SIRT1 Activation

BBB: blood–brain barrier DCI: delayed cerebral ischemia DMH: dorsomedial EBI: early brain injury Enos: endothelial nitric oxide synthase FOXO1: Forkhead box O1 FOXO3: Forkhead box O3; HIF-1α: hypoxia-inducible factor 1alpha LH: lateral hypothalamic MMP-9: metalloproteinase-9 Nkx2-1: Nk2 homeobox NPCs: neural progenitor cells NSCs: neural stem cells SAH: subarachnoid haemorrhage SIRT1: Sirtuin 1 SECONDARY BRAIN INJURY AFTER SUBARACHNOID HEMORRHAGE Aneurysmal subarachnoid hemorrhage (SAH) affects nearly 30 000 Americans every year and survivors experience significant morbidity, with nearly a third of them becoming functionally dependent. The 2 principal contributors to poor outcome after SAH are early brain injury (EBI) and delayed cerebral ischemia (DCI). EBI is initiated by the acute increase in intracranial pressure and consequent transient global cerebral ischemia that occurs after aneurysm rupture, and typically manifests in the first 72 h after ictus.1 EBI is characterized by neuroinflammation, blood–brain barrier (BBB) breakdown, cerebral edema, and early neuronal cell death. DCI is multifactorial in etiology with large artery vasospasm being the primary contributor and other pathophysiological events including microvessel autoregulatory dysfunction, microvessel thrombosis, and neuroinflammation being significant contributors.2-5 DCI typically occurs 4 to 14 d after ictus, and is characterized by delayed neurological decline with or without radiographic evidence of cerebral infarction.5 Due to the stereotypical delay between ictus and DCI, a window of opportunity exists to institute a therapeutic intervention that can ameliorate the effects of DCI, or even prevent the occurrence of DCI. Given the multifactorial etiology of DCI, a therapeutic strategy that influences several of these etiological factors is needed to combat DCI and consequently improve outcome after SAH. ENDOGENOUS NEUROPROTECTION Cells and tissues possess an innate ability to resist injury. The innate protective mechanisms can be activated by a process referred to as conditioning, wherein a sub-lethal quantity of a normally injurious stimulus is administered in a controlled manner.6 The activated endogenous protective mechanisms reduce the severity of subsequent injuries and enhance reparative processes. This protective phenotype is achieved through a cascade of conditioning stimulus-induced cellular changes involving molecular sensors, transducers, and effectors that produces a coordinated response at the genomic, molecular, cellular, tissue, and organ levels.7 In the central nervous system, conditioning-induced protection is mediated through changes occurring in neurons, glia, and cerebral vasculature. ROLE OF ENDOGENOUS NEUROPROTECTION IN SAH For a variety of reasons, DCI after SAH represents an ideal pathology for application of a conditioning-based strategy. First, despite decades of extensive research the incidence of DCI remains unacceptably high and there are no effective therapies to reduce the morbidity resulting from DCI, thereby creating the need for an unconventional approach to combat the problem. Second, the stereotypical delay between the ictus and onset of DCI provides a window of opportunity to intervene with a conditioning based stimulus. Third, the multifaceted protection afforded by conditioning can be leveraged to target the multiple etiological factors contributing to DCI. While prior review articles have suggested the suitability of SAH for application of a conditioning strategy,8,9 our group provided the first experimental evidence demonstrating the protective effect of conditioning against DCI after SAH.10 We demonstrated that a conditioning stimulus of hypoxia (8% oxygen for 4 h) administered to mice prior to experimental SAH provides robust protection against SAH-induced vasospasm and neurological dysfunction. Furthermore, our study also began unraveling the molecular mechanisms underlying conditioning induced protection and demonstrated that the protective effect of conditioning against SAH-induced DCI is mediated by activation of endothelial nitric oxide synthase (eNOS).10 In order to translate a conditioning strategy to clinical use in SAH patients, it is imperative to develop a conditioning stimulus or pharmacological agent that can activate innate protective mechanisms and target the various etiological factors implicated in the development of DCI, can be administered to humans, and is effective when administered after ictus. As an initial step towards this goal, our group subsequently demonstrated that conditioning with isoflurane, an inhalational anesthetic, administered at clinically relevant time points after SAH attenuated multiple components of DCI including cerebral vasospasm, microvessel thrombosis, and microvessel dysfunction, and improved neurological outcome after experimental SAH.11 In that study, isoflurane conditioning-induced protection was found to be critically dependent on vascular endothelial hypoxia-inducible factor 1alpha (HIF-1α). However, administration of repetitive conditioning stimuli of isoflurane to SAH patients in an intensive care unit is practically difficult, thereby limiting its immediate translational potential. Simultaneously, Gonzalez and colleagues12 examined remote ischemic limb preconditioning in SAH patients. Remote ischemic conditioning is a strategy wherein administration of a sub-lethal ischemic stimulus at one site confers protection against subsequent ischemia at a distal site. Their work has demonstrated that repetitive lower limb ischemic preconditioning is safe and largely well-tolerated in SAH patients.12 Preliminary results from their work also suggest a positive effect of repetitive lower limb ischemic preconditioning on functional outcomes after SAH.13 However, completion of a repetitive limb ischemic preconditioning protocol in the window of opportunity before the onset of DCI can be challenging and could limit its clinical utility,