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 alpha-syntrophin (alpha-Syn(-/-)) that lack the perivascular aquaporin-4 pool but retain the endothelial pool of this protein.


METHODS
Prospective laboratory animal study.


METHODS
Research laboratory in a university teaching hospital.


RESULTS
Halothane-anesthetized adult male wildtype C57B/6 and alpha-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 alpha-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 alpha-Syn(-/-) mice; alpha-Syn(-/-) deletion alone had no effect on blood-brain barrier integrity. In the third series of experiments (n = 34), alpha-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.
Zeynalov
Emil
E
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Chen
Chih-Hung
CH
Froehner
Stanley C
SC
Adams
Marvin E
ME
Ottersen
Ole Petter
OP
Amiry-Moghaddam
Mahmood
M
Bhardwaj
Anish
A
D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001834:Body Water / Q000378:metabolism; D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D002545:Brain Ischemia / Q000150:complications*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics*; D009995:Osmosis; D012462:Saline Solution, Hypertonic / Q000627:therapeutic use*
D051401:Aquaporin 4; D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D012462:Saline Solution, Hypertonic; C091825:syntrophin alpha1