Is carbon monoxide sufficient to reduce delayed cerebral ischemia and provide neuroprotection after SAH?

SAH is a serious medical condition that is caused by bleeding into the subarachnoid space. One-third of the patients who suffer from SAH survive with good recovery, whereas one-third survives with a disability, and one-third dies. The treatment of SAH focuses on stopping the bleeding, maintaining normal blood flow, mitigating vasospasm, relieving the pressure, and preventing neuronal cell death. This project focuses on the preclinical development of a novel, effective, and noninvasive therapeutic strategy using low-dose carbon monoxide (CO) or a CO-donor, ie CO-releasing molecule 401 (CORM401) for SAH treatment. We and others have shown that CO can be neuroprotective at low doses through anti-inflammatory, anti-apoptotic, and vasodilation effects. Previously, my mentor's lab also discovered that CO is sufficient to decrease infarct size in ischemic stroke via regulation of the master antioxidant switch Nrf2. The lab was also the first to demonstrate the powerful protective nature of downstream pathway of Nrf2, notably by inducing numerous antioxidant enzymes and multitude of cytoprotective proteins. AIM 1: First, to replicate whether CO is protective at 250ppm and then determine whether CORM401 will alleviate SAH-induced vasospasm and other anatomical/functional outcomes. We will establish the optimal doses and therapeutic window for CO (vs air control) and CORM401 (vs inactive iCORM401 control) treatment using the first primary outcomes as neurobehavioral, and secondary as vasospasm and other anatomical outcomes. It should indicate whether CO/CORM401 would be sufficient to protect and decrease vasospasm, early brain injury, iron overload, microglial activation, and neuronal death, etc. AIM 2: To determine whether the beneficial effects of CO/CORM401 are attenuated in Nrf2 knockout mice compared to wildtype littermates. To investigate the role of Nrf2 in SAH-induced neurological/neurocognitive deficits, and anatomical changes in the neuroprotective mechanism of CO and the CORM401. Together, we will be able to test the efficacy of CO/CORM401 and test whether or not Nrf2 would be part of the neuroprotective pathway. I know I will learn tremendously from this hypothesis-driven proposal. This is the best team/environment that allows me to further advance my passion for academic research. This will provide for me the stepping-stone to continue to gather new data and publish papers, such that I can then be competitive for an independent research career. (AHA Program: Postdoctoral Fellowship)