Blockade of tetrahydrobiopterin synthesis protects neurons after transient forebrain ischemia in rat

A novel role for the cofactor

Cho Sunghee, Bruce T. Volpe, Youngmee Bae, Onyou Hwang, Hyun J. Choi, Gal Judit, Larry C.H. Park, Chu Chung K, Du Jinfa, Joh Tong H

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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 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.

Original languageEnglish
Pages (from-to)878-889
Number of pages12
JournalJournal of Neuroscience
Volume19
Issue number3
StatePublished - 1 Feb 1999

Fingerprint

Prosencephalon
Ischemia
Neurons
Nitric Oxide
Nitric Oxide Synthase
GTP Cyclohydrolase
Biopterin
Hippocampal CA1 Region
NADPH Dehydrogenase
Nerve Degeneration
Wounds and Injuries
Nitrites
Caspase 3
Hippocampus
Gene Expression
sapropterin
N-acetyl-3-O-methyldopamine
Enzymes

Keywords

  • CA1 hippocampus
  • N-acetyl-3-O- methyldopamine
  • Neuroprotection
  • Selective neuronal injury
  • Tetrahydrobiopterin (BH)
  • Transient forebrain ischemia

Cite this

Sunghee, Cho ; Volpe, Bruce T. ; Bae, Youngmee ; Hwang, Onyou ; Choi, Hyun J. ; Judit, Gal ; Park, Larry C.H. ; Chung K, Chu ; Jinfa, Du ; Tong H, Joh. / Blockade of tetrahydrobiopterin synthesis protects neurons after transient forebrain ischemia in rat : A novel role for the cofactor. In: Journal of Neuroscience. 1999 ; Vol. 19, No. 3. pp. 878-889.
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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 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.",
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Sunghee, C, Volpe, BT, Bae, Y, Hwang, O, Choi, HJ, Judit, G, Park, LCH, Chung K, C, Jinfa, D & Tong H, J 1999, 'Blockade of tetrahydrobiopterin synthesis protects neurons after transient forebrain ischemia in rat: A novel role for the cofactor', Journal of Neuroscience, vol. 19, no. 3, pp. 878-889.

Blockade of tetrahydrobiopterin synthesis protects neurons after transient forebrain ischemia in rat : A novel role for the cofactor. / Sunghee, Cho; Volpe, Bruce T.; Bae, Youngmee; Hwang, Onyou; Choi, Hyun J.; Judit, Gal; Park, Larry C.H.; Chung K, Chu; Jinfa, Du; Tong H, Joh.

In: Journal of Neuroscience, Vol. 19, No. 3, 01.02.1999, p. 878-889.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Volpe, Bruce T.

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AU - Hwang, Onyou

AU - Choi, Hyun J.

AU - Judit, Gal

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AU - Chung K, Chu

AU - Jinfa, Du

AU - Tong H, Joh

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N2 - 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.

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