Files
Abstract
Although the National Institutes of Health and American Heart Association (AHA) have committed millions of dollars in research funding over decades, with AHA funding 838 new research endeavors worth more than $188.7 million in 2018-2019 alone, only two Food and Drug Administration (FDA)-approved therapies are available to stroke patients. Recently, transplanted induced pluripotent stem cell-derived neural stem cells (iNSCs) have shown particular therapeutic promise as these cells led to decreased ischemic lesion volumes and improvements in behavioral and sensorimotor functions by integrating into host neural circuitry and secreting trophic factors, thus replacing lost neural tissue and promoting endogenous protective pathways. To facilitate these effects, administration of a neuroprotectant agent prior to iNSC transplantation may be warranted to quail the cytotoxic stroke environment leading to increased cell survival and engraftment. Tanshinone IIA (Tan IIA) treatment has shown both antioxidative and anti-inflammatory effects in stroke and limits blood-brain barrier breakdown leading to improved outcomes in rodent models and human patients. An alternative agent, neural stem cell-derived extracellular vesicles (NSC EVs), may also ameliorate the secondary injury cascade by modifying the activation of microglia and the release of inflammatory cytokines through the transfer of microRNAs and proteins. Individually, these neuroprotective agents have induced reductions in lesion size, hemorrhage, white matter damage, and functional deficits. However, further investigation in a large animal model with comparable anatomy and physiology to humans is warranted. Preclinical testing in a pig model may provide critical insight into iNSC, Tan IIA, and NSC EV therapeutic efficacy to determine if these treatments are suitable for translation into human clinical trials.