title: Nitroxyl exacerbates ischemic cerebral injury and oxidative neurotoxicity.
abstract: Nitroxyl (HNO) donor compounds function as potent vasorelaxants, improve myocardial contractility and reduce ischemia-reperfusion injury in the cardiovascular system. With respect to the nervous system, HNO donors have been shown to attenuate NMDA receptor activity and neuronal injury, suggesting that its production may be protective against cerebral ischemic damage. Hence, we studied the effect of the classical HNO-donor, Angeli's salt (AS), on a cerebral ischemia/reperfusion injury in a mouse model of experimental stroke and on related in vitro paradigms of neurotoxicity. I.p. injection of AS (40 mumol/kg) in mice prior to middle cerebral artery occlusion exacerbated cortical infarct size and worsened the persistent neurological deficit. AS not only decreased systolic blood pressure, but also induced systemic oxidative stress in vivo indicated by increased isoprostane levels in urine and serum. In vitro, neuronal damage induced by oxygen-glucose-deprivation of mature neuronal cultures was exacerbated by AS, although there was no direct effect on glutamate excitotoxicity. Finally, AS exacerbated oxidative glutamate toxicity - that is, cell death propagated via oxidative stress in immature neurons devoid of ionotropic glutamate receptors. Taken together, our data indicate that HNO might worsen cerebral ischemia-reperfusion injury by increasing oxidative stress and decreasing brain perfusion at concentrations shown to be cardioprotective in vivo.
authors.affiliation: Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Chi-un
authors.initials: CU
authors.lastname: Choe
authors.forename: Jan
authors.initials: J
authors.lastname: Lewerenz
authors.forename: Gerry
authors.initials: G
authors.lastname: Fischer
authors.forename: Tracy F
authors.initials: TF
authors.lastname: Uliasz
authors.forename: Michael Graham
authors.initials: MG
authors.lastname: Espey
authors.forename: Friedhelm C
authors.initials: FC
authors.lastname: Hummel
authors.forename: Stephen Bruce
authors.initials: SB
authors.lastname: King
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
authors.forename: Christian
authors.initials: C
authors.lastname: Gerloff
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hewett
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.forename: Sonia
authors.initials: S
authors.lastname: Donzelli
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D002478:Cells, Cultured; D015237:Dinoprost / Q000031:analogs & derivatives / Q000652:urine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D028441:F2-Isoprostanes / Q000097:blood; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D018698:Glutamic Acid / Q000633:toxicity*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009573:Nitrites / Q000009:adverse effects; D009589:Nitrogen Oxides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D018709:Statistics, Nonparametric; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors
chemical_list: D028441:F2-Isoprostanes; D018696:Neuroprotective Agents; D009573:Nitrites; D009589:Nitrogen Oxides; D013778:Tetrazolium Salts; D013844:Thiazoles; C021229:oxyhyponitrite; C075750:8-epi-prostaglandin F2alpha; D018698:Glutamic Acid; D015237:Dinoprost; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; C039900:nitroxyl