Prevention of Calbindin Recruitment into Nigral Dopamine Neurons from MPTP-Induced Degeneration in Macaca fascicularis

摘要

Dopaminergic neurons in the substantia nigra pars compacta that express the calcium-binding protein calbindin selectively survive the cell death period in Parkinson's disease. On the basis of this finding, we examined the preventive effect of calbindin recruitment into nigral dopamine neurons on toxic insults induced by l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). A recombinant adenoviral vector encoding the calbindin gene was injected unilaterally into the striatum of macaque monkeys. One totwo weeks later, expression of calbindin through retrograde transduction was observed in cell bodies of nigral dopamine neurons on the side ipsilateral to vector treatment. In these monkeys, MPTP was administered systemically by repeated intravenous injections. Parkinsonian motor signs, such as akinesia, rigidity, and flexed posture, appeared less severely in the limbs contral-ateral to vector treatment. Histological analysis revealed that tyrosine hydroxylase immunoreactivity in the striatum was preserved better on the calbindin-recruited side, whereas a-synuclein was expressed in nigral dopamine neurons much more strongly on the nonrecruited side. These results indicate that gene delivery of calbindin into nigral dopamine neurons protects against MPTP-induced parkinsonian symptoms in monkeys.