Angiotensin II protects cultured midbrain dopaminergic neurons against rotenone-induced cell death.
In this study, we demonstrate that angiotensin II (Ang II) protects dopamine (DA) neurons from rotenone toxicity in vitro. Primary ventral mesencephalic (VM) cultures from E15 rats were grown for 5 days and then cultured in the presence of the mitochondrial complex I inhibitor, rotenone. Acute exposure (20 h) to 20 nM rotenone reduced the number of tyrosine hydroxylase-positive (TH+) neurons by 50 +/- 6% when compared to untreated cultures. Pre-treatment of VM cultures with 100 nM Ang II decreased TH+ neuronal loss to 25 +/- 10% at the 20-nM rotenone concentration. Ang II in the presence of the angiotensin type 1 receptor (AT1R) antagonist, losartan, was even more effective in protecting DA neurons showing a loss of only 13 +/- 4% at 20 nM rotenone. Conversely, the AT2R antagonist, PD123319, abolished the protective effects of Ang II. Furthermore, both the NMDA receptor antagonist, MK801, and the antioxidant, alpha-tocopheryl succinate (vitamin E analogue), prevented rotenone-induced toxicity. Here, we show that acute exposure of VM cultures to the pesticide rotenone leads to dopaminergic neuronal cell death and that angiotensin acting through the AT2 receptor protects dopamine neurons from rotenone toxicity.
Grammatopoulos
Tom N
TN
Division of Clinical Pharmacology and Toxicology, Department of Medicine, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Ahmadi
Ferogh
F
Jones
Susan M
SM
Fariss
Marc W
MW
Weyhenmeyer
James A
JA
Zawada
W Michael
WM
D000804:Angiotensin II / Q000494:pharmacology* / Q000627:therapeutic use; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007306:Insecticides / Q000037:antagonists & inhibitors; D019808:Losartan / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000037:antagonists & inhibitors*; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D018691:Excitatory Amino Acid Antagonists; D007306:Insecticides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D012402:Rotenone; D000804:Angiotensin II; D014446:Tyrosine 3-Monooxygenase; D019808:Losartan; D004298:Dopamine