Inhibitors of iNOS protects PC12 cells against the apoptosis induced by oxygen and glucose deprivation.
It has been shown that deletion of the gene encoding the inducible form of nitric oxide synthase (iNOS) results in a reduction of ischemia-induced apoptotic cell death, suggesting the detrimental role of iNOS. The signaling pathways by which iNOS mediates apoptotic cell death under ischemic conditions remain unclear. Understanding the molecular mechanisms of iNOS-mediated apoptotic cell death in ischemia may offer opportunities for potential therapeutic intervention. In the current study, undifferentiated rat pheochromocytoma PC12 cells, exposed to oxygen and glucose deprivation (OGD) followed by reperfusion (adding back oxygen and glucose, OGD-R), were used as an in vitro model of ischemia. The iNOS expression and activity were increased during OGD-R. OGD-R-induced apoptosis was demonstrated by the increase of LDH release, cytosolic release of cytochrome C and caspase-3 activity. Inhibition of iNOS activity by selective iNOS inhibitors, aminoguanidine and 1400W, reduces OGD-R-induced apoptotic cell death, as demonstrated by the decrease of LDH release, cytochrome C release, and caspase-3 activity. These results suggest the critical role of iNOS in mediating apoptosis under ischemic conditions, likely through the induction of caspase-3 activity.
Jiang
Hao
H
William T. Gossett Neurology Laboratories, Henry Ford Health System, One Ford Place, 4D, Detriot, MI 48202, USA.
Koubi
David
D
Zhang
Lijie
L
Kuo
Jarret
J
Rodriguez
Alba I
AI
Hunter
Tangella Jackson
TJ
Gautam
Subhash C
SC
Levine
Robert A
RA
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001596:Benzylamines / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004347:Drug Interactions; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005947:Glucose / Q000172:deficiency*; D006146:Guanidines / Q000494:pharmacology; D000860:Hypoxia; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D016716:PC12 Cells; D051381:Rats; D013997:Time Factors
D000578:Amidines; D001596:Benzylamines; D006146:Guanidines; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005947:Glucose; C004479:pimagedine