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Reduced Glutathione Protects against Cisplatin-induced Neurotoxicity in Rats¹

Rudolf Magnus Institute, Department of Medical Pharmacology, Utrecht State University, Vondellaan 6, 3521 GD Utrecht, the Netherlands [F. P. T. H., J. H. B., W. H. G.]; Boehringer Mannheim Italia S.p.A., Research Laboratories, Monza, Italy [E. C., M. T., L. M., G. P.]; and Section of Oncology, Department of Internal Medicine, Utrecht University Hospital, Utrecht, the Netherlands [J. P. N.]

Reduced glutathione (GSH) is reported to diminish cisplatin-induced neurotoxicity, and it was for this reason that we studied GSH in an animal model of cisplatin neuropathy. The neuropathy was evaluated by measuring the sensory nerve conduction velocity (SNCV) in young adult Wistar rats. GSH injections (i.v.) were given twice weekly, within five minutes before cisplatin was injected (i.p.). In a first experiment GSH (500 mg/kg) in combination with a low-dose cisplatin treatment (1 mg/kg, 10 weeks) was investigated. Animals treated with cisplatin and placebo developed a neuropathy (SNCV at week 10: age controls, 61.9 m/s; cisplatin alone, 44.2 m/s), whereas rats treated with cisplatin and GSH did not (SNCV, 61.9 m/s). The same dose of GSH was used in combination with a high-dose cisplatin schedule (2 mg/kg, 5 weeks' treatment plus 5 weeks' recovery). Again, GSH protected animals against the development of neuropathy (SNCV at week 10: age controls, 61.9 m/s; cisplatin alone, 50.6 m/s; cisplatin plus GSH, 61.1 m/s). In another experiment four lower doses of GSH (25, 50, 100, and 200 mg/kg) were tested in combination with the low-dose cisplatin protocol (1 mg/kg, 11 weeks). The cisplatin group developed a neuropathy (SNCV at week 11: cisplatin alone, 50.2 m/s; age controls, 60.6 m/s). Only the dose of 200 mg GSH/kg was found to protect against the development of a neuropathy (SNCV, 61.0 m/s). In an antitumor study GSH administered at 300 mg/kg in combination with cisplatin at 1.5 mg/kg did not diminish the curative effect of cisplatin. We conclude that GSH prevents cisplatin-induced neuropathy and that it should be investigated further in the clinic.

¹ Supported by Grant IKMN 90-12 from the Dutch Cancer Society.

² To whom requests for reprints should be addressed.

Received 5/14/92. Accepted 11/18/92.

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