Sodium cyanate alters glutathione homeostasis in rodent brain: relationship to neurodegenerative diseases in protein-deficient malnourished populations in Africa

Sodium cyanate, a neurotoxic chemical in rodents, primates and humans, is i mplicated in neurodegenerative disorders in protein-deficient populations s ubsisting in parts of Africa on the cyanogenic plant cassava. The molecular and cellular mechanisms of cyanate neurotoxicity are not understood. This study investigates the effect of sodium cyanate on glutathione (GSH) homeos tasis in rodent brain and liver in vitro and in vivo. GSH levels in mouse b rain were rapidly, time- and dose-dependently decreased following intraperi toneal administration of 100, 200 or 300 mg/kg sodium cyanate. By contrast, GSH disulfide (GSSG) levels were increased and GSH/GSSG ratios were decrea sed in a dose-dependent manner in rat brain. Sodium cyanate depleted GSH le vels in all regions of mouse brain. Brain glutathione reductase activity wa s dose-dependently inhibited, while glutathione peroxidase activity was not affected by sodium cyanate. The disruption of GSH homeotasis, as evidenced by reduced tissue GSH/GSSG ratios, likely results from cyanate-induced inh ibition of glutathione reductase activity. The results of this study sugges t that cyanate neurotoxicity, and perhaps cassava-associated neurodegenerat ive diseases, are mediated in part by disruption of glutathione homeostasis in neural tissue. (C) 1999 Elsevier Science B.V. All rights reserved.