Administration of tetrahydrobiopterin restored the decline of dopamine in the striatum induced by an acute action of MPTP
Autor: | Kentaro Yamaguchi, Kohei Man-yoshi, Hiroki Kurosaki, Shin-ichi Muramatsu, Hiroshi Ichinose, Satoshi Hara |
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Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine medicine.medical_specialty Mice 129 Strain Tyrosine 3-Monooxygenase Dopamine Striatum Mice 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Dihydrobiopterin Internal medicine medicine Animals Neurotoxin Tyrosine hydroxylase MPTP Dopaminergic MPTP Poisoning Cell Biology Tetrahydrobiopterin Biopterin Corpus Striatum Mice Inbred C57BL 030104 developmental biology Endocrinology nervous system chemistry 030217 neurology & neurosurgery medicine.drug |
Zdroj: | Neurochemistry International. 125:16-24 |
ISSN: | 0197-0186 |
Popis: | Parkinson's disease (PD) is the second common neurodegenerative disorder. Deficit of the nigro-striatal dopaminergic neurons causes the motor symptoms of PD. While the oxidative stress is thought to be deeply involved in the etiology of PD, molecular targets for the oxidative insults has not been fully elucidated. 6R-5,6,7,8-Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase (TH), the rate-limiting enzyme for production of dopamine, and easily oxidized to its dihydro-form. In this study, we examined the alteration in the metabolism of BH4 caused by a parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP reduced the dopamine content and the in vivo activity of TH in the striatum prior to degeneration of the dopaminergic neurons. We found that administration of BH4 could restore the dopamine content and in vivo TH activity in the striatum of MPTP-treated mice. Unexpectedly, when BH4 was administered with MPTP, BH4 contents in the brain were far higher than those injected without MPTP even at 23 h after the last injection. Because MPTP has been shown to increase ROS production in the dopaminergic neurons, we assumed that the increased ROS oxidizes BH4 into its dihydro-form, excreted from the dopaminergic neurons, taken-up by the neighboring cells, reduced back to BH4, and then accumulated in the brain. We also investigated the action of MPTP in mice lacking quinonoid-dihydropteridine reductase (Qdpr), an enzyme catalyzing regeneration of BH4 from quinonoid dihydrobiopterin. The dopamine depletion induced by MPTP was severer in Qdpr-deficient mice than in wild-type mice. The present data suggest that perturbation of the BH4 metabolism would be the cause of early and persistent dopamine depletion in the striatum. |
Databáze: | OpenAIRE |
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