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The Journal of Neuroscience, February 1, 1999, 19(3):878-889

Blockade of Tetrahydrobiopterin Synthesis Protects Neurons after Transient Forebrain Ischemia in Rat: A Novel Role for the Cofactor

Sunghee Cho¹, Bruce T. Volpe¹, Youngmee Bae¹, Onyou Hwang², Hyun J. Choi², Judit Gal¹, Larry C. H. Park¹, Chung K. Chu³, Jinfa Du³, and Tong H. Joh¹

¹ Department of Neurology and Neuroscience, Cornell University Medical College at W. M. Burke Medical Research Institute, White Plains, New York 10605, ² Department of Biochemistry, University of Ulsan College of Medicine, Seoul, 138-736 Korea, and ³ Center for Drug Discovery, Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia 30602

The generation of nitric oxide (NO) aggravates neuronal injury. (6R)-5,6,7,8-Tetrahydro-L-biopterin (BH₄) is an essential cofactor in the synthesis of NO by nitric oxide synthase (NOS). We attempted to attenuate neuron degeneration by blocking the synthesis of the cofactor BH₄ using N-acetyl-3-O-methyldopamine (NAMDA). In vitro data demonstrate that NAMDA inhibited GTP cyclohydrolase I, the rate-limiting enzyme for BH₄ biosynthesis, and reduced nitrite accumulation, an oxidative metabolite of NO, without directly inhibiting NOS activity. Animals exposed to transient forebrain ischemia and treated with NAMDA demonstrated marked reductions in ischemia-induced BH₄ levels, NADPH-diaphorase activity, and caspase-3 gene expression in the CA1 hippocampus. Moreover, delayed neuronal injury in the CA1 hippocampal region was significantly attenuated by NAMDA. For the first time, these data demonstrate that a cofactor, BH₄, plays a significant role in the generation of ischemic neuronal death, and that blockade of BH₄ biosynthesis may provide novel strategies for neuroprotection.

Key words: tetrahydrobiopterin (BH₄); selective neuronal injury; CA1 hippocampus; transient forebrain ischemia; neuroprotection; N-acetyl-3-O-methyldopamine

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Copyright © 1999 Society for Neuroscience  0270-6474/99/193878-12$05.00/0

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