Neuroprotective effect of aquaporin-4 deficiency in a mouse model of severe global cerebral ischemia produced by transient 4-vessel occlusion

Astrocyte water channel aquaporin-4 (AQP4) facilitates water movement across the blood–brain barrier and into injured astrocytes. We previously showed reduced cytotoxic brain edema with improved neurological outcome in AQP4 knockout mice in water intoxication, infection and cerebral ischemia. Here, we established a 4-vessel transient occlusion model to test the hypothesis that AQP4 deficiency in mice could improve neurological outcome following severe global cerebral ischemia as occurs in cardiac arrest/resuscitation. Mice were subjected to 10-min transient bilateral carotid artery occlusion at 24 h after bilateral vertebral artery cauterization. Cerebral blood flow was reduced during occlusion by >94% in both AQP4+/+ and AQP4−/− mice. The primary outcome, neurological score, was remarkably better at 3 and 5 days after occlusion in AQP4−/− than in AQP4+/+ mice, and survival was significantly improved as well. Brain water content was increased by 2.8 ± 0.4% in occluded AQP4+/+ mice, significantly greater than that of 0.3 ± 0.6% in AQP4−/− mice. Histological examination and immunofluorescence of hippocampal sections at 5 days showed significantly greater neuronal loss in the CA1 region of hippocampus in AQP4+/+ than AQP4−/− mice. The neuroprotection in mice conferred by AQP4 deletion following severe global cerebral ischemia provides proof-of-concept for therapeutic AQP4 inhibition to improve neurological outcome in cardiac arrest.