Characterization of acute and chronic neuropathies induced by oxaliplatin in mice and differential effects of a novel mitochondria-targeted antioxidant on the neuropathies.
BACKGROUND
Oxaliplatin, a chemotherapeutic agent used for the treatment of colorectal cancer, induces dose-limiting neuropathy that compromises quality of life. This study aimed to reproduce, in mice, patients' symptoms of oxaliplatin-induced neuropathy and to observe effects of SS-31, a mitochondria-targeted antioxidant on the neuropathy.


METHODS
Neuropathy was induced by single or repeated injections of oxaliplatin. Cold and mechanical hypersensitivities were assessed by 15°C-cold plate, temperature preference, and von Frey tests. Morphology of peripheral nerves and dorsal root ganglions, expression of spinal cord c-Fos, density of intraepidermal nerve fibers, and levels of dorsal root ganglion-reactive oxygen/nitrogen species were examined. SS-31 was administered concomitantly or after oxaliplatin injections.


RESULTS
Single injection of oxaliplatin induced cold hypersensitivity in forepaws but not in hind paws which resolved within days (maximal forepaw shakes: 28 ± 1.5 vs. 9.3 ± 1.6/150 s, mean ± SEM, P < 0.001, n = 6 per group). Oxaliplatin-administered mice disfavored 10° and 15°C plates more than control. Paw stimulation at 15°C induced c-Fos-positive cells within superficial laminae of the dorsal horn in C7-T1 segments. Weekly administrations induced gradual development of persistent mechanical allodynia in the hind paws (minimal mechanical threshold: 0.19 ± 0.08 vs. 0.93 ± 0.11 g, P < 0.001, n = 10 per group). Microscopy revealed no overt morphological changes in peripheral nerves and dorsal root ganglions. Concomitant SS-31 administration with repeated oxaliplatin administration attenuated both cold and mechanical hypersensitivity. Decrease in intraepidermal nerve fibers and increase in dorsal root ganglion-reactive oxygen/nitrogen species were also attenuated. Acute SS-31 administration after symptoms were established reversed only cold hypersensitivity.


CONCLUSIONS
This model of oxaliplatin-induced neuropathy mimicked patients' conditions. SS-31 has potentials to prevent both acute and chronic neuropathies but is only helpful in treatment of acute neuropathy. (Anesthesiology 2014; 120:459-73).
From the Department of Anesthesiology (S.T., N.S., M.S.) and Department of Pathology (Y.I., T.K.), Teikyo University Chiba Medical Center, Ichihara, Chiba, Japan; Division of Palliative Medicine, Department of Anesthesiology (N.S.), Jikei Medical University Hospital, Tokyo, Japan; and Department of Pharmacology (H.H.S.), Weill Cornell Medical College, New York, New York.
Satoshi
S
Toyama
Naohito
N
Shimoyama
Yasuo
Y
Ishida
Takayoshi
T
Koyasu
Hazel H
HH
Szeto
Megumi
M
Shimoyama
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D000975:Antioxidants / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002908:Chronic Disease; D003080:Cold Temperature; D005727:Ganglia, Spinal / Q000187:drug effects; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects*; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000633:toxicity*; D000077150:Oxaliplatin; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy*; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D000975:Antioxidants; D009944:Organoplatinum Compounds; D016760:Proto-Oncogene Proteins c-fos; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D000077150:Oxaliplatin