一种选择性 5-HT3 受体拮抗剂（3mg/kg）在长春新碱注射前 1 小时腹腔内给药。热板、旷场试验（总移动距离、平均速度和运动时间的百分比）和运动神经传导速度（MNCV）用于评估感觉和运动神经病。此外，还评估了血浆肿瘤坏死因子-α（TNF-α）和白细胞介素-2（IL-2）水平以及坐骨神经中 TNF-α的水平以及组织学检查。只有长春新碱治疗的大鼠的热板潜伏期明显增加，总移动距离、平均速度、运动时间的总持续时间和坐骨神经 MNCV 明显低于对照组。在托烷司琼和托烷司琼加 mCPBG 组中，每次长春新碱注射前注射 1 次托烷司琼，可显著降低 TNF-α和 IL-2 水平，并通过降低死亡率、改善一般情况、行为和电生理研究，预防混合感觉运动神经病。此外，病理证据证实了从其他发现中获得的结果。但是，格拉司琼和 mCPBG 对上述参数没有显著影响。总之，这些研究表明，托烷司琼显著抑制长春新碱诱导的周围神经病，并且可能是一种通过受体非依赖性途径预防长春新碱诱导的周围神经病的神经保护剂。
