Neuroprotective effect of the angiotensin-converting enzyme inhibitor perindopril in MPTP-treated mice.
The angiotensin -converting enzyme (ACE) inhibitor perindopril has been shown to exert beneficial effects on the dopaminergic system. Here, we investigated the effects of perindopril on the dopaminergic system in mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment, in comparison with a Ca(2+) antagonist, amlodipine. Administration of perindopril showed dose-dependent neuroprotective effects against MPTP-induced striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) depletion. However, administration of amlodipine showed no significant effects on striatal dopamine depletion after MPTP treatment. In our immunohistochemical studies with antibodies against tyrosine hydroxylase (TH), microtubule-associated protein 2a, b (MAP2), dopamine transporter (DAT), parvalbumin (PV), glial fibrillary acidic protein (GFAP) and Cu/Zn-superoxide dismutase (Cu/Zn-SOD), the administration of perindopril significantly attenuated MPTP-induced substantia nigra and striatal damage. This drug also blocked the increases in GFAP-positive astrocytes in the striatum and substantia nigra after MPTP treatment. Furthermore, the administration of perindopril showed a protective effect against the intense Cu/Zn-SOD immunoreactivity in the neurons and glial cells in both the striatum and substantia nigra after MPTP treatment. These results indicated that the ACE inhibitor perindopril can protect against MPTP-induced striatal dopamine and DOPAC depletion in mice. The protective effect may be, at least in part, caused by the reduction of free radicals caused by MPTP. The present study also demonstrated that perindopril is effective against MPTP-induced neurodegeneration of the nigro-striatal dopaminergic pathway. Furthermore, our results provided further evidence that free radical scavengers may be effective in the treatment of neurodegenerative diseases such as Parkinson's disease.
Kurosaki
R
R
Department of Drug Metabolism and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, University of Tokushima, Tokushima, Japan.
Muramatsu
Y
Y
Imai
Y
Y
Kato
H
H
Araki
T
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020913:Perindopril / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000806:Angiotensin-Converting Enzyme Inhibitors; D018696:Neuroprotective Agents; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D020913:Perindopril