Cerebral edema associated with large hemispheric infarctions is frequently encountered in clinical practice and is a major cause of morbidity and mortality. Clinically, osmotherapy is the mainstay of medical management of cerebral edema associated with ischemic stroke. While mannitol has been the conventional osmotic agent of choice, its therapeutic efficacy is limited by several untoward side effects. A few experimental studies and clinical case series suggest that hypertonic saline (HS) is efficacious in the treatment of cerebral edema in some brain injury paradigms, but its effects in ischemic stroke are not well studied. The overall goal of this research proposal is to test the hypotheses that institution and maintenance of a hyper-osmolar state with HS is an important treatment of cerebral edema following experimental ischemic stroke. We will further utilize HS as a tool to delineate the complex interactions of aquaporins and ariginine-vasopressin (A VP) in the pathogenesis of ischemia-evoked cerebral edema.
In Aim 1, we will define the most efficacious treatment paradigm with HS for cerebral edema following transient as well as permanent middle cerebral artery occlusion (MCAO). We will discern the optimal serum osmolality necessary for ameliorating cerebral edema and test the hypothesis, utilizing magnetic resonance imaging in vivo, that treatment duration, timing of withdrawal from therapy and integrity of the blood brain barrier determine anti-edema efficacy of HS in focal cerebral ischemia.
Aim 2 will test the hypothesis that amelioration in brain edema with HS occurs via modulation of AQP4 in injured and contralateral non-ischemic brain following MCAO. We will determine if systemic osmolar changes a) alter 3erivascular localization of AQP4 in the brain and b) alter the evolution (rate and degree) of cerebral edema following MCAO in mice lacking alpha-syntrophin (alpha-syn -/-) (a component of the dystrophin protein complex required for perivascular localization of AQP4) as compared to wild type (WT) mice.
Aim 3 will determine if AVP release plays a significant role in ischemia-induced cerebral edema and test the hypothesis that it serves as an important link in how HS attenuates brain edema via alterations in AQP4 following focal ischemia. Specifically, we will determine if plasma and brain AVP levels are a) modulated by changes in systemic osmolality with HS treatment, and b) are attenuated in alpha-syn -/-mice as compared to WT mice following focal cerebral ischemia. These studies 1) have important translational significance for treatment of cerebral edema in patients with large cerebral infarctions, 2) will enhance our understanding of the complex mechanisms of edema formation following ischemic stroke, and 3) provide insights into potential newer therapeutic targets and strategies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CDIN (01))
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Jacobs, Tom P
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Oregon Health and Science University
Schools of Medicine
United States
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Nakayama, Shin; Migliati, Elton; Amiry-Moghaddam, Mahmood et al. (2016) Osmotherapy With Hypertonic Saline Attenuates Global Cerebral Edema Following Experimental Cardiac Arrest via Perivascular Pool of Aquaporin-4. Crit Care Med 44:e702-10
Yang, Sufang; Abrahams, Matthew S; Hurn, Patricia D et al. (2011) Local anesthetic Schwann cell toxicity is time and concentration dependent. Reg Anesth Pain Med 36:444-51
Liu, Xiaoqin; Nakayama, Shin; Amiry-Moghaddam, Mahmood et al. (2010) Arginine-vasopressin V1 but not V2 receptor antagonism modulates infarct volume, brain water content, and aquaporin-4 expression following experimental stroke. Neurocrit Care 12:124-31
Yang, Sufang; Alkayed, Nabil J; Hurn, Patricia D et al. (2009) Cyclic adenosine monophosphate response element-binding protein phosphorylation and neuroprotection by 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP). Anesth Analg 108:964-70
Zeynalov, Emil; Chen, Chih-Hung; Froehner, Stanley C et al. (2008) The perivascular pool of aquaporin-4 mediates the effect of osmotherapy in postischemic cerebral edema. Crit Care Med 36:2634-40
Liu, Xiaoqin; Zhang, Wenri; Alkayed, Nabil J et al. (2008) Lack of sex-linked differences in cerebral edema and aquaporin-4 expression after experimental stroke. J Cereb Blood Flow Metab 28:1898-906
Liu, Kenneth C; Bhardwaj, Anish (2007) Use of prophylactic anticonvulsants in neurologic critical care: a critical appraisal. Neurocrit Care 7:175-84
Yang, Sufang; Bhardwaj, Anish; Cheng, Jian et al. (2007) Sigma receptor agonists provide neuroprotection in vitro by preserving bcl-2. Anesth Analg 104:1179-84, tables of contents
Bhardwaj, Anish (2007) Osmotherapy in neurocritical care. Curr Neurol Neurosci Rep 7:513-21
Chen, Chih-Hung; Xue, Rong; Zhang, Jiangyang et al. (2007) Effect of osmotherapy with hypertonic saline on regional cerebral edema following experimental stroke: a study utilizing magnetic resonance imaging. Neurocrit Care 7:92-100

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