Glutamate ameliorates experimental vincristine neuropathy.
The dose-limiting toxicity of the chemotherapeutic agent vincristine is peripheral neuropathy, for which there is no established therapy. The amino acid glutamate has been proposed as a neuroprotectant for vincristine, but a full preclinical evaluation of its efficacy, safety and mechanism of action has been hampered by a lack of suitable animal models. We report the development of a Dark Agouti rat model of sensorimotor peripheral neuropathy, to investigate the neurotoxicity of cytotoxic drugs. Neuropathy was manifested as gait disturbance in 100% of vincristine-treated animals (n = 12), significant elevation of the tail-flick threshold (5.1 +/- 2 sec) and significantly impaired mean Rotarod times (55 +/- 41 sec) developing after administration of 1.5 mg/kg vincristine over 2 weeks. Among vincristine-treated animals supplemented p.o. with sodium glutamate (500 mg/kg/day in drinking water) from 24 hr before vincristine treatment, only one (8%, P = .01) developed gait disturbance, the tall-flick threshold was not significantly different from controls and the mean Rotarod score was 188 +/- 18 sec (P = .004). Glutamate thus significantly protected against both sensory and motor neuropathy. We observed no intrinsic neurotoxicity with glutamate and no interference with the cytotoxic efficacy of vincristine against a transplantable rat mammary adenocarcinoma grown s.c. in Dark Agouti rats. Our findings suggest that glutamate is likely to be a safe and effective neuroprotectant for patients receiving vincristine, and it warrants further clinical evaluation. The mechanism of this selective neuroprotection by glutamate remains to be elucidated. Our rat model may be of use in determining whether glutamate offers protection from other neurotoxic drugs.
Boyle
F M
FM
Department of Clinical Oncology, Royal North Shore Hospital, Sydney, Australia.
Wheeler
H R
HR
Shenfield
G M
GM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D005260:Female; D005684:Gait / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D012684:Sensory Thresholds / Q000187:drug effects; D014750:Vincristine / Q000633:toxicity*
D000972:Antineoplastic Agents, Phytogenic; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D014750:Vincristine