Nitroxyl exacerbates ischemic cerebral injury and oxidative neurotoxicity

被引:23
|
作者
Choe, Chi-un [1 ]
Lewerenz, Jan [1 ]
Fischer, Gerry
Uliasz, Tracy F. [2 ]
Espey, Michael Graham [3 ]
Hummel, Friedhelm C. [1 ]
King, Stephen Bruce [4 ]
Schwedhelm, Edzard [5 ]
Boeger, Rainer H. [5 ]
Gerloff, Christian [1 ]
Hewett, Sandra J. [2 ]
Magnus, Tim [1 ]
Donzelli, Sonia [1 ,5 ]
机构
[1] Univ Hosp Hamburg Eppendorf, Dept Neurol, Hamburg, Germany
[2] Univ Connecticut, Sch Med, Dept Neurosci, Farmington, CT USA
[3] NIDDK, Mol & Clin Nutr Sect, NIH, Bethesda, MD USA
[4] Wake Forest Univ, Dept Chem, Winston Salem, NC 27109 USA
[5] Univ Hosp Hamburg Eppendorf, Cardiovasc Res Ctr, Hamburg, Germany
关键词
ischemia-reperfusion damage; nitroxyl; oxidative stress; oxygen-glucose-deprivation; NITRIC-OXIDE SYNTHASE; PROGRAMMED CELL-DEATH; IN-VIVO; NMDA RECEPTOR; CYTOCHROME-C; ANGELIS SALT; GLUTATHIONE DEPLETION; SUPEROXIDE-DISMUTASE; GLUTAMATE TOXICITY; BRAIN-DAMAGE;
D O I
10.1111/j.1471-4159.2009.06266.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 mu mol/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.
引用
收藏
页码:1766 / 1773
页数:8
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