Protection against cisplatin induced neurotoxicity by ORG 2766: histological and electrophysiological evidence.
Prolonged administration of the anti-tumor agent cisplatin may cause a neuropathy in patients. In an animal model, too, neurotoxicity, as evidenced by a decrease in H-related sensory nerve conduction velocity (SNCV), can be induced by repetitive injections of cisplatin. In an attempt to further the insight into the effects of cisplatin on the peripheral nervous system a combined electrophysiological and histomorphological investigation was performed on 2 groups of 6 rats, treated with cisplatin for 7.5 weeks, and a control group (n = 6). Concomitant administration of ORG 2766, an ACTH(4-9) analog, was previously shown to prevent cisplatin neurotoxicity in this model and more recently in patients as well. One group of rats was therefore co-treated with this peptide during the complete treatment period. A marked decrease in SCNV was observed in cisplatin/saline treated rats, but not in cisplatin/ORG 2766 treated rats. Though no statistically significant difference was seen in the total number of myelinated fibers in the sural nerves of cisplatin treated rats, a decrease in the proportion of thick myelinated fibers was present in the cisplatin/saline treated rats. This shift in fiber distribution was absent in ORG 2766 co-treated animals. Mean internodal distances and g-ratios were not affected, and signs of axonal degeneration, or de- or remyelination were not observed.
Department of Medical Pharmacology, University of Utrecht, The Netherlands.
R
R
Gerritsen van der Hoop
F P
FP
Hamers
J P
JP
Neijt
H
H
Veldman
W H
WH
Gispen
F G
FG
Jennekens
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002945:Cisplatin / Q000009:adverse effects*; D004594:Electrophysiology; D005260:Female; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009412:Nerve Fibers / Q000187:drug effects / Q000648:ultrastructure; D009420:Nervous System / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D009431:Neural Conduction / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D013497:Sural Nerve / Q000187:drug effects / Q000473:pathology
D018696:Neuroprotective Agents; D010446:Peptide Fragments; C013765:Org 2766; D000324:Adrenocorticotropic Hormone; D002945:Cisplatin