Blockade of peroxynitrite-mediated astrocyte death by manganese(III)-cyclam.
Under glucose-deprived conditions, astrocytes rapidly underwent death due to their increased susceptibility to endogenously produced peroxynitrite (Gila 31, 155-164; J. Neuroimmunol. 112, 55-62; J. Neurochem. 74, 1989-1998). In the present study, the cell membrane-permeable synthetic superoxide dismutase (SOD) mimetic cyclam manganese(III) 1,4,8,11-tetraazacyclodecane (Mn(III)-cyclam) completely inhibited the death of glucose-deprived immunostimulated astrocytes. However, the structurally related compounds Ni(II)-cyclam, Co(II)-cyclam, and H(2)-cyclam, which lacks metals, had no or a little cytoprotective effect. Of the cyclams used in this study, only Mn(III)-cyclam completely scavenged the peroxynitrite produced in glucose-deprived immunostimulated astrocytes and significantly blocked the depolarization of mitochondrial transmembrane potential in those cells. The present results suggest that cell membrane-permeable synthetic SOD mimetics such as Mn(III)-cyclam may be potential therapeutic agents for various diseases associated with the endogenous production of peroxynitrite.
Choi
Young
Y
Department of Pharmacology, College of Medicine, Laboratory of Neurodegenerative Diseases, Ewha Institute of Neuroscience, Seoul 110-783, South Korea.
Jin
Youngnam
Y
Nam
Wonwoo
W
Kim
Hyoung-Chun
HC
Kim
Won-Ki
WK
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D008345:Manganese / Q000737:chemistry / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000737:chemistry / Q000494:pharmacology
D006571:Heterocyclic Compounds; D030421:Peroxynitrous Acid; C024560:cyclam; D008345:Manganese; D013482:Superoxide Dismutase