Aneurysmal subarachnoid hemorrhage (SAH) is a highly morbid condition - much of which is due to delayed cerebral ischemia (DCI), which is caused by a combination of large-artery vasospasm and microcirculatory deficits including autoregulatory dysfunction, microvascular thrombosis, and blood-brain- barrier (BBB) breakdown. Conditioning refers to the phenomenon whereby exposure of the brain to a sub- lethal stimulus renders it more resistant to a subsequent lethal stimulus. Most have examined the protective effects of conditioning on neurons, but we and others have established that the cerebral vessels are also a target. Given that DCI is caused by wide-ranging vascular deficits (from large arteries to the microcirculation) and that conditioning appears capable of preventing these deficits, a conditioning- based therapeutic strategy applied to SAH holds great promise. In our past study, we showed that powerful endogenous protective mechanisms against DCI exist, can be induced by a conditioning stimulus (brief hypoxia prior to SAH; termed hypoxic preconditioning or HPreC), and are dependent on endothelial nitric oxide synthase (eNOS). In a pilot study, we show that the same stimulus (hypoxia) when initiated at a clinically relevant time point (3h after SAH; termed hypoxic postconditioning or HPostC) provides similarly strong DCI protection. The molecular inducer(s) of this protection, however, are unknown. We believe sirtuin1 (SIRT1) is a key inducer, as hypoxia augments SIRT1 expression, HPreC-induced DCI protection is lost with the SIRT1 inhibitor EX527, and the SIRT1 activator resveratrol mimics the DCI protection afforded by HPreC and HPostC. The long-term goal of our project is to test the hypotheses that HPostC induces robust and multifaceted DCI protection, SIRT1 is a key inducer of this protection, and SIRT1 activation is a novel strategy for SAH that has exceptional translational potential.
The Specific Aims are 1) Determine the breadth and sustainability of HPostC-induced DCI protection; 2) Test whether SIRT1 is a key inducer of HPostC-induced DCI protection; and 3) Determine the translational potential of SIRT1 activation in SAH. Methods used include: a) assessment of SIRT1, eNOS, MMP-9, TIMP-1, and TF expression and activity; b) assessment of SAH-induced vasospasm, microcirculatory deficits (autoregulatory impairment, microvessel thrombosis, and BBB breakdown), and neurological deficits in mice; c) assessment of SAH-induced vasospasm, microcirculatory deficits, neurological deficits, neuronal cell death, and long-term neurobehavioral deficits in rats; d) pharmacologic and genetic inhibition of SIRT1; and g) pharmacologic and genetic augmentation of SIRT1. If successful, these studies will result in an improved understanding of the breadth, mechanism, and sustainability of HPostC-induced neurovascular protection in SAH, will identify SIRT1 as a novel and druggable therapeutic target for DCI, will determine the translatability of SIRT1-directed therapeutics for DCI, and will identify CSF and serum biomarkers that can be used to directly test for pharmacodynamic efficacy in future human studies.
Translating Endogenous Vascular Protective Cascades into Therapy for Aneurysmal Subarachnoid Hemorrhage Relevance The largest treatable cause of poor outcome after brain aneurysm rupture (termed subarachnoid hemorrhage or SAH) is delayed cerebral ischemia (DCI). In the present proposal, we plan to capitalize on the body's innate protective machinery to resist injury (a phenomenon called 'conditioning') to combat DCI. In particular, we will test a novel conditioning-based therapy (SIRT1 activation), which if successful will establish SIRT1-directed drugs as a new and promising treatment for patients with ruptured brain aneurysms.
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