noc-18 and Necrosis

In this study we sought to determine whether NO donor NOC-18 can protect brain mitochondria against ischemia-induced dysfunction, particularly opening of mitochondrial permeability transition pore (MPTP), and cell death. We found that inhibition of respiration with NAD-dependent substrates, but not with succinate, was observed after 30 min ischemia indicating that complex I of the mitochondrial respiratory chain is the primary site affected by ischemia. There was no loss of mitochondrial cytochrome c during 30-120 min of brain ischemia. Prolonged, 90 min ischemia substantially decreased calcium retention capacity of brain mitochondria suggesting sensitization of mitochondria to Ca(2+)-induced MPTP opening, and this was prevented by NOC-18 infusion prior to ischemia. NOC-18 did not prevent ischemia-induced inhibition of mitochondrial respiration, however, it partially protected against ischemia-induced necrosis. Protective effects of NOC-18 were abolished in the presence of selective inhibitors of protein kinase G (PKG) and protein kinase C (PKC). These results indicate that pre-treatment with NOC-18 protected brain mitochondria against ischemia-induced MPTP opening by decreasing mitochondrial sensitivity to calcium and partly protected brain cells against necrotic death in PKG- and PKC-depending manner.

Topics: Animals; Brain Ischemia; Calcium; Cell Death; Cyclic GMP-Dependent Protein Kinases; Cytochromes c; Male; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Necrosis; Neuroprotective Agents; Nitric Oxide Donors; Nitroso Compounds; Protein Kinase C; Rats, Wistar

Topics: Animals; Apoptosis; Azides; Caspases; Cysteine Proteinase Inhibitors; Glucose; Methacrylates; Mitochondria; Necrosis; Nitric Oxide; Nitric Oxide Donors; Nitroso Compounds; Oxygen Consumption; PC12 Cells; Rats; Thiazoles