Degeneration of the nigrostriatal pathway and induction of motor deficit by tetrahydrobiopterin: an in vivo model relevant to Parkinson's disease.
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.
Kim
Seong Who
SW
Department of Biochemistry, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea.
Jang
Yeon Joo
YJ
Chang
Jin Woo
JW
Hwang
Onyou
O
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced; D005260:Female; D007150:Immunohistochemistry; D009069:Movement Disorders / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000139:chemically induced; D009434:Neural Pathways / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D010300:Parkinson Disease; D017729:Presynaptic Terminals; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D009498:Neurotoxins; D001708:Biopterins; D014446:Tyrosine 3-Monooxygenase; C003402:sapropterin; D004298:Dopamine