Neuroprotective effects of nitric oxide donor NOC-18 against brain ischemia-induced mitochondrial damages: role of PKG and PKC. (23rd January 2015)

• Record Type: Journal Article
• Authors: Arandarcikaite, Odeta; Jokubka, Ramunas; Borutaite, Vilmante
• Is Part Of: Neuroscience letters. Volume 586(2015)
• Page Start: 65
• Page End: 70
• Publication Date: 2015-01-23
• Subjects: CRC calcium retention capacity -- LDH lactate dehydrogenase -- MPTP mitochondrial permeability transition pore -- NOC-18 NO donor 3, 3-bis(aminoethyl)-1-hydroxy-2-oxo-1-triazene synonims 2, 2′-(hydroxynitrosohydrazino)bis-ethanamine -- NOS nitric oxide synthase -- PKG protein kinase G -- PKCɛ protein kinase C epsilion.; Ischemia -- Nitric oxide -- Mitochondria -- Protein kinases; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2014.09.012
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Brain ischemia causes early inhibition of mitochondrial respiration at complex I. There is no release of cytochrome c from mitochondria during brain ischemia. Brain ischemia causes opening of mitochondrial permeability transition pore (MPTP). Injection of NOC-18 in rats protects against ischemia-induced MPTP and necrosis. NOC-18-induced protective mechanism is mediated by 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.