Oxidative stress induced by administration of the neuroleptic drug haloperidol is attenuated by higher doses of haloperidol.
The effect of haloperidol administration on lipid peroxidation and glutathione/protein thiol homeostasis in the brain was examined 4 h following subcutaneous administration of a single dose of haloperidol; 1.0, 1.5, 2.0 or 2.5 mg/kg b.wt. Glutathione (GSH) levels decreased significantly in cortex, striatum and midbrain after haloperidol administration. Maximal decrease of GSH was observed in the striatum. The depleted GSH was recoverable as protein glutathione mixed disulfide (Pr-SSG) with concomitant loss of protein thiols (Pr-SH) in all the regions of the brain examined. Administration of 1.5 mg/kg b.wt. of haloperidol resulted in significant depletion of GSH in striatum and midbrain as compared to that after administration of the lower dose of 1.0 mg/kg b.wt. of haloperidol. However, administration of higher doses of haloperidol (2.0 and 2.5 mg/kg b.wt.) did not result in greater depletion of GSH; the GSH levels were not significantly different from that observed following the administration of 1.5 mg/kg b.wt. of haloperidol. However, Pr-SSG levels increased dose-dependently following haloperidol administration. The total GSH recovered as sum of GSH and Pr-SSG was significantly higher than controls in striatum and midbrain following administration of higher doses of haloperidol, namely, 2.0 and 2.5 mg/kg b.wt. The depleted GSH was not recoverable as glutathione disulfide (GSSG). GSSG levels were not significantly different from controls 4 h after administration of 1.5 mg/kg b.wt. of haloperidol. The levels of malondialdehyde (indicative of lipid peroxidation) increased significantly as compared to control levels (280-220%) following administration of 1.0 and 1.5 mg/kg b.wt. of haloperidol.(ABSTRACT TRUNCATED AT 250 WORDS)
Shivakumar
B R
BR
Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Ravindranath
V
V
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D005456:Fluorescent Dyes; D005978:Glutathione / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology* / Q000633:toxicity; D006706:Homeostasis / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008315:Malondialdehyde / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000378:metabolism*
D004220:Disulfides; D005456:Fluorescent Dyes; D008315:Malondialdehyde; D005978:Glutathione; D006220:Haloperidol