Effect of angiotensin-converting enzyme inhibitor perindopril on interneurons in MPTP-treated mice.
We examined the effects of perindopril 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 at 1-h intervals. Administration of perindopril showed dose-dependent neuroprotective effects against striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletion 3 days after MPTP treatment. Our immunohistochemical study showed that MPTP can severe damage in tyrosine hydroxylase (TH)-immunoreactive neurons after MPTP treatment. The administration of perindopril significantly attenuated MPTP-induced substantia nigra and striatal damage. The present study also showed that the immunoreactivity of parvalbumin (PV)- or neuronal nitric oxide synthase (nNOS)-positive cells in the substantia nigra was decreased 7 days after MPTP treatment, whereas no significant changes were observed in these cells of the striatum throughout the experiments. The administration of perindopril significantly attenuated MPTP-induced decrease of the PV- or nNOS-immunoreactivity in the nigral cells. In double-labeled immunostaining with anti-PV and anti-nNOS antibody, PV-immunoreactive cell bodies and fibers were not double-labeled for nNOS-immunoreactive cell bodies and fibers in both the striatum and substantia nigra after MPTP treatment. Furthermore, PV- or nNOS-immunoreactive cell bodies and fibers in both the striatum and substantia nigra were not double-labeled for TH-immunoreactive cell bodies and fibers. These results demonstrate that the ACE inhibitor perindopril has a dose-dependent protective effect against MPTP-induced striatal dopamine, DOPAC and HVA depletion in mice. The present study also demonstrates that perindopril is effective against MPTP-induced degeneration of the nigral neurons and interneurons. Furthermore, our immunohistochemical study suggests that PV-immunoreactive cells and nNOS-immunoreactive cells are different interneurons in both the striatum and substantia nigra. Thus, our results provide further evidence that the ACE inhibitor perindopril may offer a novel therapeutic strategy for Parkinson's disease (PD).
Kurosaki
Rumiko
R
Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Science and Medicine, Sendai, Japan.
Muramatsu
Yasuko
Y
Kato
Hiroyuki
H
Watanabe
Yu
Y
Imai
Yutaka
Y
Itoyama
Yasuto
Y
Araki
Tsutomu
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002452:Cell Count / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004563:Electrochemistry / Q000379:methods; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D010320:Parvalbumins / Q000378:metabolism; D020913:Perindopril / Q000494:pharmacology*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D015259:Dopamine Agents; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid; D020913:Perindopril