Blockade of tetrahydrobiopterin synthesis protects neurons after transientforebrain ischemia in rat: A novel role for the cofactor

Citation
S. Cho et al., Blockade of tetrahydrobiopterin synthesis protects neurons after transientforebrain ischemia in rat: A novel role for the cofactor, J NEUROSC, 19(3), 1999, pp. 878-889
Citations number
72
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROSCIENCE
ISSN journal
0270-6474 → ACNP
Volume
19
Issue
3
Year of publication
1999
Pages
878 - 889
Database
ISI
SICI code
0270-6474(19990201)19:3<878:BOTSPN>2.0.ZU;2-Y
Abstract
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 degene ration by blocking the synthesis of the cofactor BH, using N-acetyl-3-O-met hyldopamine (NAMDA). In vitro data demonstrate that NAMDA inhibited GTP cyc lohydrolase l, the rate-limiting enzyme for BH, biosynthesis, and reduced n itrite accumulation, an oxidative metabolite of NO, without directly inhibi ting NOS activity. Animals exposed to transient forebrain ischemia and trea ted with NAMDA demonstrated marked reductions in ischemia-induced BH, level s, NADPH-diaphorase activity, and caspase-3 gene expression in the CA1 hipp ocampus. Moreover, delayed neuronal injury in the CA1 hippocampal region wa s significantly attenuated by NAMDA. For the first time, these data demonst rate that a cofactor, BH4, plays a significant role in the generation of is chemic neuronal death, and that blockade of BH, biosynthesis may provide no vel strategies for neuroprotection.