title: The neuroprotective effect of tropisetron on vincristine-induced neurotoxicity.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Anita
authors.initials: A
authors.lastname: Barzegar-Fallah
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago, P.O. Box 913, Dunedin, New Zealand.
authors.forename: Houman
authors.initials: H
authors.lastname: Alimoradi
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Saeed
authors.initials: S
authors.lastname: Mehrzadi
authors.affiliation: Department of Pharmacology, Islamic Azad University of Pharmaceutical Sciences, Tehran, Iran.
authors.forename: Niloofar
authors.initials: N
authors.lastname: Barzegar-Fallah
authors.affiliation: Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Germany.
authors.forename: Adib
authors.initials: A
authors.lastname: Zendedel
authors.affiliation: Department of Pathology, Tehran University of Medical Science, Tehran, Iran.
authors.forename: Ata
authors.initials: A
authors.lastname: Abbasi
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: dehpour@yahoo.com.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology; D007211:Indoles / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000097:blood; D008297:Male; D009431:Neural Conduction / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000209:etiology* / Q000401:mortality / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D000077526:Tropisetron; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014750:Vincristine / Q000633:toxicity*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D007376:Interleukin-2; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D014750:Vincristine; D000077526:Tropisetron
keywords: Granisetron; Neuroprotective; Peripheral neuropathy; Tropisetron; Vincristine