title: NXY-059 maintains Akt activation and inhibits release of cytochrome C after focal cerebral ischemia.
abstract: Stroke is the third leading cause of death in the US, with a prevalence of 750,000 patients per year, and a social cost estimated at $50 billion. Current therapeutics are targeted at restoring blood flow rather than on preventing the actual mechanisms associated with neuronal cell death. Here, we show that, following transient (2 h) middle cerebral artery occlusion (tMCAO) in male, Wistar rats, neuronal damage determined using MAP-2 staining increased progressively after the tMCAO. Notably, such neuronal degeneration was first associated with a decrease in p-Akt in both the focus and penumbra of the infarct region and, later with an increase in cytosolic cytochrome C levels in cortical neurons in the infarct area. These findings implicate that Akt alterations and consequent release of cytochrome C are involved in neuronal death. To further address this issue, NXY-059 (disodium 4-[(tert.-butylimino)methyl]benzene-1,3-disulfonate N-oxide) administered i.v. (30 mg/kg bolus, followed by 30 mg/kg/h infusion for up to 24 h), commencing 1 h after reperfusion, not only prevented the increase in infarct area but also attenuated the postreperfusion increase in neuronal cytosolic cytochrome C and the postperfusion decrease in neuronal p-Akt. Thus, NXY-059, by preventing mitochondrial cytochrome C release by maintaining activation of the Akt pathway, appears to protect neurons from damage after ischemia.
authors.affiliation: Center for the Study of Neurological Disease, Queen's Medical Center, UH Tower, 8th Floor, 1356 Lusitana Street, Honolulu, HI 96813, USA.
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Palanisamy
authors.initials: P
authors.lastname: Kanakaraj
authors.forename: Jing
authors.initials: J
authors.lastname: Ying Ma
authors.forename: Mingshan
authors.initials: M
authors.lastname: Cheng
authors.forename: Irene
authors.initials: I
authors.lastname: Kerr
authors.forename: Latha
authors.initials: L
authors.lastname: Malaiyandi
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Watson
authors.forename: Bo K
authors.initials: BK
authors.lastname: Siesjö
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Maples
mesh_terms: D000818:Animals; D001557:Benzenesulfonates; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D003574:Cytochrome c Group / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D020768:Middle Cerebral Artery; D008928:Mitochondria / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001557:Benzenesulfonates; D003574:Cytochrome c Group; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D011518:Proto-Oncogene Proteins; C120851:disufenton sodium; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt