Project Details

Stem cells in addition to hypothermia for neuroprotection in perinatal hypoxic-ischemic brain injury

Janessa Law, MD

Summary

BACKGROUND: Perinatal hypoxic ischemic encephalopathy (HIE) is due to the often unpredictable and unpreventable loss of blood and oxygen supply to neonatal brain around the time of delivery resulting in diffuse brain injury. GAP: Therapeutic hypothermia (HT) is the current standard of care for HIE. Prior work demonstrates that human neural stem cells (hNSCs) salvage injured brain tissue leading to improved imaging, histologic, and behavioral outcomes in a rodent model of HIE. We suggest that combining HT and hNSC therapies is feasible and must be completed prior to progression to human studies. HYPOTHESIS: We hypothesize that hNSCs will work synergistically with HT by providing neuroprotection via different yet complementary mechanisms to improve imaging, histologic, and behavioral outcomes in a rodent model of HIE. METHODS: To approximate a term human neonate, developmentally equivalent ten day old rat pups were subjected to HIE via unilateral common carotid artery occlusion followed by hypoxia. We assessed the effect of hNSCs transplantation 3 days following hypoxic ischemic brain injury treated with either normothermia or HT (the current standard of care). Anatomic brain injury and standardized behavioral outcomes at 1 month after injury were evaluated. RESULTS: Seventy-seven rats survived to behavioral testing and sacrifice following HIE with or without HT; n=38 (49%) were treated with saline and n=39 (51%) received hNSC transplantation. There was no difference in early MRI percent injury in either group (p=0.45). Animals treated with hNSCs had lower brain gross injury scores at P43 (p= 0.04), spent less time in the corners of the open field (p=0.03), had a lower novel object recognition discrimination index (p=0.03) and a higher recognition index (p=0.02), and had more paw contact are (p=0.0002) than saline-treated animals. IMPACT: hNSCs provide hypoxic-ischemic injury neuroprotection as evidenced by decreased gross brain injury and improved behavioral outcomes relative to saline-treated animals. This study provides concrete groundwork for a future clinical trial employing hNSCs for neuroprotection against perinatal HIE.

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