Protective action of neuronal nitric oxide synthase inhibitor in the MPTP mouse model of Parkinson's disease.
We examined the effects of 7-nitroindazole on the dopaminergic system in mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. The mice received four intraperitoneal injections of MPTP (20 mg/kg) at 2 h-intervals. Administration of 7-nitroindazole showed dose-dependent neuroprotective effects against striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletion 7 days after MPTP treatment. Behavioral testing showed that MPTP-treated mice exhibited motor deficits in the catalepsy test after 7 days, but 7-nitroindazole prevented the appearance of motor abnormalities in this test. The MPTP-treated mice exhibited the loss of tyrosine hydroxylase-containing dopaminergic neurons in mice after 1, 3 and 7 days, but 7-nitroindazole-treated mice showed a protective effect. GFAP (glial fibrillary acidic protein)-positive astrocytes were accumulated in the striatum 3 and 7 days and in the substantia nigra 1, 3 and 7 days after MPTP treatment. In contrast, 7-nitroindazole prevented a significant increase in the number of GFAP-positive astrocytes in the striatum and substantia nigra after MPTP treatment. The reactive astrocytes in the striatum and substantia nigra after MPTP treatment increased the production of S100beta protein, which is thought to promote neuronal damage, but 7-nitoindazole suppressed the expression of S100 beta protein. Activation of microglia, with an increase in staining intensity and morphological changes, was observed in the striatum and substantia nigra 1 and 3 days after MPTP treatment, but 7-nitroindazole prevented a significant increase in the number of isolectin B(4) positive microglia in the striatum and substantia nigra. On the other hand, nestin-immunoreactive cells were increased significantly in the striatum 3 and 7 days after MPTP treatment. 7-Nitroindazole treatment facilitated nestin expression in the striatum 7 days after MPTP treatment. Thus, nNOS inhibitor 7-nitroindazole protected dopaminergic neurons against MPTP neurotoxicity in mice and ameliorated neurological deficits. The results suggest that the neuroprotection is mediated though the modulation of glial activation, including the inhibition of S100beta synthesis and the prevention of microglial activation. These results suggest the therapeutic strategy targeted to glial modulation with 7-nitoindazole offers a great potential for the development of new neuroprotective therapies for Parkinson's disease.
Watanabe
Yu
Y
Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima, Japan.
Kato
Hiroyuki
H
Araki
Tsutomu
T
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000906:Antibodies; D001253:Astrocytes / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D004298:Dopamine / Q000502:physiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D007191:Indazoles / Q000627:therapeutic use*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D020267:MPTP Poisoning / Q000473:pathology / Q000517:prevention & control* / Q000523:psychology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D009418:S100 Proteins / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D007191:Indazoles; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D009418:S100 Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D052248:Nitric Oxide Synthase Type I; D014446:Tyrosine 3-Monooxygenase; C080122:7-nitroindazole; D004298:Dopamine; D006719:Homovanillic Acid