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Nitroxyl exacerbates ischemic cerebral injury and oxidative neurotoxicity
Author(s) -
Choe Chiun,
Lewerenz Jan,
Fischer Gerry,
Uliasz Tracy F.,
Espey Michael Graham,
Hummel Friedhelm C.,
King Stephen Bruce,
Schwedhelm Edzard,
Böger Rainer H.,
Gerloff Christian,
Hewett Sandra J.,
Magnus Tim,
Donzelli Sonia
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06266.x
Subject(s) - neurotoxicity , oxidative stress , glutamate receptor , excitotoxicity , ischemia , pharmacology , medicine , anesthesia , in vivo , endocrinology , receptor , biology , toxicity , microbiology and biotechnology
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 .