Putative neurotrophic factors in the protection of cisplatin-induced peripheral neuropathy in rats.
One of the major side effects of cisplatin is its neurotoxicity. In rats, this neurotoxicity can be measured as a slowing of the H-reflex-related sensory nerve conduction velocity. In this study the ability of the neurotrophic peptide ORG 2766 (an ACTH4-9 analog) to prevent this neurotoxic side effect was investigated in rats subjected to a high-dose cisplatin regime (2 mg/kg, 2/wk). Furthermore, the efficacy of nimodipine (a calcium entry blocker of the 1,4-dihydropyridine type with presumed neurotrophic or neuroprotective activity) to prevent the neuropathy induced by both a low (1 mg/kg, 2/wk) and a high (2 mg/kg, 2/wk) dose cisplatin regime was studied. In cisplatin-treated rats concurrently treated with vehicle (saline for ORG 2766, polyethylene glycol for nimodipine) a significant slowing of the H-related sensory nerve conduction velocity was observed whereas in rats treated with both cisplatin and ORG 2766 or nimodipine, no decrease of this conduction velocity occurred. The possibility that nimodipine hampers the antitumor activity of cisplatin was investigated in an immunocytoma model in the LOU/M rat. Similar tumor regression was observed in cisplatin-treated rats concurrently treated with nimodipine or vehicle. These data suggest that both ORG 2766 and nimodipine protect from the induction of a cisplatin-induced neuropathy, at least in this animal model, and thus warrant investigation of their neuroprotective efficacy in humans subjected to a cisplatin-based chemotherapy.
Hamers
F P
FP
Department of Pharmacology, Rudolf Magnus Institute, State University Utrecht, The Netherlands.
van der Hoop
R G
RG
Steerenburg
P A
PA
Neijt
J P
JP
Gispen
W H
WH
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002945:Cisplatin / Q000633:toxicity*; D004594:Electrophysiology; D005260:Female; D009431:Neural Conduction / Q000187:drug effects; D009553:Nimodipine / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000517:prevention & control; D051381:Rats; D011919:Rats, Inbred Strains
D010446:Peptide Fragments; C013765:Org 2766; D009553:Nimodipine; D000324:Adrenocorticotropic Hormone; D002945:Cisplatin