Rapid Cerebral Ischemic Preconditioning in Mice Deficient in Endothelial and Neuronal Nitric Oxide Synthases

Atochin, Dmitriy N.; Clark, Jeffrey W.; Demchenko, Ivan T.; Moskowitz, Michael A.; Huang, Paul L.

doi:10.1161/01.str.0000066870.70976.57

Cited by 108 publications

(100 citation statements)

References 24 publications

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“…For example, Atochin et al (2003) have provided evidence that the endothelial (eNOS) and neuronal (nNOS) isoforms of NOS participate in the early preconditioning induced by transient cerebral ischemia, whereas eNOS may be involved in hypoxic preconditioning in a neonatal model of cerebral hypoxic-ischemic injury (Gidday et al, 1999). We recently found that nNOS and eNOS, but not iNOS, play a role in the early preconditioning induced by LPS .…”

Section: Discussionmentioning

confidence: 99%

Neurovascular Protection by Ischemic Tolerance: Role of Nitric Oxide and Reactive Oxygen Species

Kunz¹,

Park²,

Abe³

et al. 2007

J. Neurosci.

132

117

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Cerebral ischemic preconditioning or tolerance is a powerful neuroprotective phenomenon by which a sublethal injurious stimulus renders the brain resistant to a subsequent damaging ischemic insult. We used lipopolysaccharide (LPS) as a preconditioning stimulus in a mouse model of middle cerebral artery occlusion (MCAO) to examine whether improvements in cerebrovascular function contribute to the protective effect. Administration of LPS 24 h before MCAO reduced the infarct by 68% and improved ischemic cerebral blood flow (CBF) by 114% in brain areas spared from infarction. In addition, LPS prevented the dysfunction in cerebrovascular regulation induced by MCAO, as demonstrated by normalization of the increase in CBF produced by neural activity, hypercapnia, or by the endotheliumdependent vasodilator acetylcholine. These beneficial effects of LPS were not observed in mice lacking inducible nitric oxide synthase (iNOS) or the nox2 subunit of the superoxide-producing enzyme NADPH oxidase. LPS increased reactive oxygen species and the peroxynitrite marker 3-nitrotyrosine in wild-type mice but not in nox2 nulls. The peroxynitrite decomposition catalyst 5,10,15, 20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III) attenuated LPS-induced nitration and counteracted the beneficial effects of LPS on infarct volume, ischemic CBF, and vascular reactivity. Thus, LPS preserves neurovascular function and ameliorates CBF in regions of the ischemic territory at risk for infarction. This effect is mediated by peroxynitrite formed from iNOS-derived NO and nox2-derived superoxide. The data indicate that preservation of cerebrovascular function is an essential component of ischemic tolerance and suggest that combining neuroprotection and vasoprotection may be a valuable strategy for treating ischemic brain injury.

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Section: Discussionmentioning

confidence: 99%

Neurovascular Protection by Ischemic Tolerance: Role of Nitric Oxide and Reactive Oxygen Species

Kunz¹,

Park²,

Abe³

et al. 2007

J. Neurosci.

132

117

View full text Add to dashboard Cite

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“…They showed that NO production and activity were critical to the induction of ischemic tolerance and that endothelial nitric oxide synthase (eNOS), not neuronal nitric oxide synthase (nNOS) or inducible nitric oxide synthase (iNOS), was the isoform responsible for producing ischemic tolerance. In the study by Sunghee Cho and his colleagues, both inhibiting nitric oxide synthase (NOS) and scavenging NO during preconditioning significantly attenuated the induced ischemic tolerance, however, neither eNOS nor nNOS knockout mice demonstrated altered ischemic preconditioning [14,69,70] . Meanwhile, preconditioning by volatile anesthetics also appears to involve the NO pathway.…”

Section: Nitric Oxide/reactive Oxygen Species and Neuroprotectionmentioning

confidence: 99%

The neuroprotective mechanism of brain ischemic preconditioning

2009

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Brain ischemia is one of the most common causes of death and the leading cause of adult disability in the world. Brain ischemic preconditioning (BIP) refers to a transient, sublethal ischemia which results in tolerance to later, otherwise lethal, cerebral ischemia. Many attempts have been made to understand the molecular and cellular mechanisms underlying the neuroprotection offered by ischemic preconditioning. Many studies have shown that neuroprotective mechanisms may involve a series of molecular regulatory pathways including activation of the N-methyl-D-aspartate (NMDA) and adenosine receptors; activation of intracellular signaling pathways such as mitogen activated protein kinases (MAPK) and other protein kinases; upregulation of Bcl-2 and heat shock proteins (HSPs); and activation of the ubiquitin-proteasome pathway and the autophagic-lysosomal pathway. A better understanding of the processes that lead to cell death after stroke as well as of the endogenous neuroprotective mechanisms by which BIP protects against brain ischemic insults could help to develop new therapeutic strategies for this devastating neurological disease. The purpose of the present review is to summarize the neuroprotective mechanisms of BIP and to discuss the possibility of mimicking ischemic preconditioning as a new strategy for preventive treatment of ischemia.

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“…Available pharmacologic evidence is even more indicative of NO involvement in the initial mechanisms that trigger PC, with model-specific effects of various inhibitors to eliminate PC when given during the priming insult (Cho et al, 2005;Gidday et al, 1999;Puisieux et al, 2000). Failure to observe acute PC in both neuronal NOS and eNOS knockout mice (Atochin et al, 2003) or delayed protection in iNOS knockout mice (Cho et al, 2005) could reflect effects on both the development and the expression of PC. Nitric oxide is also implicated in cellular PC mechanisms (Nandagopal et al, 2001), independent of vascular effects.…”

Section: Perfusion Changes and Ischemic Preconditioningmentioning

confidence: 99%

CBF Changes Associated with Focal Ischemic Preconditioning in the Spontaneously Hypertensive Rat

Zhao

Nowak

2006

J Cereb Blood Flow Metab

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Experimental stroke models exhibit robust protection after prior preconditioning (PC) insults. This study comprehensively examined cerebral blood flow (CBF) responses to permanent middle cerebral artery (MCA) occlusion in spontaneously hypertensive rats preconditioned by noninjurious transient focal ischemia, using [ 14 C]iodoantipyrine autoradiography at varied occlusion intervals. Preconditioning was produced by 10-min occlusion of the MCA and ipsilateral common carotid artery under halothane anesthesia. These vessels were permanently coagulated 24 h later in naïve, PC, and sham-operated rats. Infarct volumes were determined from hematoxylin-eosin-stained frozen sections after 1 or 3 days. Edema-corrected infarct volume was reduced from 127621 in naïve rats to 101631 and 52628 mm 3 in sham and PC groups, respectively, at 1 day, with similar results at 3 days. All animals exhibited a consistent CBF threshold for infarction (approximately 30 mL/100 g/ min). Tissue volumes below this threshold were identical in naïve and PC groups after 15-min occlusion. However, by 3 h the volume of ischemic cortex decreased in the PC group but remained unchanged in naïve rats, predicting final infarct volumes. Cerebral blood flow recovery was confirmed in brains of individual rats evaluated by repeated laser Doppler perfusion imaging during the same 3-h interval. Modest sham protection correlated with better-maintained global perfusion, detectable also in the contralateral cortex, apparently reflecting the PC effects of prior anesthesia. These results establish that timely reperfusion of penumbra, achieved by synergistic mechanisms, is a primary determinant of PC-induced protection in experimental stroke.

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Rapid Cerebral Ischemic Preconditioning in Mice Deficient in Endothelial and Neuronal Nitric Oxide Synthases

Cited by 108 publications

References 24 publications

Neurovascular Protection by Ischemic Tolerance: Role of Nitric Oxide and Reactive Oxygen Species

Neurovascular Protection by Ischemic Tolerance: Role of Nitric Oxide and Reactive Oxygen Species

The neuroprotective mechanism of brain ischemic preconditioning

CBF Changes Associated with Focal Ischemic Preconditioning in the Spontaneously Hypertensive Rat

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