Angiotensin type-1-receptor antagonists reduce 6-hydroxydopamine toxicity for dopaminergic neurons.
Angiotensin II activates (via type 1 receptors) NAD(P)H-dependent oxidases, which are a major source of superoxide, and is relevant in the pathogenesis of several cardiovascular diseases and certain degenerative changes associated with ageing. Given that there is a brain renin-angiotensin system and that oxidative stress is a key contributor to Parkinson's disease, we investigated the effects of angiotensin II and angiotensin type 1 (AT(1)) receptor antagonists in the 6-hydroxydopamine model of Parkinson's disease. Rats subjected to intraventricular injection of 6-hydroxydopamine showed bilateral reduction in the number of dopaminergic neurons and terminals. Injection of angiotensin alone did not induce any significant effect. However, angiotensin increased the toxic effect of 6-hydroxydopamine. Rats treated with the AT(1) receptor antagonist ZD 7155 and then 6-hydroxydopamine (with or without exogenous administration of angiotensin) showed a significant reduction in 6-hydroxydopamine-induced oxidative stress (lipid peroxidation and protein oxidation) and dopaminergic degeneration. Dopaminergic degeneration was also reduced by the NAD(P)H inhibitor apocynin. Angiotensin may play a pivotal role, via AT(1) receptors, in increasing the oxidative damage of dopaminergic cells, and treatment with AT(1) antagonists may reduce the progression of Parkinson's disease.
Rey
P
P
Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain.
Lopez-Real
A
A
Sanchez-Iglesias
S
S
Muñoz
A
A
Soto-Otero
R
R
Labandeira-Garcia
J L
JL
D018663:Adrenergic Agents / Q000633:toxicity*; D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008636:Mesencephalon / Q000166:cytology; D009287:Naphthyridines / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018663:Adrenergic Agents; D047228:Angiotensin II Type 1 Receptor Blockers; D009287:Naphthyridines; D017392:Thiobarbituric Acid Reactive Substances; C095905:ZD 7155; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine