The perivascular pool of aquaporin-4 mediates the effect of osmotherapy in postischemic cerebral edema

OBJECTIVE: Osmotherapy with hypertonic saline ameliorates cerebral edema associated with experimental ischemic stroke. We tested the hypothesis that hypertonic saline exerts its antiedema effect by promoting an efflux of water from brain via the perivascular aquaporin-4 pool. We used mice with targeted disruption of the gene encoding α-syntrophin (α-Syn) that lack the perivascular aquaporin-4 pool but retain the endothelial pool of this protein. DESIGN: Prospective laboratory animal study. SETTING: Research laboratory in a university teaching hospital. MEASUREMENTS AND MAIN RESULTS: Halothane-anesthetized adult male wildtype C57B/6 and α-Syn mice were subjected to 90 min of transient middle cerebral artery occlusion and treated with either a continuous intravenous infusion of 0.9% saline or 3% hypertonic saline (1.5 mL/kg/hr) for 48 hr. In the first series of experiments (n = 59), increased brain water content analyzed by wet-to-dry ratios in the ischemic hemisphere of wildtype mice was attenuated after hypertonic saline (79.9% ± 0.5%; mean ± sem) but not after 0.9% saline (82.3% ± 1.0%) treatment. In contrast in α-Syn mice, hypertonic saline had no effect on the postischemic edema (hypertonic saline: 80.3% ± 0.7%; 0.9% saline: 80.3% ± 0.4%). In the second series of experiments (n = 32), treatment with hypertonic saline attenuated postischemic blood-brain barrier disruption at 48 hr in wildtype mice but not in α-Syn mice; α-Syn deletion alone had no effect on blood-brain barrier integrity. In the third series of experiments (n = 34), α-Syn mice treated with either hypertonic saline or 0.9% saline had smaller infarct volume as compared with their wildtype counterparts. CONCLUSIONS: These data demonstrate that 1) osmotherapy with hypertonic saline exerts antiedema effects via the perivascular pool of aquaporin-4, 2) hypertonic saline attenuates blood-brain barrier disruption depending on the presence of perivascular aquaporin-4, and 3) deletion of the perivascular pool of aquaporin-4 alleviates tissue damage after stroke, in mice subjected to osmotherapy and in nontreated mice.