Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice

Abstract

A hallmark of stroke is water accumulation (edema) resulting from dysregulation of osmotic homeostasis. Brain edema contributes to tissue demise and may lead to increased intracranial pressure and lethal herniation. Currently, there are only limited treatments to prevent edema formation following stroke. Aquaporin 4 (AQP4), a brain water channel, has become a focus of interest for therapeutic approaches targeting edema. At present, there are no pharmacological tools to block AQP4. The role of AQP4 in edema after brain injury remains unclear with conflicting results from studies using AQP4 À/À mice and of AQP4 expression following stroke. Here, we studied AQP4 and its role in edema formation by testing AQP4À/À mice in a model of middle cerebral artery occlusion using novel quantitative MRI water content measurements, histology and behavioral changes as outcome measures. Absence of AQP4 was associated with decreased mortality and increased motor recovery 3 to 14 days after stroke. Behavioral improvement was associated with decreased lesion volume, neuronal cell death and neuroinflammation in AQP4 À/À compared to wild type mice. Our data suggest that the lack of AQP4 confers an overall beneficial role at long term with improved neuronal survival and reduced neuroinflammation, but without a direct effect on edema formation.

Apelin-13 Protects against Ischemic Blood-Brain Barrier Damage through the Effects of Aquaporin-4

“…However, the effects of AQP4 on cerebral ischemia are very complex and far from being clear till now. Studies using AQP4 deletion mice reveal that the presence of AQP4 aggravates ischemic injury in the early stage, while it may have a long-term protective effect [9,26,27]. We speculate that in the early stage, owing to the inhibition of relatively single cytotoxic edema, AQP4 should exhibit protective effects.…”

“…It is well known that AQP4 facilitates the formation of cytotoxic edema but promotes clearance of vasogenic edema [6]. The predominant type in the early stage of cerebral ischemia is cytotoxic edema and it has been confirmed that AQP4 knock-out reduces brain edema at this stage [25,26]. However, the effects of AQP4 on cerebral ischemia are very complex and far from being clear till now.…”

Involvement of p38 mitogen‐activated protein kinase in altered expressions of AQP1 and AQP4 after carbon monoxide poisoning in rat astrocytes

“…We demonstrated that the indicator of cerebral oedema, brain water content of rats in the CO group significantly increased at 6, 12 and 24 hours after CO injection and obviously decreased at 48 hours. Water channels AQP1 and AQP4 are two critical proteins in regulating water distribution and metabolism in the rodent brain, which have been shown to be involved in cerebral oedema of neurological disorders . We measured levels of AQP1 and AQP4 in the frontal cortex and hippocampal CA1 and found that expressions of AQP1 and AQP4 were significantly elevated at 6, 12 and 24 hours following CO injection.…”

“…So far, at least 17 isoforms of AQPs in mammals have been identified, and AQP1 and AQP4 are two of the most widely distributed subtypes in the rodent brain . The dysregulations of AQP1 and AQP4 are associated with cerebral oedema in multiple neurological disorders …”

“…14 The dysregulations of AQP1 and AQP4 are associated with cerebral oedema in multiple neurological disorders. [15][16][17] AQP1 is selectively and constitutively expressed on apical membranes of the choroidal plexus epithelium and end feet of astrocytes. 18 Previous studies have shown that AQP1 was up-regulated in the astrocytes of brains with oedema caused by traumatic injury.…”