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

• Published in: The Journal of neuroscience Vol. 19; no. 3; pp. 878 - 889
• Main Authors: Cho, Sunghee, Volpe, Bruce T, Bae, Youngmee, Hwang, Onyou, Choi, Hyun J, Gal, Judit, Park, Larry C. H, Chu, Chung K, Du, Jinfa, Joh, Tong H
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01.02.1999; Society for Neuroscience
• Subjects: Animals; Biopterins - analogs & derivatives; Biopterins - antagonists & inhibitors; Biopterins - metabolism; Biopterins - physiology; Brain - metabolism; Brain - pathology; Caspase 3; Caspases - genetics; Dopamine - analogs & derivatives; Dopamine - pharmacology; GTP Cyclohydrolase - antagonists & inhibitors; Hippocampus - metabolism; Ischemic Attack, Transient - metabolism; Ischemic Attack, Transient - pathology; Male; Mice; Microglia - metabolism; NADPH Dehydrogenase - antagonists & inhibitors; NADPH Dehydrogenase - metabolism; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - pharmacology; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type I; Nitrites - antagonists & inhibitors; Prosencephalon - blood supply; Rats; Rats, Wistar; RNA, Messenger - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.19-03-00878.1999

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.