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Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke

Abstract

Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.

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Figure 1: Effect of water intoxication on survival in AQP4+/+ and AQP4−/− mice.
Figure 2: Localization and quantitation of cerebral edema following water intoxication.
Figure 3: Neurological outcome following MCA occlusion AQP4+/+ and AQP4−/− mice.
Figure 4: Histological analysis of AQP4+/+ and AQP4−/− mice after ischemia.

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Acknowledgements

We thank R. Fishman and A. Marmarou for advice and critical discussions about edema models and quantitation of brain tissue water. We also thank. L. Qian for breeding and genotyping of transgenic mice and electron microscopy technologists J. Beck and M. Yoshimura. This work was supported by grants from the National Institutes of Health and National Cystic Fibrosis Foundation.

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Correspondence to Geoffrey T. Manley.

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Manley, G., Fujimura, M., Ma, T. et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6, 159–163 (2000). https://doi.org/10.1038/72256

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