Protective effects of rilmenidine and AGN 192403 on oxidative cytotoxicity and mitochondrial inhibitor-induced cytotoxicity in astrocytes.
Oxidative stress and mitochondrial dysfunction are important aspects of pathogenesis, particularly in the brain, which is highly dependent on oxygen, and the protection of astrocytes is essential for neuroprotection. In this context, imidazoline drugs have been reported to be neuroprotective. Our recent study showed that imidazoline drugs, including guanabenz, inhibit the naphthazarin-induced oxidative cytotoxicity associated with lysosomal destabilization. We now report on a study into the protective effects of rilmenidine and AGN 192403, which have affinity for imidazoline-1 receptors, on the cytotoxicity induced by naphthazarin and inhibitors of mitochondrial respiration in astrocytes. Cytotoxicity was measured grossly by LDH release and by measuring changes in lysosomal membrane stability and features of mitochondrial membrane permeabilization. Naphthazarin-induced cytotoxicity was evidenced by the ordered development of lysosomal acridine orange relocation, decrease in mitochondrial potential, cytochrome c release, and caspase-9 activation, and was inhibited by guanabenz, rilmenidine, and AGN 192403. Antimycin A and rotenone induced mitochondrial dysfunction primarily, and their cytotoxicities were inhibited only by AGN 192403. Rilmenidine and guanabenz may have a lysosomal stabilizing effect, which underlies their protective effects. AGN 192403 might affect the mitochondrial cell death cascades, and had a novel protective effect on the cytotoxicity associated with mitochondrial dysfunction.
Choi
Dong-Hee
DH
Department of Pharmacology, Korea University College of Medicine, Seoul, South Korea.
Kim
Dong-Hoon
DH
Park
Yun-Gyu
YG
Chun
Boe-Gwun
BG
Choi
Sang-Hyun
SH
D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D006536:Heptanes / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D008956:Models, Chemical; D009285:Naphthoquinones / Q000494:pharmacology; D009457:Neuroglia / Q000166:cytology; D010080:Oxazoles / Q000494:pharmacology*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D000077769:Rilmenidine; D013997:Time Factors
C098523:AGN 192403; D000959:Antihypertensive Agents; D001643:Bridged Bicyclo Compounds; D003574:Cytochrome c Group; D005609:Free Radicals; D006536:Heptanes; D009285:Naphthoquinones; D010080:Oxazoles; D017382:Reactive Oxygen Species; C005503:naphthazarin; D000968:Antimycin A; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases; D000077769:Rilmenidine; D010100:Oxygen