Nitroxyl exacerbates ischemic cerebral injury and oxidative neurotoxicity

Chi Un Choe, Jan Lewerenz, Gerry Fischer, Tracy F. Uliasz, Michael Graham Espey, Friedhelm C. Hummel, Stephen Bruce King, Edzard Schwedhelm, Rainer H. Böger, Christian Gerloff, Sandra Hewett, Tim Magnus, Sonia Donzelli

Research output: Contribution to journalArticle

26 Scopus citations

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 μmol/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.

Original languageEnglish (US)
Pages (from-to)1766-1773
Number of pages8
JournalJournal of Neurochemistry
Volume110
Issue number6
DOIs
StatePublished - Sep 2009
Externally publishedYes

    Fingerprint

Keywords

  • Ischemia-reperfusion damage
  • Nitroxyl
  • Oxidative stress
  • Oxygen-glucose- deprivation

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Choe, C. U., Lewerenz, J., Fischer, G., Uliasz, T. F., Espey, M. G., Hummel, F. C., King, S. B., Schwedhelm, E., Böger, R. H., Gerloff, C., Hewett, S., Magnus, T., & Donzelli, S. (2009). Nitroxyl exacerbates ischemic cerebral injury and oxidative neurotoxicity. Journal of Neurochemistry, 110(6), 1766-1773. https://doi.org/10.1111/j.1471-4159.2009.06266.x