Homocysteine-induced brain lipid peroxidation: Effects of NMDA receptor blockade, antioxidant treatment, and nitric oxide synthase inhibition
Received: 01 October 2002 Revised: 14 November 2002 Accepted: 16 November 2002 DOI:
Cite this article as: Jara-Prado, A., Ortega-Vazquez, A., Ruano, L.M. et al. neurotox res (2003) 5: 237. doi:10.1007/BF03033381 Abstract
The effect of homocysteine (HCY) on lipid peroxidation (LP), a current mechanism of oxidative neurotoxicity, was investigated in rat brain synaptosomes. LP was assessed by measuring the amount of thiobarbituric acid-reactive substances (TBARS) formed from synaptosomal fractions following HCY treatment. Increasing HCY concentrations (5–1000 μM) enhanced the TBARS formation in brain synaptosomes in a concentration-dependent manner. When compared at equimolar concentrations (100 μM), the oxidative potency of HCY was lower than that of the oxidant ferrous sulfate, similar to that produced by glutamate (Glu) and the mitochondrial toxin 3-nitropropionic acid, and higher than that of the Glu agonists, kainate and quinolinate. The
N-methyl-D-aspartate receptor (NMDAr) antagonist dizocilpine (MK-801) completely blocked the HCY-induced LP at concentrations from 5 to 1000 μM, whereas the well-known antioxidant N-acetylcysteine (NAC) was less effective, but still protective against the HCY oxidative toxicity at higher concentrations (400 and 1000 μM). Three nitric oxide synthase (NOS) inhibitors, 7-nitroindazole (7-NI), Nω-nitro-L-arginine (L-NARG) and Nω-nitro-L-arginine methyl ester (L-NAME), were also tested on HCY-induced LP at increasing concentrations. Both nonspecific NOS effectively the HCY-induced LP than did the selective neuronal NOS inhibitor, 7-NI. These results show that submillimolar concentrations of HCY can induce oxidative injury to nerve terminals, and this effect involves NMDAr stimulation, NOS activation, and associated free radicals formation. Keywords Homocysteine Lipid peroxidation Nitric oxide synthase NOS inhibitors NMDA receptor MK-801 N-acetylcysteine Free radicals References
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