Selective modulation of glutathione in mouse brain regions and its effect on acrylamide-induced neurotoxicity.
Selective modulation of brain glutathione (GSH) may assist the elucidation of the role of GSH in the central nervous system. Subcutaneous administration of diethyl maleate (DEM) depleted both cerebral and hepatic GSH in a dose- and time-dependent manner. While hepatic GSH levels returned to control levels 6 hr after DEM administration, brain GSH levels remained significantly lowered for up to 12 hr after administration of DEM. However, intrathecal administration of DEM resulted in a selective lowering of brain GSH without altering hepatic levels. Intrathecal administration of L-buthionine sulfoximine (L-BSO; 1.0 mmol/kg body wt) also depleted the GSH content of the brain and the levels remained low 24 hr after L-BSO administration. The extent of GSH depletion varied in different regions of the brain; maximal depletion was observed in the brainstem, followed by the cerebellum, striatum, cortex and hippocampus. Intrathecal administration of L-2-oxothiazolidine 4-carboxylate (OTC) resulted in a marginal elevation of GSH levels in the brain. There was considerable regional variation. A maximal elevation of 134% was seen in the hippocampus, 6 hr following the intrathecal administration of 8.0 mmol of OTC/kg body wt. The effect of the modulation of brain GSH levels on acrylamide (ACR)-induced neurotoxicity was examined. Depletion of GSH by pretreatment of mice with L-BSO or DEM (administered intrathecally) enhanced the toxicity of ACR as measured by the inhibition of brain glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. The inhibition of GAPDH by ACR was attenuated by pretreatment of animals with OTC. Thus, brain GSH may play an important role in the detoxification of xenobiotics, in situ within the central nervous system.
Shivakumar
B R
BR
Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Ravindranath
V
V
D000178:Acrylamides / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019328:Buthionine Sulfoximine; D004347:Drug Interactions; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors*; D007278:Injections, Spinal; D008099:Liver / Q000187:drug effects; D008298:Maleates / Q000008:administration & dosage / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D011761:Pyrrolidonecarboxylic Acid; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines
D000178:Acrylamides; D008298:Maleates; D013844:Thiazoles; D053778:Thiazolidines; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; C014476:diethyl maleate; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid