Neuroprotection in ischemic stroke: AhR we making progress?

Abstract

HomeCirculationVol. 130, No. 23Neuroprotection in Ischemic Stroke Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBNeuroprotection in Ischemic StrokeAhR We Making Progress? Arun Padmanabhan, MD, PhD and Saptarsi M. Haldar, MD Arun PadmanabhanArun Padmanabhan From the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (A.P.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH (S.M.H.). Search for more papers by this author and Saptarsi M. HaldarSaptarsi M. Haldar From the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (A.P.); Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH (S.M.H.); and Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH (S.M.H.). Search for more papers by this author Originally published30 Oct 2014https://doi.org/10.1161/CIRCULATIONAHA.114.013533Circulation. 2014;130:2002–2004Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: December 2, 2014: Previous Version 1 Cerebrovascular accidents, more commonly referred to as strokes, remain the second most common cause of mortality and the third most common cause of disability worldwide.1 It has been estimated that more than three quarters of all strokes in the United States are attributable to ischemia, with the remainder principally related to intracranial hemorrhage.2,3 Although our attempts to address modifiable risk factors for stroke have decreased the incidence of stroke, stroke-related death and disability are increasing at concerning rates.4,5 These observations lie in stark contrast to contemporary metrics for acute myocardial infarction, for which both short-term mortality and long-term mortality have been decreasing over the past 30 years,6,7 concomitant with the increasing use of prompt reperfusion strategies, including primary percutaneous coronary intervention. The cell types affected in the context of stroke and myocardial infarction (neurons and cardiomyocytes, respectively) are similar in that both are terminally differentiated cells that are exquisitely sensitive to ischemic insults. Following the adage that “time is brain” in the setting of acute ischemic stroke, the benefit of restoring blood flow with thrombolytic therapy decreases in a continuous fashion over time, with studies demonstrating that each 15-minute delay in the time to initiation of therapy is associated with reduced odds of independent ambulation and survival.8,9 However, compared with coronary revascularization, the temporal window for safe and effective cerebral reperfusion therapy is exceedingly narrow and complicated by the challenges associated with identifying stroke symptoms and obtaining rapid neuroimaging, issues that can further delay rapid triage and initiation of treatment. Therefore, a huge unmet need remains for the development of novel therapeutic strategies for ischemic neuroprotection to improve outcomes in acute stroke. Toward that end, elucidating the precise molecular mechanisms that govern neuronal susceptibility to ischemia is a critical step in identifying pathways that may ultimately be amenable to pharmacological manipulation for patients with stroke.Article see p 2040In this issue of Circulation, Cuartero et al10 use mouse models of stroke to demonstrate that a signaling pathway involving the tryptophan metabolite L-kynurenine (L-kyn) and the aryl hydrocarbon receptor (AhR) is an important mediator of ischemic neuronal damage that can be pharmacologically manipulated in vivo. AhR is a member of the Per-Arnt-Sim family of basic helix-loop-helix transcription factors that are activated by a range of structurally divergent ligands, including environmental pollutants (eg, dioxins) and the endogenous tryptophan catabolite L-kyn.11,12 AhR is normally inactive under basal conditions and retained in the cellular cytoplasm bound to several chaperone proteins. On ligand binding, AhR translocates to the nucleus and heterodimerizes with the AhR nuclear translocator to bind DNA and to alter gene expression.13 Endogenous AhR signaling has been shown to play important roles in cardiovascular development and physiology and in the modulation of inflammatory signals.14,15 Previous work has also demonstrated that ablation of AhR results in enhancement of ischemia-induced angiogenesis.16 As noted above, L-kyn (a byproduct of the tryptophan-degrading tryptophan-2,3-dioxygenase [TDO] enzyme) was recently discovered to be an endogenous AhR ligand that plays important roles in cancer pathobiology and immune activation.12From this rationale, Cuartero et al used in vitro and in vivo models to test the hypothesis that the L-Kyn–AhR signaling pathway potentiates acute ischemic brain injury. They found that AhR protein abundance, nuclear translocation, and transcriptional activity in cortical neurons are increased in a mouse model of stroke induced by middle cerebral artery occlusion (MCAO). Using pharmacological AhR inhibitors and activators and mice with genetic Ahr deficiency, they demonstrate that AhR is an important mediator of acute ischemic damage during MCAO. Mechanistic studies suggest that AhR activation during ischemia may mediate certain pathological effects via inhibition of cAMP response element binding protein signaling. The authors go on to demonstrate that L-kyn accumulates in the brain during acute ischemia where it functions as an endogenous activator of AhR. Exogenously administered L-kyn exacerbates stroke, as assessed by infarct volume, in an AhR-dependent fashion. Perhaps most intriguingly, the authors also demonstrate that inhibition of L-kyn production via pharmacological blockade of TDO decreased AhR activation and reduced infarct volume after MCAO. Taken together, these studies implicate the L-Kyn–AhR pathway as a novel mediator of brain damage during stroke and identify TDO and AhR as new “druggable” targets in this disease (Figure).Download figureDownload PowerPointFigure. The L-kynurenine–aryl hydrocarbon receptor (L-Kyn–AhR) signaling pathway mediates neuronal susceptibility to ischemia. Using the middle cerebral artery occlusion mouse model of stroke, Cuartero et al10 demonstrate that genetic Ahr deficiency, pharmacological AhR inhibition, and inhibition of L-Kyn production (via pharmacological inhibition of tryptophan-2,3-dioxygenase [TDO]) all confer ischemic neuroprotection (left). Right, A mechanistic framework for the present findings. CREB indicates cAMP response element binding protein.The work of Cuartero and colleagues raises a number of interesting questions that have important translational implications for cerebrovascular disease. First, although the authors demonstrate that L-Kyn functions as an endogenous activator of AhR, they also find increased protein abundance of AhR during ischemia. Are these additional mechanisms governing AhR accumulation potential targets for ischemic neuroprotection? Second, this study uses systemic delivery of L-Kyn or TDO inhibitors in the MCAO model of stroke. It will be important to understand which cell types are responsible for producing L-kyn during cerebral ischemia because a significant quantity of this metabolite is produced by the liver. Mouse models harboring a conditional allele of TDO may prove useful in this regard. Given the link among tryptophan metabolism, AhR, and immune cell activation,12 the current observations in the brain raise the possibility that similar pathways may be involved in other cardiovascular conditions (eg, atherogenesis, myocardial infarction, heart failure) or neurodegenerative disorders (eg, Alzheimer disease). Third, what pathways downstream of AhR are responsible for mediating ischemia-induced neurotoxicity? Although repression of cAMP response element binding protein signaling is certainly plausible, AhR may well be working through multiple mechanisms. Unbiased approaches to identify AhR-mediated effects in neurons, coupled with studies of neuron-specific AhR deletion, will be particularly informative. This work also begs the epidemiological question of whether environmental dioxin exposure contributes to stroke risk. Studies of individuals exposed to agent orange, a herbicide used extensively during the Vietnam War and known to be contaminated with the dioxin 2,3,7,8-tetrachlorodibenzodioxin, may be informative in this context. Finally, apart from L-kyn, are there other as-yet uncharacterized endogenous or exogenous AhR ligands that confer stroke risk? Conversely, are there any endogenous inhibitors of the AhR pathway? Future work that builds on the index observations of Cuartero and colleagues may elucidate additional therapeutic strategies for the prevention and treatment of stroke.Providers caring for patients suffering from acute stroke are rarely afforded the opportunity to intervene immediately after the onset of ischemia. Although this study provides proof of principle that early inhibition of the L-Kyn–AhR axis confers neuroprotection in the setting of ischemic stroke, the most pressing question that arises is whether pathway blockade at a later time point remains efficacious. Furthermore, how does manipulation of this pathway interact with reperfusion therapies, and could this strategy potentially expand the relatively limited window during which cerebral revascularization is effective? Ultimately, the questions of whether such observations in mouse models such as MCAO eventually translate to larger mammals or humans remain a major challenge for the field.17 Despite these long-term hurdles, this work represents an exciting new inroad for the development of novel neuroprotective strategies and suggests that we are indeed making progress.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Saptarsi M. Haldar, MD, Case Western Reserve University School of Medicine, 2103 Cornell Rd, Room 4-525, Cleveland, OH 44106. E-mail [email protected]