Oxaliplatin causes selective atrophy of a subpopulation of dorsal root ganglion neurons without inducing cell loss.
Peripheral neuropathy is induced by multiple doses of oxaliplatin and interferes with the clinical utility of the drug in patients with colorectal cancer. In this study, we sought to determine whether cell loss or selective neuronal damage was the basis for the peripheral neuropathy caused by oxaliplatin. Adult female rats were given 1.85 mg/kg oxaliplatin twice per week for 8 weeks. Nerve conduction and L5 dorsal root ganglia (DRG) were studied 1 week after the completion of all treatment. No mortality occurred during oxaliplatin treatment, but the rate of body weight gain was reduced compared to age-matched vehicle-treated controls. Oxaliplatin slowed conduction velocity and delayed conduction times in peripheral sensory nerves, without affecting central or motor nerve conduction. In L5 DRG, total numbers of neurons were unchanged by oxaliplatin, but there were significant reductions in neuronal size distribution, ganglion volume, average cell size and the relative frequency of large cells. In addition, the relative frequency of small DRG cells was increased by oxaliplatin. Oxaliplatin significantly altered the size distribution and average cell body area of the predominantly large parvalbumin-immunoreactive DRG neurons without affecting the frequency of parvalbumin staining. On the contrary, neither the staining frequency nor the size distribution of the predominantly small substance P-immunoreactive DRG neurons was changed by oxaliplatin. In conclusion, oxaliplatin causes selective atrophy of a subpopulation of DRG neurons with predominantly large parvalbumin-expressing cells without inducing neuronal loss. Because DRG cell body size and axonal conduction velocity are positively correlated, neuronal atrophy may be the morphological basis for the development of decreased sensory nerve conduction velocity that characterizes oxaliplatin-induced peripheral neuropathy.
Jamieson
S M F
SM
Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Liu
J
J
Connor
B
B
McKeage
M J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects*; D009431:Neural Conduction / Q000187:drug effects*; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D010320:Parvalbumins / Q000302:isolation & purification; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013373:Substance P / Q000302:isolation & purification
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010320:Parvalbumins; D000077150:Oxaliplatin; D013373:Substance P