Ciclopirox prevents peroxynitrite toxicity in astrocytes by maintaining their mitochondrial function: a novel mechanism for cytoprotection by ciclopirox.
Previously we have reported that astrocytes deprived of glucose were highly vulnerable to peroxynitrite (Choi and Kim, J. Neurosci. Res. 54 (1998) 870; Neurosci. Lett. 256 (1988) 109; Ju et al., J. Neurochem. 74 (2000) 1989). Here we report that ciclopirox, which is clinically used as an anti-fungal agent, completely prevents the increased death in glucose-deprived astrocytes exposed to 3-morpholinosydnonimine (SIN-1, a peroxynitrite-releasing reagent). The increased vulnerability was in good correlation with the peroxynitrite-evoked decrease of mitochondrial transmembrane potential (MTP) in astrocytes. A simultaneous exposure to glucose deprivation and SIN-1 rapidly depolarized MTP and depleted ATP in astrocytes. Inclusion of ciclopirox initially increased the MTP, maintained it high, and blocked the ATP depletion in glucose-deprived SIN-1-treated astrocytes. However, ciclopirox did not prevent the depletion of reduced glutathione in glucose-deprived SIN-1-treated astrocytes. Consistently, ciclopirox did not scavenge various kinds of oxidants including peroxynitrite, nitric oxide, superoxide anion, hydrogen peroxide and hydroxyl radical. Ciclopirox has been experimentally used as a cell cycle G1/S phase transition blocker (Hoffman et al., Cytometry 12 (1991) 26). Flow cytometry analysis, however, showed that the cytoprotective effect of ciclopirox was not attributed to its inhibition of the cell cycle progression. The present results indicate that ciclopirox protects astrocytes from peroxynitrite cytotoxicity by attenuating peroxynitrite-induced mitochondrial dysfunction.
Choi
J-J
JJ
Department of Pharmacology, College of Medicine, Ewha Institute of Neuroscience, Ewha Women's University, 70 Chongro-6-ga, Chongro-ku, Seoul 110-783, South Korea.
Kong
M Y
MY
Lee
S J
SJ
Kim
H-C
HC
Ko
K H
KH
Kim
W-K
WK
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D000077768:Ciclopirox; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012235:Rhodamines; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D018696:Neuroprotective Agents; D011728:Pyridones; D012235:Rhodamines; C058319:dihydrorhodamine 123; D013481:Superoxides; D030421:Peroxynitrous Acid; D000077768:Ciclopirox; D012710:Serum Albumin, Bovine; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D014443:Tyrosine; C002385:linsidomine; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D008981:Molsidomine; D007770:L-Lactate Dehydrogenase; D005978:Glutathione