title: Neuroprotective effects of nitric oxide donor NOC-18 against brain ischemia-induced mitochondrial damages: role of PKG and PKC.
abstract: 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.
authors.affiliation: Institute of Neurosciences, Lithuanian University of Health Sciences, Eiveniu Str. 4, LT-50009 Kaunas, Lithuania. Electronic address: oddetina@gmail.com.
authors.forename: Odeta
authors.initials: O
authors.lastname: Arandarcikaite
authors.affiliation: Institute of Neurosciences, Lithuanian University of Health Sciences, Eiveniu Str. 4, LT-50009 Kaunas, Lithuania.
authors.forename: Ramunas
authors.initials: R
authors.lastname: Jokubka
authors.affiliation: Institute of Neurosciences, Lithuanian University of Health Sciences, Eiveniu Str. 4, LT-50009 Kaunas, Lithuania.
authors.forename: Vilmante
authors.initials: V
authors.lastname: Borutaite
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D000083162:Mitochondrial Permeability Transition Pore; D009336:Necrosis; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020030:Nitric Oxide Donors / Q000494:pharmacology* / Q000627:therapeutic use; D009603:Nitroso Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D011493:Protein Kinase C / Q000378:metabolism*; D017208:Rats, Wistar
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C093285:NOC 18; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D045304:Cytochromes c; D017869:Cyclic GMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002118:Calcium
keywords: Ischemia; Mitochondria; Nitric oxide; Protein kinases