Abstract TMP114: Modulation Of P75ntr Improves Neuroprotection Following Ischemic Stroke

Abstract

Background: Stroke is a serious cause of mortality in the United States. Tissue plasminogen activator (tPA) is the only effective drug. However, it increases the risk of cerebral hemorrhage due to its narrow therapeutic window. Previous studies have shown the role of neurotrophins in several brain diseases. P75 NTR which is the receptor of tumor necrosis family is highly expressed in stroke and associated with neuronal apoptosis. Downregulation of p75 NTR attenuates brain injury. This study aims to find the role of p75 NTR in the outcome of stroke. Methods: Two different sets of experiments were performed. 1. Young adult C57BL/6 mice were subjected to ischemic stroke using intraluminal suture model. P75 NTR modulator (LM11A-31) was administered following stroke. Brain samples were collected 24 hours after injury. 2. Young adult C57BL/6 and p75 heterozygous mice were subjected to stroke using Rose Bengal photothrombotic method. Mice were tested for neurobehavioral analysis and samples were collected 72h after stroke. Results: We found that administration of LM11A-31 significantly reduced infarction volume, edema, and hemorrhagic transformation 24h after stroke in mice. Also, LM11A-31 reduced several inflammatory markers including tumor necrosis factor- alpha (TNF-α), nuclear factor kappa-light-chain (p-NFκb/t-NFκb), and c- Jun N-terminal kinases (p-JNK/t-JNK), and significantly increased the expression of several anti-inflammatory signaling, including protein kinase B (p-Akt/t-Akt) and extracellular signal-regulated kinase ½ (p-ERK1/2/t-ERK1/2) after stroke. Furthermore, we found that p75 NTR heterozygous mice remarkably demonstrated less infarction, edema, and hemorrhagic transformation than wild-type mice after stroke. Moreover, p75 NTR heterozygous significantly showed better motor function. Conclusion: This study suggests that p75 NTR modulation can be a potential pharmacological target for improving the outcome of ischemic stroke.