HNO exacerbates ischemic cerebral injury and oxidative neurotoxicity.
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HNO exacerbates ischemic cerebral injury and oxidative neurotoxicity. / Choe, Chi-Un; Lewerenz, Jan; Fischer, Gerry; Uliasz, Tracy F; Espey, Michael Graham; Hummel, Friedhelm; Bruce King, S; Schwedhelm, Edzard; Böger, Rainer; Gerloff, Christian; Hewett, Sandra J; Magnus, Tim; Donzelli, Sonia.
In: J NEUROCHEM, 2009.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - HNO exacerbates ischemic cerebral injury and oxidative neurotoxicity.
AU - Choe, Chi-Un
AU - Lewerenz, Jan
AU - Fischer, Gerry
AU - Uliasz, Tracy F
AU - Espey, Michael Graham
AU - Hummel, Friedhelm
AU - Bruce King, S
AU - Schwedhelm, Edzard
AU - Böger, Rainer
AU - Gerloff, Christian
AU - Hewett, Sandra J
AU - Magnus, Tim
AU - Donzelli, Sonia
PY - 2009
Y1 - 2009
N2 - 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 N-methyl-D-aspartic acid (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. Intraperitoneal injection of AS (40mumol/kg) in mice prior to middle cerebral artery occlusion (MCAO) 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 (OGD) 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.
AB - 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 N-methyl-D-aspartic acid (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. Intraperitoneal injection of AS (40mumol/kg) in mice prior to middle cerebral artery occlusion (MCAO) 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 (OGD) 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.
M3 - SCORING: Zeitschriftenaufsatz
JO - J NEUROCHEM
JF - J NEUROCHEM
SN - 0022-3042
ER -
