We determined whether the preferential toxicity of tetrahydrobiopterin (BH4) on dopamine-producing cells, which we have previously observed in vitro, might also occur in vivo and generate characteristics associated with Parkinson's disease. Intrastriatal BH4 injection caused a loss of tyrosine hydroxylase immunoreactivity and decreased dopamine content. The dopaminergic cell bodies topologically corresponding to the lesioned terminals were selectively degenerated. This was accompanied by a dose-dependent and asymmetric movement deficit in the contralateral forepaw. Direct injection of BH4 into the substantia nigra caused a loss of tyrosine hydroxylase immunoreactivity, but injection into the dorsal raphe was without effect on the GTP cyclohydrolase-immunoreactive serotonergic neurons, demonstrating selectivity for the dopaminergic system. BH4 exhibited a range of potency comparable to that of 6-hydroxydopamine. Thus, this animal model generated by the administration of BH4, the molecule endogenously present in the monoaminergic neurons, exhibited morphological, biochemical, and behavioral characteristics associated with Parkinson's disease and may be useful for studies in dopaminergic degeneration.
Bibliographical noteFunding Information:
SWK and YJJ contributed equally to this study. This work was supported by grants from the Asan Institute for Life Sciences (2001-278; 2003-278), the Molecular Medicine Research Group Program (M1-0106-00-0047) of the Ministry of Science and Technology, and KOSEF (1999-1-213-001-5), Korea. The authors are grateful to Yong Jin Lee, Eun Jung Lee, Kyong Mi Lee, and Seung Ja Baik for their excellent technical assistance, Dr. Hyun Jin Choi for helpful discussion, and Dr. I. Nagatsu for GTPCH antisera.
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