Tetrahydrobiopterin precursor sepiapterin provides protection against neurotoxicity of 1-methyl-4-phenylpyridinium in nigral slice cultures

Autor: Jakob Torp Madsen, Jan Bert Gramsbergen, Morten Meyer, Christian Hesslinger, Jens Zimmer, Pernille Jansen
Rok vydání: 2003
Předmět:
Zdroj: Journal of Neurochemistry. 85:214-223
ISSN: 1471-4159
0022-3042
DOI: 10.1046/j.1471-4159.2003.01666.x
Popis: Complex-I inhibition and oxidative processes have been implicated in the loss of nigral dopamine neurones in Parkinson’s disease and the toxicity of MPTP and its metabolite MPP + . Tetrahydrobiopterin, an essential cofactor for tyrosine hydroxylase, may act as an antioxidant in dopaminergic neurones and protects against the toxic consequences of glutathione depletion. Here we studied the effects of manipulating tetrahydrobiopterin levels on MPP + toxicity in organotypic, rat ventral mesencephalic slice cultures. In cultures exposed to 30 lM MPP + for 2 days, followed by 8 days ‘recovery’ in control medium, we measured dopamine and its metabolites in the tissue and culture medium by HPLC, lactate dehydrogenase release to the culture medium, cellular uptake of propidium iodide and counted the tyrosine hydroxylaseimmunoreactive neurones. Inhibition of tetrahydrobiopterin synthesis by 2,4-diamino-6-hydroxypyrimidine had no significant synergistic effect on MPP + toxicity. In contrast, the tetrahydrobiopterin precursor L-sepiapterin attenuated the MPP + -induced dopamine depletion and loss of tyrosine hydroxylase-positive cells in a dose-dependent manner with 40 l ML -sepiapterin providing maximal protection. Accordingly, increasing intracellular tetrahydrobiopterin levels may protect
Databáze: OpenAIRE
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