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. 2011 Jul 11;589(Pt 17):4137–4145. doi: 10.1113/jphysiol.2011.210831

Neurovascular protection by ischaemic tolerance: role of nitric oxide

Costantino Iadecola 1, Timo Kahles 1, Eduardo F Gallo 1, Josef Anrather 1
PMCID: PMC3180574  PMID: 21746790

Abstract

Abstract

Nitric oxide (NO) has emerged as a key mediator in the mechanisms of ischaemic tolerance induced by a wide variety of preconditioning stimuli. NO is involved in the brain protection that develops either early (minutes–hours) or late (days–weeks) after the preconditioning stimulus. However, the sources of NO and the mechanisms underlying the protective effects differ substantially. While in early preconditioning NO is produced by the endothelial and neuronal isoform of NO synthase, in delayed preconditioning NO is synthesized by the inducible or ‘immunological’ isoform of NO synthase. Furthermore, in early preconditioning, NO acts through the canonical cGMP pathway, possibly through protein kinase G and opening of mitochondrial KATP channels. In late preconditioning, the protection is mediated by peroxynitrite formed by the reaction of NO with superoxide derived from the enzyme NADPH oxidase. The mechanisms by which peroxynitrite exerts its protective effect may include improvement of post-ischaemic cerebrovascular function, leading to enhancement of blood flow to the ischaemic territory, and expression of prosurvival genes resulting in cytoprotection. The evidence suggests that NO can engage highly effective and multifunctional prosurvival pathways, which could be exploited for the prevention and treatment of cerebrovascular pathologies.

Costantino Iadecola, MD, is the G. C. Cotzias Distinguished Professor of Neurology and Neuroscience and Chief of the Division of Neurobiology at Weill Cornell Medical College, New York City. His research focuses on neurovascular regulation, the molecular pathology of ischaemia, and on the interface between stroke and Alzheimer's disease. He has published over 200 papers. He has served on the Research Committee of the AHA and on the Stroke Council. He has chaired the International Stroke Conference, is President (Chair) of the Scientific Advisory Committee of the Fondation Leducq and an advisor to the Canadian, European and German Stroke Networks. He is consulting editor for Stroke, reviewing editor for The Journal of Neuroscience, and guest editor for PNAS and Circulation. He is on the editorial board of the Annals of Neurology, the American Journal of Physiology (Heart Circ Physiol), Cerebrovascular Diseases, and the Journal of Cerebral Blood Flow and Metabolism. He has received the Laurence McHenry Award (AAN), the Louis Sklarow Memorial Award, the Established Investigator Award (AHA), and the Jacob Javits Award (NINDS). In 2009, he received the Willis Award, the highest honour bestowed by the AHA in stroke research.

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Introduction

Organisms face various destructive threats, such as infection, ischaemia or trauma, and, consequently, have developed mechanisms for self-protection from tissue damage. In this context, the term ‘preconditioning’ describes a process by which a potentially harmful stimulus ameliorates tissue damage when applied in a sub-lethal fashion before the injury. For example, short periods of non-lethal cerebral ischaemia reduce the brain damage produced by a subsequent lethal ischaemic insult (Gidday, 2006). This phenomenon, called ischaemic tolerance, was first reported in vivo in 1964 (Dahl & Balfour, 1964) and is fittingly described by the quote of the German philosopher Friedrich Nietzsche: ‘What does not destroy me makes me stronger’ (Nietzsche, 2007).

Preconditioning can be induced by a wide variety of stimuli, including hypoxia-ischaemia, anaesthetics, hyperthermia, cortical spreading depressions, mitochondrial toxins, or proinflammatory agents, such as lipopolysaccharide (LPS) (Gidday, 2006). Tolerance can develop minutes to hours after the preconditioning stimulus (early preconditioning). Early preconditioning does not require protein synthesis and depends on signalling pathways activated by the preconditioning stimulus (Stagliano et al. 1999; Orio et al. 2007). A longer-lasting type of tolerance (delayed or late preconditioning) occurs days after the inducing stimulus and can last for weeks (Reis et al. 1998; Gidday, 2006; Stowe et al. 2011). Delayed preconditioning requires de novo protein synthesis (Kitagawa et al. 1990). The mechanisms of preconditioning have been studied extensively and have been recently reviewed (Perez-Pinzon et al. 2005; Gidday, 2006; Stenzel-Poore et al. 2007; Dirnagl et al. 2009). The evidence suggests that preconditioning is mediated by multiple pathways that act in concert to protect the brain by reducing energy expenditures, improving the delivery of blood flow, suppressing the pathogenic pathways triggered by cerebral ischaemia, and maximizing the repair potential of the damaged tissue (Dirnagl et al. 2009). In the context of delayed preconditioning, these effects are associated with, and perhaps driven by, a profound reprogramming of post-ischaemic gene expression (Stenzel-Poore et al. 2003).

Among the many factors involved in the complex chain of events leading to ischaemic preconditioning, nitric oxide (NO), a pleiotropic mediator implicated both in cell death and survival, has emerged as a key player. The purpose of this brief review is to examine the role of NO in ischaemic tolerance and to evaluate the potential translational relevance of using manipulations of the NO system to protect the brain from the consequences of cerebral ischaemia. A more comprehensive appraisal of this topic can be found in several excellent reviews (Gidday, 2006; Stenzel-Poore et al. 2007; Dirnagl et al. 2009).

Nitric oxide: sources, targets and reactions with oxygen radicals

NO is synthesized from l-arginine and oxygen by the oxidoreductase nitric oxide synthase, an enzyme present in three isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible or ‘immunological’ NOS (iNOS) (Alderton et al. 2001). NO exerts its biological effects by reacting with oxygen, superoxide, or transitional metal centres (Gross & Wolin, 1995; Pacher et al. 2007). These reactions support additional nitrosative reactions (reaction of NO+) with thiol groups that induce post-translational modifications of proteins (nitrosylation) (Stamler et al. 1992). NO reacts with haem groups of enzymes, such as guanylyl cyclase, leading to modulation of enzymatic activity (Gross & Wolin, 1995). However, NO has the greatest affinity for the free radical superoxide, with which it reacts to form peroxynitrite, a highly reactive agent that mediates some of the biological effects of NO (Beckman et al. 1990; Pacher et al. 2007). There are many sources of superoxide including cyclooxygenases, lipoxygenases, xanthine oxidase and mitochondrial enzymes (Adibhatla & Hatcher, 2009). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is another enzyme that has recently emerged as a major source of superoxide in cerebral blood vessels and brain parenchyma (Chrissobolis & Faraci, 2008; Sorce & Krause, 2009). NADPH oxidase, a multi-unit enzyme first described in neutrophils (Bedard & Krause, 2007) is involved in the superoxide production evoked by a wide variety of agonists, ranging from inflammatory mediators, to β-amyloid and angiotensin II (Iadecola et al. 2009). As discussed in the next sections, the reaction of NADPH oxidase-derived superoxide with NO plays a key role in delayed preconditioning.

Cytoprotective effects of NO

The cytoprotective effects of NO typically occur through direct post-translational modification of proteins (S-nitrosylation), through activation of the cGMP second messenger system and through reaction with superoxide to form peroxynitrite (Table 1). S-Nitrosylation, produced by the direct reaction of NO with cysteine thiol groups, has been linked to neuroprotection through inhibition of NMDA receceptor activity (Lei et al. 1992; Lipton et al. 1993; Kim et al. 1999). In addition, S-nitrosylation may confer neuroprotection by inhibition of apoptosis, particularly through inactivation of caspases, proteases that degrade key intracellular proteins (Melino et al. 1997; Budihardjo et al. 1999; Zhou et al. 2005). S-Nitrosylation also leads to activation of the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway (Yun et al. 1998), which triggers the expression of prosurvival genes in cortical neurons. S-Nitrosylation can also play a role in gene expression through modification of transcription factors involved in neuronal survival, such as CREB (cyclic adenosine monophosphate response element binding; Lonze & Ginty, 2002). Recently, a study in cortical neurons found that the brain-derived neurotrophic factor (BDNF), well known for its role in cell survival, induced CREB binding to target DNA (Riccio et al. 2006). These effects of NO on CREB-DNA binding are mediated by S-nitrosylation of histone deacetylase 2 (HDAC2) (Riccio et al. 2006). In addition, nuclear factor erythroid 2-related factor 2 (Nrf2), a neuroprotective redox-sensitive transcription factor linked to antioxidant defences (Shih et al. 2005), is activated by S-nitrosylation of its cytoplasmic inhibitor KEAP1 (kelch-like ECH-associated protein 1; Li et al. 2009). The resulting conformational changes lead to the dissociation of Nrf2/KEAP1 complexes and nuclear translocation of Nrf2, which, in turn, induces the transcription of antioxidant genes including glutathione reductase, peroxiredoxin, thioredoxin, thioredoxin reductase, haemoxygenase-1, catalase, and extracellular superoxide dismutase, among others (Calabrese et al. 2009). In addition, S-nitrosylation of the p50 subunit negatively regulates the pro-inflammatory transcription factor NF-κB (nuclear factor κ lightchain enhancer of activated B cells), possibly contributing to an anti-inflammatory environment (Colasanti & Persichini, 2000).

Table 1.

Cytoprotective effects of NO

Cellular effect Possible protective mechanisms Reference(s)
S-Nitrosylation
Inhibits NR2A-containing NMDAR Modifies channel properties, reduces Ca2+ influx and mitigates neurotoxicity Lipton et al. 1993; Choi et al. 2000
Inhibits caspase-3 activity Reduces apoptosis and apoptotic morphological features Melino et al. 1997; Zhou et al. 2005
Dissociates HDAC2 from CREB-related promoters BDNF increases CREB-DNA binding and CRE-dependent expression of neuroprotective genes Riccio et al. 2006; Nott et al. 2008
Dissociates Nrf2/KEAP complexes Nuclear translocation of Nrf2 and transcription of antioxidant genes Calabrese et al. 2009; Li et al. 2009
Activates p21Ras Activates the ERK signalling pathway, which plays a role in neuronal survival Yun et al. 1998
cGMP/PKG
CREB phosphorylation, Bcl-2 expression and activation of prosurvival Akt-GSK3 pathway Growth factor expression and inhibition of apoptosis leading to survival of cerebellar granule neurons Ciani et al. 2002a, 2002b
Contributes to ERK signalling and the expression of BDNF in cortical neurons May provide trophic support to neurons Gallo & Iadecola, 2011
Activates mitoKATP channels in cardiomyocytes following ischaemic injury Possible inhibition of mitochondrial transition pore Ockaili et al. 1999; Qin et al. 2004; Costa & Garlid, 2008
Improves synaptic function and amyloid-β accumulation in AD mouse model Possible CREB activation Puzzo et al. 2009
Phosphorylation of the proapoptotic protein Bad at key functional residue Inhibits apoptosis by binding to Bcl-xL Johlfs & Fiscus, 2010
Activation of Kv1.1/1.2 channels; increased GABA release probability Increased GABAergic transmission may reduce cell death Li et al. 2004; Dave et al. 2005; Yang et al. 2007
Peroxynitrite
Protects from ischaemia–reperfusion injury in cardiac ischaemia May inhibit neutrophil–endothelium interactions Lefer et al. 1997
Nitration or oxidation of tyrosine residues on proteins May lead to activation of key neuroprotective pathways, such as ERK or Akt Jope et al. 2000; Pesse et al. 2005; Li et al. 2006
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HDAC2: histone deacetylase 2; CREB: cAMP responsive element-binding protein; Nrf2: nuclear factor erythroid 2-related factor 2; KEAP1: Kelch-like ECH-associated protein 1; AD: Alzheimer's disease; Bcl: B-cell lymphoma.

A main biological target of NO is the haem-containing enzyme soluble guanylyl cyclase (sGC), which catalyses the conversion of GTP to cGMP. Numerous studies suggest that NO-dependent elevations in cGMP and consequent activation of protein kinase G (PKG) inhibit cell death and activate prosurvival pathways (Table 1). A role for NO in the expression of specific neuroplasticity-associated proteins, including BDNF, was recently demonstrated in cortical neurons and in the whisker barrel cortex, an effect that involves cGMP/PKG and ERK signalling (Gallo & Iadecola, 2011). Similarly, cGMP improves synaptic function and CREB activation in a mouse model of Alzheimer's disease (Puzzo et al. 2009). A glimpse into the cellular mechanisms of NO protection downstream of PKG is provided by studies in cardiomyocytes. Following ischaemia–reperfusion, NO-dependent PKG activity leads to activation of protein kinase Cɛ, which phosphorylates mitochondrial ATP-sensitive K+ (mitoKATP) channels (Costa & Garlid, 2008). The subsequent opening of the channels results in cytoprotection by inhibiting the mitochondrial transition pore (Costa & Garlid, 2008). Opening of mitoKATP channels is also associated with neuroprotection through mechanisms related to stabilization of mitochondrial function and prevention of apoptosis (Liu et al. 2002; Mayanagi et al. 2006).

NO rapidly reacts with superoxide to form peroxynitrite (Beckman et al. 1990). Besides its well-established toxic potential at high concentrations (Calabrese et al. 2009), at low concentrations peroxynitrite can act as a signalling molecule (Liaudet et al. 2009). For instance, in the vasculature, peroxynitrite is able to induce vascular relaxation and inhibition of platelet aggregation (Liu et al. 1994; Moro et al. 1994). Peroxynitrite protects cardiomyocytes from ischaemia–reperfusion injury (Lefer et al. 1997), an effect associated with inhibition of leukocyte adhesion to endothelial cells (Table 1). In addition, peroxynitrite leads to redox modulation of proteins within signalling cascades that mediate neuroprotection (Liaudet et al. 2009). For example, peroxynitrite activates ERK and Akt signalling in different cells promoting their survival (Jope et al. 2000; Pesse et al. 2005; Li et al. 2006).

These observations suggest that NO has powerful protective effects that involve not only pro-survival signalling pathways, but also blood flow and vascular inflammatory events that play a prominent role in ischaemic brain injury. As discussed below, these aspects of NO biology are critical for understanding the protective effect that NO exerts in the context of ischaemic preconditioning.

Role of NO in early preconditioning

As illustrated in Table 2, NO has been implicated both in early and late preconditioning, and in the newborn as well in the adult brain. NO derived from eNOS and nNOS is essential for induction of tolerance in models of early preconditioning. For example, the lesion produced by neocortical injection of the glutamate receptor agonist NMDA was markedly reduced 1 h after administration of the pro-inflammatory mediator LPS in mice (Orio et al. 2007). The effect was not abolished by the protein synthesis inhibitor anisomycin, attesting to the fact that the protection did not require new protein synthesis, a hallmark of early preconditioning. The protection conferred by LPS was abolished by inhibitors of nNOS, and could be reconstituted by neocortical injection of a NO donor. Furthermore, the tolerance was not observed in nNOS or eNOS null mice, but was preserved in iNOS null mice and in mice treated with the iNOS inhibitor aminoguanidine (AG) (Orio et al. 2007). In agreement with LPS preconditioning in NMDA lesions, the early tolerance to focal ischaemic injury produced by a transient episode of focal cerebral ischaemia was not observed in eNOS or nNOS null mice (Atochin et al. 2003), suggesting that eNOS and nNOS-derived NO is also involved in other preconditioning and injury modalities. These observations implicate eNOS and nNOS, but not iNOS, as sources of NO. There is evidence that the mechanisms by which NO induces early tolerance involve the second messenger cGMP. Thus, the early tolerance conferred by LPS is abolished by the sGC inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one and is re-established by exogenous cGMP (Orio et al. 2007). As discussed in the section ‘Cytoprotective effects of NO’ above, the mechanisms by which cGMP leads to tissue protection may involve PKG and mitoKATP channels. These observations, collectively, indicate that NO is critical for the establishment of ischaemic tolerance induced by transient ischaemia or by the proinflammatory mediator LPS, an effect involving activation of sGC and cGMP production (Fig. 1).

Table 2.

Selected in vivo studies on the involvement of NO in ischaemic tolerance

Species PC stimulus Type of PC Injury model Presumed source of NO Reference
Mouse tMCAO Early (0.5 h) pMCAO eNOS Atochin et al. 2003
nNOS
Mouse LPS Early (1 h) NMDA lesion eNOS Orio et al. 2007
nNOS
Rat, neonatal Hypoxia Late (24 h) pCCAO and hypoxia eNOS Gidday, 2006
Rat, neonatal Isoflurane Late (24 h) pCCAO and hypoxia iNOS Zhao et al. 2007
Rat, neonatal LPS Late (24 h) pCCAO and hypoxia eNOS Lin et al. 2010
Rat neonatal Prenatal hypoxia Late (48 h) pCCAO and hypoxia iNOS Zhao & Zuo, 2005
Rat Isoflurane Late (6–24 h) tBCCAO and pMCAO iNOS Kapinya et al. 2002
Mouse tBCCAO or LPS Late (24 h) tMCAO iNOS Cho et al. 2005
Mouse tBCCAO or LPS Late (24 h) NMDA lesion iNOS Kawano et al. 2007
Mouse LPS Late (24 h) tMCAO iNOS Kunz et al. 2007
Rat Isoflurane Late (24 h) pMCAO iNOS Chi et al. 2010
Mouse Hypoxia Late (24 h) Subarachnoid haemorrhage eNOS Vellimana et al. 2011
Rat tMCAO Late (36 h) tMCAO iNOS Wen & Chen, 2007
Mouse tBCCAO Late (48 h) pMCAO iNOS Pradillo et al. 2009
Rat LPS Late (72 h) tMCAO n.d. Puisieux et al. 2000
Rat t4VO Late (72 h) t4VO n.d. Liu et al. 2006
Gerbil tBCCAO Late (72 h) tBCCAO eNOS Hashiguchi et al. 2004
Rat CSD Late (96 h) tMCAO n.d. Horiguchi et al. 2005
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4VO: four vessel occlusion; BCCAO: bilateral common carotid artery occlusion; CCAO: common carotid artery occlusion (unilateral); CSD: cortical spreading depression; MCAO: middle cerebral artery occlusion; PC, preconditioning; tMCAO: transient MCAO; pMCAO: permanent MCAO; n.d.: not determined.

Figure 1. Nitric oxide in LPS-induced early preconditioning.

Figure 1

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The pro-inflammatory mediator lipopolysaccharide (LPS) rapidly triggers a protein-synthesis-independent form of brain preconditioning, which is mediated by eNOS and nNOS-derived NO production and cGMP. The neuroprotective effect may involve activation of the cGMP effector kinase PKG and the consequent opening of mitochondrial KATP channels. Dashed lines refer to pathways which have not been elucidated.

Role of NO in delayed preconditioning

Mounting evidence suggests that NO is also involved in delayed preconditioning. In hypoxic preconditioning in a neonatal rat model of ischaemic–hypoxic damage, the protection is abolished by the non-selective NOS inhibitor nitro-l-arginine, but not by the nNOS inhibitor 7-nitroindazole or the iNOS inhibitor AG (Table 2), implicating eNOS as the source of NO. Similar results were obtained in another model of preconditioning in neonatal rats (Lin et al. 2010). With some exceptions (Hashiguchi et al. 2004; Vellimana et al. 2011), the majority of studies on the role of NO in delayed preconditioning in the adult have indicated that the source of NO is iNOS (Table 2). Studies in adult mice have revealed a key role of iNOS in the preconditioning produced by LPS or transient forebrain ischaemia. iNOS null mice do not develop tolerance to focal ischaemia or NMDA lesions after treatment with LPS or transient forebrain ischaemia (Cho et al. 2005; Kawano et al. 2007; Kunz et al. 2007). Similarly, AG prevents the development of tolerance in these models. The preconditioning is associated with an increase in mitochondrial resistance to calcium-mediated depolarization (Cho et al. 2005), supporting the involvement of mitochondria also in the mechanisms of delayed tolerance (see Table 1 and section ‘Cytoprotective effects of NO’ above).

There is increasing evidence that preconditioning stimuli, in addition to changes in gene expression and mitochondrial function, also improve cerebrovascular function (Gidday, 2006). Therefore, the mechanisms of ischaemic tolerance may also include vascular effects that lead to an improvement of cerebral perfusion and blood–brain barrier function. In support of this possibility, LPS or ischaemic preconditioning improves cerebral blood flow and microvascular perfusion in vulnerable regions at the periphery of the ischaemic territory (ischaemic penumbra) (Dawson et al. 1999; Furuya et al. 2005; Hoyte et al. 2006; Zhao & Nowak, 2006; Kunz et al. 2007). After cerebral ischaemia, the mechanisms regulating cerebral circulation, such as the ability of neurons and endothelial cells to increase cerebral blood flow (CBF), are markedly impaired (Kunz & Iadecola, 2009). Such impairment may compromise the ability of cerebral blood vessels to compensate for the reduction in CBF in the ischaemic area by redistributing flow from adjacent vascular territories that are normally perfused (collateral circulation) (Kunz & Iadecola, 2009). We found that LPS preconditioning ameliorates the neurovascular alterations associated with focal cerebral ischaemia and increases CBF in regions of the ischaemic territory that are spared from infarction (Kunz et al. 2007). Such restoration of cerebrovascular function is not observed in mice treated with AG or in iNOS null mice, implicating iNOS in the mechanisms of the protection. Administration of preconditioning doses of LPS also increases the production of reactive oxygen species (ROS), an effect mediated by NADPH oxidase (Nox2) (Kunz et al. 2007). This observation raises the possibility that the ROS superoxide reacts with NO to form peroxynitrite, which, in turn, mediates the preconditioning effects of NO. The following observations support this hypothesis. First, Nox2-null mice are not susceptible to LPS preconditioning, attesting to the need for superoxide to induce tolerance. Second, the peroxynitrite marker 3-nitrotyrosine is upregulated in the brain parenchyma and blood vessels by LPS preconditioning, an effect that is dependent on iNOS and Nox2. Third, the peroxynitrite decomposition catalyst FeTTPS (5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III)) blocks the beneficial vascular effects of LPS and counteracts, in part, the beneficial effects of LPS preconditioning on ischaemic injury (Kunz et al. 2007). Ischaemic preconditioning induced iNOS expression and accumulation of 3-nitrotyrosine in cerebral blood vessels (Cho et al. 2005), whereas LPS preconditioning was associated with accumulation of 3-nitrotyrosine in neurons and vessels (Kunz et al. 2007). Therefore, both vascular and neuronal sources could be involved in LPS preconditioning, whereas vascular sources may predominate in preconditioning induced by cerebral ischaemia.

In a model of brain injury produced by neocortical injection of NMDA (Kawano et al. 2007), the tolerance induced by LPS was not observed in iNOS null mice, but was present in cyclooxygenase-2 (COX-2)-null mice, ruling out a role of COX-2 in the mechanisms of preconditioning. A NO donor was able to re-establish LPS tolerance in mice in which iNOS was inhibited by AG or in iNOS null mice, indicating that NO is an absolute requirement for the tolerance. Unlike early tolerance, a cGMP analogue was unable to re-establish the protection conferred by LPS preconditioning. Rather, the delayed tolerance was associated with increased 3-nitrotyrosine immunoreactivity, which was not observed in iNOS or Nox2-null mice supporting a role for peroxynitrite (Kawano et al. 2007). Accordingly, the peroxynitrite decomposition catalyst FeTTPS abolished the preconditioning effect of LPS. Therefore, peroxynitrite is involved both in the tolerance to ischaemic lesions and excitotoxicity.

These observations, collectively, suggest that LPS preconditioning induces iNOS-derived NO, which reacts with Nox2-derived superoxide to form peroxynitrite, which, in turn, is responsible for the protection (Fig. 2). The mechanisms by which peroxynitrite mediates the tissue protection remain to be elucidated, but may involve both cytoprotective and vasoprotective effects of low doses of peroxynitrite (Table 1). As discussed in section ‘Cytoprotective effects of NO’ above, NO could also be protective by additional mechanisms involving nitrosylation of nuclear proteins leading to activation of CREB-dependent transcription and expression of protective proteins (Table 1).

Figure 2. Nitric oxide in LPS-induced delayed preconditioning.

Figure 2

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NO production via the activation of iNOS by LPS results in reduced brain damage most likely through a combination of cytoprotective and vasoprotective effects. Peroxynitrite, a product of the reaction of NO with superoxide (O2·−) derived from Nox2, may lead to increased cerebral blood flow to vulnerable regions near the ischaemic territory. NO may also activate prosurvival programmes, such as the expression of CREB-dependent genes, through S-nitrosylation.

Clinical implications

The findings reviewed above highlight the essential role of NO in the tolerance induced by ischaemia or the proinflammatory mediator LPS, strongly supporting the concept that NO serves as a key inducer of preconditioning. Therefore, NO could be of clinical value in patients at high risk of ischaemic stroke. Because NO can also be damaging in cerebral ischaemia, its beneficial effects in preconditioning need to be weighed against potential deleterious effects on the ischaemic tissue. The actions of NO on the ischaemic brain are time and context dependent (Iadecola, 1997). NO is protective in the early phase after induction of ischaemia, when modulation of CBF ameliorates tissue damage, and destructive in the late phase, when the deleterious effects of NO on mitochondrial enzymes and DNA worsen the metabolic state of the tissue (Iadecola, 1997). Our data in NMDA lesions suggest that administration of NO donors 20 h prior to the ischaemic insult is beneficial (Kawano et al. 2007), but it remains unclear whether a similar timing will be effective in focal ischaemia. Furthermore, NO donors were administered after LPS, indicating that other factors induced by LPS, such as free radicals, are required to enable the preconditioning potential of NO. Studies addressing these issues would be a welcome addition to the field. The hypotensive effects of systemic administration of NO donors may be a complicating factor that also needs to be considered. Targeting NO delivery to the specific tissue and cellular compartments remains a challenge for all NO-based therapies. Perhaps, pharmacological activation of protective downstream pathways linked to NO preconditioning (Table 1) may overcome some of these difficulties. Despite these challenges, the realization that NO has a critical role in preconditioning opens new avenues in the prevention of ischaemic stroke in high risk patients, while providing valuable clues to brain protection in acute stroke.

Acknowledgments

This work was supported by NIH grants NS34179 (C.I., J.A.), NS35806 (C.I., J.A.) and AG35067 (E.F.G.), and by the Deutsche Forschungsgemeinschaft KA 2279/4-1(T.K.).

Glossary

Abbreviations

AG

aminoguanidine

BDNF

brain derived neurotrophic factor

CBF

cerebral blood flow

COX-2

cyclooxygenase-2

CREB

cyclic adenosine monophosphate response element binding

eNOS

endothelial nitric oxide synthase

ERK

extracellular-signal-regulated kinase

FeTTPS

5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III)

HDAC2

histone deacetylase 2

iNOS

inducible nitric oxide synthase

KEAP1

kelch-like ECH-associated protein 1

LPS

lipopolysaccharide

NADPH

nicotinamide adenine dinucleotide phosphate

nNOS

neuronal nitric oxide synthase

NO

nitric oxide

Nox2

NADPH oxidase 2

Nrf2

nuclear factor erythroid 2-related factor 2

PKG

protein kinase G

sGC

soluble guanylyl cyclase

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