Nitric oxide and cerebral ischemic preconditioning

doi:10.1016/j.ceca.2004.02.007

Cell Calcium

Volume 36, Issues 3–4, September–October 2004, Pages 323-329

https://doi.org/10.1016/j.ceca.2004.02.007 Get rights and content

Abstract

Nitric oxide (NO) is an important mediator of cerebral blood flow and metabolism. As a vasodilator, NO regulates cerebral blood flow, and couples regional brain perfusion with metabolic activity. Following cerebral ischemia, NO levels rise significantly due to activation of neuronal nitric oxide synthase by NMDA receptor mediated calcium entry. Depending on its tissue and enzymatic source, NO may be protective or toxic. This article reviews the effects of NO following cerebral ischemia, the signaling pathways through which NO acts, and its potential roles in cerebral ischemic preconditioning.

Section snippets

Functions of nitric oxide (NO) in the brain

NO is produced by nitric oxide synthases (NOS), of which there are three isoforms: neuronal, endothelial, and inducible (nNOS, eNOS, and iNOS) [1]. Although populations of neurons contain nNOS and eNOS, cerebral vessels and glial cells express eNOS and iNOS. Thus, all three NOS isoforms are potential sources of NO in the brain. The nNOS isoform is activated by a rise in intracellular calcium, for example, when glutamate binds to the NMDA receptor. The NO produced diffuses across cell membranes

Vascular and toxic effects of NO following ischemia

In 1993, Malinski et al. [9] first measured nitric oxide production in the brain using a porphyrinic microsensor. They found that while basal levels of NO are in the nanomolar range, the amount rapidly increases to micromolar levels following cerebral ischemia. Studies using non-selective NOS inhibitors were confounded by simultaneous drug effects on more than one NOS isoform. It is now known that the source of the acute increase in NO is the nNOS isoform. Furthermore, it became apparent that

Interactions between NO and the Ras/Raf/MEK/ERK pathway and the PI3K/Akt pathway

The concept that NO can be both protective and toxic is now well-established. The overall effects depend on the redox state of the tissue, the NOS isoforms involved, the precise localization of the NO, and the presence of other species, such as superoxide anion [26], [27]. There is yet another layer of complexity to the effects of NO. NO interacts with two signalling pathways important to neuronal survival: the Ras/Raf/MEK/ERK pathway, and the PI3 kinase Akt pathway, as shown in Fig. 2. Both of

Regulation of eNOS by Akt kinase

Like nNOS, eNOS is activated by a rise in intracellular calcium concentrations, explaining the acute moment-to-moment regulation of its activity. Recent evidence suggests that eNOS is also regulated on a longer time scale by phosphorylation of key serine and threonine residues [33], [34]. Phosphorylation of Ser1179 activates eNOS, and phosphorylation at Thr 497 inactivates it [35], [36]. Furthermore, phosphorylation of these two residues in many cases shows a reciprocal pattern. Akt kinase

Cerebral ischemic preconditioning

Ischemic preconditioning (IPC) refers to processes by which brief, sublethal episodes of ischemia stimulate a protective response against subsequent, more severe, ischemia [39]. IPC has been described in many tissues, including the heart, the brain, liver, and gastrointestinal tract. Although there are similarities between IPC in various tissues, it is not known whether the triggers and mediators of IPC are the same in all tissues. The molecular mechanisms of IPC are not fully understood,

Potential roles of NO in IPC

NO may play several separate roles in IPC [39]. First, NO may be involved as a trigger of IPC, where nNOS-derived NO is required to stimulate downstream steps involved in the mechanisms of IPC. Second, NO may be involved as a mediator of protection by affecting neuronal resistance to ischemic phenomena. Third, as a vasodilator, NO may improve perfusion and diminish interactions between the endothelium and circulating platelets and leukocytes, thus reducing the functional effects of ischemia.

NO and in vivo models of IPC

In a newborn rat model of hypoxia-ischemia, Gidday et al. [47] found that preconditioning by mild hypoxia (8% O₂) for 3 h results in development of protection against more severe hypoxia 24 h later. Development of IPC protection was prevented by non-selective NOS inhibitor L-NA, but not the nNOS-specific inhibitor 7-nitroindazole or iNOS specific inhibitor aminoguanidine. These results suggest, by process of elimination, that the eNOS isoform may be involved in protection. In this model, the NMDA

NO and cell culture models of IPC

Models of oxygen glucose deprivation (OGD) mimic ischemia in primary neuronal cultures or cell lines like the PC12 pheochromocytoma cell line. OGD models show protection from IPC, indicating that intrinsic neuronal susceptibility is altered in IPC. However, such cell culture studies can only demonstrate the effects of endogenous pathways within neurons. Importantly, they may not reflect vascular effects or interactions between different tissue compartments that may be operative during IPC in

Mechanisms of NO protection

The molecular mechanisms for IPC are not known. Several studies have documented changes in the expression of certain key genes in IPC, including bcl-2, heat shock proteins, and NMDA receptor subtypes [40], [41], [53], [54]. These changes may contribute to protection in IPC, but they are likely to be part of a larger pattern of gene expression that is activated. Further work is necessary to delineate the mechanisms by which NO is involved in IPC. The possibilities include (1) a requirement for

References (56)

P.L Huang et al.
Targeted disruption of the neuronal nitric oxide synthase gene
Cell
(1993)
J.D MacMicking et al.
Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase
Cell
(1995)
N Panahian et al.
Attenuated hippocampal damage after global cerebral ischemia in mice mutant in neuronal nitric oxide synthase
Neuroscience
(1996)
M Endres et al.
Role of peroxynitrite and neuronal nitric oxide synthase in the activation of poly(ADP-ribose) synthetase in a murine model of cerebral ischemia-reperfusion
Neurosci. Lett.
(1998)
B Elibol et al.
Nitric oxide is involved in ischemia-induced apoptosis in brain: a study in neuronal nitric oxide synthase null mice
Neuroscience
(2001)
H.M Lander et al.
Nitric oxide-stimulated guanine nucleotide exchange on p21ras
J. Biol. Chem.
(1995)
M.R Walton et al.
Is CREB a key to neuronal survival?
Trends Neurosci.
(2000)
M.B Harris et al.
Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation
J. Biol. Chem.
(2001)
B.J Michell et al.
Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase
J. Biol. Chem.
(2001)
K Hisamoto et al.
Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells
J. Biol. Chem.
(2001)

K Shimazaki et al.

Increase in bcl-2 oncoprotein and the tolerance to ischemia-induced neuronal death in the gerbil hippocampus

Neurosci. Res.

(1994)

F.R Sharp et al.

Heat-shock protein protection

Trends Neurosci.

(1999)

K Kitagawa et al.

‘Ischemic tolerance’ phenomenon found in the brain

Brain Res.

(1990)

K Kasischke et al.

NMDA-antagonists reverse increased hypoxic tolerance by preceding chemical hypoxia

Neurosci. Lett.

(1996)

F Puisieux et al.

Differential role of nitric oxide pathway and heat shock protein in preconditioning and lipopolysaccharide-induced brain ischemic tolerance

Eur. J. Pharmacol.

(2000)

K Kapinya et al.

Temporary changes of the AP-1 transcription factor binding activity in the gerbil hippocampus after transient global ischemia, and ischemic tolerance induction

Brain Res.

(2000)

M Shamloo et al.

Activation of the extracellular signal-regulated protein kinase cascade in the hippocampal CA1 region in a rat model of global cerebral ischemic preconditioning

Neuroscience

(1999)

A Brunet et al.

Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway

Curr. Opin. Neurobiol.

(2001)

W.K Alderton et al.

Nitric oxide synthases: structure, function and inhibition

Biochem. J.

(2001)

T.M Dawson et al.

A novel neuronal messenger molecule in brain: the free radical, nitric oxide

Ann Neurol.

(1992)

T.M Dawson et al.

Molecular mechanisms of nitric oxide actions in the brain

Ann. N.Y. Acad. Sci.

(1994)

G.M Edelman et al.

Nitric oxide: linking space and time in the brain

Proc. Natl. Acad. Sci. U.S.A.

(1992)

J Ma et al.

L-NNA-sensitive regional cerebral blood flow augmentation during hypercapnia in type III NOS mutant mice

Am. J. Physiol.

(1996)

J Ma et al.

Regional cerebral blood flow response to vibrissal stimulation in mice lacking type I NOS gene expression

Am. J. Physiol.

(1996)

W Meng et al.

ACh dilates pial arterioles in endothelial and neuronal NOS knockout mice by NO-dependent mechanisms

Am. J. Physiol.

(1996)

W Meng et al.

Neuronal NOS-cGMP-dependent ACh-induced relaxation in pial arterioles of endothelial NOS knockout mice

Am. J. Physiol.

(1998)

T Malinski et al.

Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middle cerebral artery occlusion

J. Cereb. Blood Flow Metab.

(1993)

P.L Huang et al.

Hypertension in mice lacking the gene for endothelial nitric oxide synthase

Nature

(1995)

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Citation Excerpt :
Yuan demonstrated that nNOS is the major source of NO production at early stages of cerebral ischemia (Yuan et al., 2010), and our results are consistent with this. Several studies have documented changes in expression of genes related to ischemic preconditioning (IPC) (Huang, 2004), including bcl-2, heat shock proteins, and NMDA receptor subtypes (Shamloo et al., 1999; Shamloo and Wieloch, 1999; Shimazaki et al., 1994; Sharp et al., 1999). The current experiment investigated the effect of EE on iNOS and nNOS expression, and the data support previous reports that antagonism of iNOS and nNOS is neuroprotective in the rat MCAO model.
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Nitric oxide and cerebral ischemic preconditioning

Abstract

Section snippets

Functions of nitric oxide (NO) in the brain

Vascular and toxic effects of NO following ischemia

Interactions between NO and the Ras/Raf/MEK/ERK pathway and the PI3K/Akt pathway

Regulation of eNOS by Akt kinase

Cerebral ischemic preconditioning

Potential roles of NO in IPC

NO and in vivo models of IPC

NO and cell culture models of IPC

Mechanisms of NO protection

Cell

Cell

Neuroscience

Neurosci. Lett.

Neuroscience

J. Biol. Chem.

Trends Neurosci.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neurosci. Res.

Trends Neurosci.

Brain Res.

Neurosci. Lett.

Eur. J. Pharmacol.

Brain Res.

Neuroscience

Curr. Opin. Neurobiol.

Nitric oxide synthases: structure, function and inhibition

Biochem. J.

A novel neuronal messenger molecule in brain: the free radical, nitric oxide

Ann Neurol.

Molecular mechanisms of nitric oxide actions in the brain

Ann. N.Y. Acad. Sci.

Nitric oxide: linking space and time in the brain

Proc. Natl. Acad. Sci. U.S.A.

L-NNA-sensitive regional cerebral blood flow augmentation during hypercapnia in type III NOS mutant mice

Am. J. Physiol.

Regional cerebral blood flow response to vibrissal stimulation in mice lacking type I NOS gene expression

Am. J. Physiol.

ACh dilates pial arterioles in endothelial and neuronal NOS knockout mice by NO-dependent mechanisms

Am. J. Physiol.

Neuronal NOS-cGMP-dependent ACh-induced relaxation in pial arterioles of endothelial NOS knockout mice

Am. J. Physiol.

Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middle cerebral artery occlusion

J. Cereb. Blood Flow Metab.

Hypertension in mice lacking the gene for endothelial nitric oxide synthase

Nature