ABSTRACT Aneurysmal subarachnoid hemorrhage (SAH) is a devastating type of hemorrhagic stroke with 50% mortality and long-term morbidity in surviving patients.1-4 Recently, the focus of SAH research has been shifted to early brain injury (EBI) which comprises the acute initial events after SAH, such as elevation of intracranial pressure (ICP), global ischemia, blood brain barrier (BBB) disruption, brain edema formation, neuronal apoptosis, activation of inflammatory and cell death pathways that contribute to delayed neurological deterioration, leading to mortality and morbidity after SAH.5-8 Pigment-epithelium derived factor (PEDF) is a pluripotent glycoprotein expressed in various tissues including the brain.9,14 PEDF reduced apoptosis in various types of cells including neurons,14,18 osteoblasts24 and cardiomyocytes.22 Likewise, PEDF reduced vascular permeability and macular edema in ophthalmologic pathologies.37,41 There have been relatively limited studies on the role of PEDF following stroke. PEDF has been shown to have protective effects on neuronal cell survival in vitro14,18 and attenuated cerebral ischemic injury in rodent models.19-21 PEDF reduced brain edema following cold-induced injury and transient cerebral ischemia in rodent models.20,21,42 However, the role of PEDF following SAH has not been explored. Furthermore, the neurovascular protective mechanisms of PEDF have not been studied. This proposal will elucidate the neurovascular protective mechanisms of PEDF through anti-apoptotic and BBB protective pathways in a rodent endovascular perforation SAH model. We will sequentially determine the role of endogenous PEDF and then evaluate the therapeutic benefits of intranasal administration of recombinant PEDF against early brain injury after SAH, specifically neuronal apoptosis and BBB disruption will be evaluated. Additionally, we will elucidate the downstream signaling pathways of PEDF receptor (PEDF-R) that contribute to anti-apoptotic and BBB protective mechanisms of PEDF. We propose that PEDF will activate PEDF-R/NPD1/Erk1/2-cRel pathway that reduces neuronal apoptosis with intranasal recombinant PEDF administration. Also, PEDF activation of the PEDF-R/Nrf2/HO-1 pathway will contribute to BBB stabilization after SAH. We will knockdown PEDF receptor and inhibit the pathways to elucidate the mechanism of PEDF-R signaling pathway mediated protection. Overall, this proposal will provide novel insights into neurovascular protective mechanisms of PEDF. Additionally, this proposal will establish the protective efficacy of intranasal administration of PEDF as a potential therapeutic target against early brain injury after SAH.