title: The neuroprotective action of candesartan is related to interference with the early stages of 6-hydroxydopamine-induced dopaminergic cell death.
abstract: Several studies have revealed that manipulation of the renin angiotensin system results in reduced progression of nigrostriatal damage in different animal models of Parkinson's disease. In the present work, the effect of daily treatment of rats with the angiotensin II (Ang II) type 1 (AT(1) ) receptor antagonist candesartan (3 mg/kg per day, s.c.) initiated 7 days before the intrastriatal injection of 6-hydroxydopamine (6-OHDA) was investigated by means of tyrosine hydroxylase-positive cell counts in the substantia nigra, and dopamine and 3,4-dihydroxyphenylacetic acid measurements in the striatum. In this experimental set-up, candesartan protected dopaminergic neurons of the nigrostriatal tract against the neurotoxin-induced cell death. However, the beneficial effects of AT(1) receptor blockade were not confirmed when treatment was started 24 h after the lesion, suggesting that candesartan interferes with the early events of the 6-OHDA-induced cell death. Stimulation of the AT(1) receptor with Ang II increased the formation of hydroxyl radicals in the striatum of intact rats as measured by the in vivo microdialysis salicylate trapping technique. This Ang II-induced production of reactive oxygen species was suppressed by candesartan perfusion. Furthermore, the Ang II-induced production of reactive oxygen species was nicotinamide adenine dinucleotide phosphate - oxidase and protein kinase C dependent as it could be blocked in the presence of apocynin, an nicotinamide adenine dinucleotide phosphate - oxidase inhibitor, and chelerythrine, an inhibitor of protein kinase C. Together, these data further support the hypothesis that Ang II might contribute in an early stage to the neurotoxicity of 6-OHDA by reinforcing the cascade of oxidative stress.
authors.affiliation: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan, Brussels, Belgium.
authors.forename: Birgit
authors.initials: B
authors.lastname: Mertens
authors.forename: Mustafa
authors.initials: M
authors.lastname: Varcin
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
authors.forename: Sophie
authors.initials: S
authors.lastname: Sarre
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018696:Neuroprotective Agents; D013777:Tetrazoles; D016627:Oxidopamine; C081643:candesartan; D004298:Dopamine