Subarachnoid hemorrhage (SAH) is a devastating disease carrying with it a mortality of 50% within the first 30 days (30% of patients die from the impact of the initial bleeding, 10% die from re-bleeding and 10% die from delayed cerebral vasospasm). Therefore, most patients die from early brain injury after the impact of bleeding. One of the most important but un-addressed issues in SAH is the early brain neurovascular injury especially cerebral endothelial apoptosis. Endothelial apoptosis initiates blood-brain barrier (BBB) disruption leading to brain edema, which expands brain volume to increase intracranial pressure, thus decreasing cerebral blood flow, impairing cerebral perfusion and oxygenation, and causing additional ischemic brain injury. Our preliminary data from an established rat filament perforate SAH model demonstrates that apoptosis occurs in endothelial cells within 24 hours and in neural cells at 24-72 hours after SAH. This time course provides a window of opportunity for clinical intervention, if basic research can identify promising therapeutic targets. Our overall hypothesis is SAH produces apoptosis in cerebral endothelial cells by activation of distinct death pathways and prevention of apoptosis in cerebral endothelial cells will reduce brain injury.
In Specific Aim 1, we will examine the hypothesis that cerebral endothelial apoptosis enhances early brain injury which is responsible for the high mortality and morbidity after SAH; therefore, the time course of apoptosis opens a window of opportunity for clinical intervention.
In Specific Aim 2, we will examine the hypothesis that mitochondrial apoptotic pathways, especially p53- and apoptosome (Apaf-1-cytochrome C-caspase-9)- dependent pathways, are involved in endothelial apoptosis and inhibition of p53 protects BBB integrity and reduce early brain injury.
In Specific Aim 3, we will examine the hypothesis that receptor apoptotic pathways, especially TNFalpha, TNFR-1, FADD, and caspase-8, contribute to endothelial apoptosis and neurovascular protection will prevent early brain injury. The established filament perforate rat SAH model will continue to be used in these preclinical studies. We expect that our results will ultimately identify potential therapeutic targets of the apoptosis pathway for the clinical treatment of early brain injury after SAH. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroscience and Disease Study Section (CND)
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Golanov, Eugene V
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Loma Linda University
Schools of Medicine
Loma Linda
United States
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Xie, Zhiyi; Enkhjargal, Budbazar; Wu, Lingyun et al. (2018) Exendin-4 attenuates neuronal death via GLP-1R/PI3K/Akt pathway in early brain injury after subarachnoid hemorrhage in rats. Neuropharmacology 128:142-151
Fujii, Mutsumi; Sherchan, Prativa; Soejima, Yoshiteru et al. (2016) Subarachnoid Hemorrhage-Triggered Acute Hypotension Is Associated with Left Ventricular Cardiomyocyte Apoptosis in a Rat Model. Acta Neurochir Suppl 121:145-50
Lekic, Tim; Hardy, Maurice; Fujii, Mutsumi et al. (2016) Brain Volume Determination in Subarachnoid Hemorrhage Using Rats. Acta Neurochir Suppl 121:99-102
Souvenir, Rhonda; Doycheva, Desislava; Zhang, John H et al. (2015) Erythropoietin in stroke therapy: friend or foe. Curr Med Chem 22:1205-13
Chen, Sheng; Wu, Haijian; Tang, Jiping et al. (2015) Neurovascular events after subarachnoid hemorrhage: focusing on subcellular organelles. Acta Neurochir Suppl 120:39-46
Altay, Orhan; Suzuki, Hidenori; Hasegawa, Yu et al. (2014) Isoflurane on brain inflammation. Neurobiol Dis 62:365-71
Chen, Sheng; Feng, Hua; Sherchan, Prativa et al. (2014) Controversies and evolving new mechanisms in subarachnoid hemorrhage. Prog Neurobiol 115:64-91
Ma, Qingyi; Chen, Sheng; Hu, Qin et al. (2014) Reply: To PMID 24273204. Ann Neurol 75:972-973
Fujii, Mutsumi; Sherchan, Prativa; Krafft, Paul R et al. (2014) Cannabinoid type 2 receptor stimulation attenuates brain edema by reducing cerebral leukocyte infiltration following subarachnoid hemorrhage in rats. J Neurol Sci 342:101-6
Zhang, John H (2014) Vascular neural network in subarachnoid hemorrhage. Transl Stroke Res 5:423-8

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