Article
The selective vasopressin 1a receptor antagonist SR49059 attenuates cytotoxic brain edema formation by AQP4 modulation
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Published: | May 20, 2009 |
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Objective: Aquaporin (AQP) 4 is a brain water channel involved in water regulation although their exact contribution to brain edema formation remains unclear. Vasopressin acts on V1a receptors, present in the choroid plexus and perivascular glial cells, and may be involved in AQP4 regulation. Utilizing two different models of brain edema formation, we examined the effect of the V1a antagonist SR49059 on cytotoxic, intracellular or vasogenic, extracellular edema and on AQP4 expression.
Methods: Male rats were randomly assigned to continuous intravenous vehicle (1% DMSO) or SR49059 (1mg/kg) infusion starting 60min before either cortical contusion injury plus hypoxia and hypotension (CCI+HH, n=12) or middle cerebral artery occlusion for 2hr (MCAO, n=8). Rats were sacrificed after 4hr for gravimetrical measurement of brain water content in different brain regions. Following MCAO, AQP4 expression was quantified in corresponding brain regions by immunoblotting and optical densitometry (n=8). Statistical analysis was performed by an analysis of variance.
Results: Following CCI+HH, SR049059 reduced brain edema in the injured and non-injured cortex (p=0.0.02 and p=0.01), but had no effect on the injured white matter. After MCAO, SR049059 decreased brain edema in the ischemic cortex and white matter (p=0.017 and p=0.013) as well as AQP expression in the ischemic cortex (p<0.05).
Conclusions: The findings imply that the V1a antagonist SR49059 reduces cytotoxic brain edema following MCAO by AQP4 modulation. While the early vasogenic edema following CCI was not affected, SR49059 may attenuate brain edema resulting from secondary insults. Thus, we provide evidence that AQP4 modulation by a vasopressin 1a antagonist may offer a new treatment avenue in cytotoxic brain edema.