Molecular mechanisms underlying isoflurane conditioning-induced neurovascular protection in subarachnoid hemorrhage

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Abstract/Project Summary: Dr. Umeshkumar Athiraman MD, is a neuroscientist and neuroanesthesiologist with the long-term goal to be an independent investigator focused on understanding the underlying mechanisms of anesthetic conditioning- induced neurovascular protection, development of anesthetic conditioning-based therapeutics for aneurysmal subarachnoid hemorrhage (SAH), and later application of these insights to other forms of brain injury. Dr. Athiraman is a member of Dr. Zipfel’s lab in the Department of Neurosurgery at Washington University in Saint Louis. The lab, department, and the university provide an exceptional training environment. Dr. Athiraman will receive training in the Zipfel lab in SAH animal models, immunohistochemistry, molecular biology techniques and assessment of short and long-term neurobehavioral outcomes after SAH. He will also receive training in optical imaging for functional connectivity assessment in the lab of collaborator, Dr. Adam Bauer. Additional support and mentorship will be provided by the applicant’s host department of anesthesiology. SAH is a severe type of hemorrhagic stroke with extremely high morbidity and mortality. Apart from the initial hemorrhage severity, secondary brain injury due to delayed cerebral ischemia (DCI) plays a significant role in patient outcomes after SAH. While many strategies to combat DCI have been developed in preclinical studies and tested in late phase clinical trials, none have proven efficacious for improving long-term functional outcome. The causes of these failures are likely multitude, but include use of therapies targeting only one element of what has proven to be multifactorial brain injury process. The proposed project examines the impact of a therapy known to have powerful, multifaceted protective effects on DCI after SAH called as – conditioning (anesthetic). Preliminary data shows that isoflurane conditioning provides robust protection against SAH-induced DCI and that this protection is likely mediated via inhibition of two critical molecules – NF-kB and iNOS. The planned experiments will rigorously test the following hypothesis through targeted genetic and pharmacological interventions: 1) Inhibition of NF-kB underlies the DCI protection afforded by isoflurane conditioning; 2) Inhibition of iNOS (a key downstream target of NF-kB) underlies the DCI protection afforded by isoflurane conditioning; and 3) Drugs that mimic the molecular effects of isoflurane conditioning (NF-kB inhibitor, PDTC-pyrrolidine dithiocarbamate; and iNOS inhibitor, 1400W) provide long-term protection against neurobehavioral and functional connectivity deficits after SAH. The results of these experiments will fundamentally establish NF-kB/iNOS pathway inhibition as the key inducer of isoflurane conditioning-induced DCI protection in SAH and identify NF-kB/iNOS inhibition as a promising new therapeutic strategy for SAH. The proposed plan will provide Dr. Athiraman with the training, mentorship and experience to transition to independence in a timely manner and obtain R01 funding.