Journal
NEUROCRITICAL CARE
Volume 12, Issue 1, Pages 124-131Publisher
HUMANA PRESS INC
DOI: 10.1007/s12028-009-9277-x
Keywords
Aquaporins; Stroke; Focal cerebral ischemia; Infarct; Cerebral edema; Arginine-vasopressin
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Funding
- Public Health Service NIH [NS046379]
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Background Aquaporin-4 (AQP4) plays an important role in the evolution of ischemia-evoked cerebral edema. Experimental studies have also demonstrated anti-edema effects of arginine-vasopressin (AVP) antagonists. In a well-characterized murine model of ischemic stroke, we tested the hypotheses that treatment with selective AVP V-1 but not V-2 receptor antagonist (1) attenuates injury volume and ischemia-evoked cerebral edema; and (2) modulates ischemia-evoked AQP4 expression. Methods Isoflurane-anesthetized adult male C57bl/6 mice were subjected to 60 min of middle cerebral artery occlusion (MCAO) by the intraluminal suture technique. Adequacy of MCAO and reperfusion was monitored with laser-Doppler flowmetry over the ipsilateral parietal cortex. Mice were treated with intracerebroventricular injection of selective AVP V-1 and V-2 receptor antagonist or control vehicle (0.9% saline). Infarct volume (tetrazolium staining), cerebral edema (wet-to-dry ratios) and AQP4 protein expression (immunoblotting) were determined in different treatment groups in separate sets of experiments at 24 h of reperfusion. Results Infarct volume (percentage of contralateral structure; mean +/- SEM) was significantly attenuated in mice treated with 500 ng V-1 receptor antagonist as well as at a dose of 1000 ng compared to controls. However, there was no difference in infarct volume following treatment with 1000 ng V-2 antagonist as compared to controls. Water content in the ischemic hemisphere was significantly attenuated with V-1 receptor antagonist (1000 ng) but not with V-2 receptor antagonist as compared to controls. Treatment with AVP V-1 receptor antagonist (1000 ng) but not V-2 receptor antagonist, significantly upregulated AQP4 protein expression (% beta-actin) compared to saline-treated mice in ipsilateral (ischemic) cerebral cortex. Conclusions These data demonstrate that following experimental stroke AVP V-1 receptor antagonism: (1) attenuates injury volume and ischemia-evoked cerebral edema; (2) modulates AQP4 expression; and (3) may serve as an important therapeutic target for neuroprotection and ischemia-evoked cerebral edema.
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