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Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke

Abstract

Pathological conditions in the central nervous system, including stroke and trauma, are often exacerbated by cerebral edema. We recently identified a nonselective cation channel, the NCCa-ATP channel, in ischemic astrocytes that is regulated by sulfonylurea receptor 1 (SUR1), is opened by depletion of ATP and, when opened, causes cytotoxic edema. Here, we evaluated involvement of this channel in rodent models of stroke. SUR1 protein and mRNA were newly expressed in ischemic neurons, astrocytes and capillaries. Upregulation of SUR1 was linked to activation of the transcription factor Sp1 and was associated with expression of functional NCCa-ATP but not KATP channels. Block of SUR1 with low-dose glibenclamide reduced cerebral edema, infarct volume and mortality by 50%, with the reduction in infarct volume being associated with cortical sparing. Our findings indicate that the NCCa-ATP channel is crucially involved in development of cerebral edema, and that targeting SUR1 may provide a new therapeutic approach to stroke.

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Figure 1: SUR1 is upregulated in MCA stroke model.
Figure 2: SUR1 but not Kir6.1 or Kir6.2 is transcriptionally upregulated in MCA stroke model.
Figure 3: Association of Sp1 and SUR1 promoter region in cerebral ischemia.
Figure 4: Expression of functional NCCa-ATP channels in cerebral ischemia.
Figure 5: Glibenclamide reduces mortality, edema and infarct volume, and improves cerebral blood flow in MCA stroke models.
Figure 6: Tissue distribution of BODIPY-glibenclamide in MCA stroke model.

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Acknowledgements

This work was supported by grants (to J.M.S.) from the National Institute of Neurological Disorders and Stroke (NS048260), National Heart, Lung, and Blood Institute (HL082517) and by a Merit Review Grant from the Veterans Affairs (Baltimore Veterans Affairs, Baltimore, Maryland, USA).

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Correspondence to J Marc Simard.

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The authors have applied for a US patent, “A novel non-selective cation channel in neural cells and methods for treating brain swelling” (application number 10/391,561).

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Simard, J., Chen, M., Tarasov, K. et al. Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke. Nat Med 12, 433–440 (2006). https://doi.org/10.1038/nm1390

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