Adenosine and purine nucleosides prevent the disruption of mitochondrial transmembrane potential by peroxynitrite in rat primary astrocytes.
Previously, we have shown that astrocytes deprived of glucose became highly vulnerable to peroxynitrite, and adenosine and its metabolites attenuated the gliotoxicity via the preservation of cellular ATP level. Here, we found that adenosine and related metabolites prevented the disruption of mitochondrial transmembrane potential (MTP) in glucose-deprived rat primary astrocytes exposed to 3-morpholinosydnonimine (SIN-1), a peroxynitrite releasing agent. Exposure to glucose deprivation and SIN-1 (2 h) significantly disrupted MTP in astrocytes, and adenosine prevented it in dose-dependent manner with an EC50 of 5.08 microM. Adenosine also partially prevented the cell death by myxothiazol, a well-known inhibitor of mitochondrial respiration. Blockade of adenosine deamination or intracellular transport with erythro-9-(-hydroxy-3-nonyl)adenosine (EHNA) or S-(4-nitrobenzyl)-6-thioinosine (NBTI), respectively, completely reversed the protective effect of adenosine. Other purine nucleos(t)ides including inosine, guanosine, ATP, ADP, AMP, ITP, and GTP also showed similar protective effects. This study indicates that adenosine and related purine nucleos(t)ides may protect astrocytes from peroxynitrite-induced mitochondrial dysfunction.
Choi
Ji Woong
JW
Department of Pharmacology, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
Yoo
Byung-Kwon
BK
Ryu
Mi Kyoung
MK
Choi
Min Sik
MS
Park
Gyu Hwan
GH
Ko
Kwang Ho
KH
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000517:prevention & control; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000172:deficiency; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D008981:Molsidomine / Q000031:analogs & derivatives; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D011684:Purine Nucleosides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
D011684:Purine Nucleosides; D030421:Peroxynitrous Acid; C002385:linsidomine; D008981:Molsidomine; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose; D000241:Adenosine