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The central role of aquaporins in the pathophysiology of ischemic stroke.

Vella J, Zammit C, Di Giovanni G, Muscat R, Valentino M - Front Cell Neurosci (2015)

Bottom Line: AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome.AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction.AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biochemistry, University of Malta Msida, Malta.

ABSTRACT
Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4- mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.

No MeSH data available.


Related in: MedlinePlus

Schematic drawing depicting three distinct roles of AQP4 (green circles) in brain function. (A) Brain water balance, (B) astroglial cell migration and (C) neuronal excitation. (A) Green. Routes of edema formation in the two types of brain edema (cytotoxic – through AQP4, vasogenic – through interendothelial spaces). Orange. Edema fluid is eliminated by AQP4 through the glial limitans into subarachnoid CSF, through ependyma and sub-ependymal astroglia into ventricular CSF, and through astroglial pericapillary foot processes into blood. (B) AQP4 polarizes to the leading edge of migrating astroglia and accelerates cell migration. AQP4 facilitates water entry into lamellipodial protrusions in response to intracellular hyperosmolality produced by actin depolymerization and ion influx. (C) AQP4 deletion reduces neuroexcitation. Active neurons (neuron a) release K+ into the extracellular space (ECS). Increased extracellular [K+] depolarizes quiescent neurons (neuron b). AQP4 deletion increases ECS volume and reduces astroglial cell K+ reuptake. This buffers the increase in extracellular [K+] by active neuron a, preventing depolarization of quiescent neuron b. Reproduced with permission from Papadopoulos and Verkman (2008).
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Figure 2: Schematic drawing depicting three distinct roles of AQP4 (green circles) in brain function. (A) Brain water balance, (B) astroglial cell migration and (C) neuronal excitation. (A) Green. Routes of edema formation in the two types of brain edema (cytotoxic – through AQP4, vasogenic – through interendothelial spaces). Orange. Edema fluid is eliminated by AQP4 through the glial limitans into subarachnoid CSF, through ependyma and sub-ependymal astroglia into ventricular CSF, and through astroglial pericapillary foot processes into blood. (B) AQP4 polarizes to the leading edge of migrating astroglia and accelerates cell migration. AQP4 facilitates water entry into lamellipodial protrusions in response to intracellular hyperosmolality produced by actin depolymerization and ion influx. (C) AQP4 deletion reduces neuroexcitation. Active neurons (neuron a) release K+ into the extracellular space (ECS). Increased extracellular [K+] depolarizes quiescent neurons (neuron b). AQP4 deletion increases ECS volume and reduces astroglial cell K+ reuptake. This buffers the increase in extracellular [K+] by active neuron a, preventing depolarization of quiescent neuron b. Reproduced with permission from Papadopoulos and Verkman (2008).

Mentions: Vasogenic edema has traditionally been thought to be cleared primarily by bulk flow of fluid through the extracellular space, through the glia limitans into the ventricles and subarachnoid space, and to a lesser extent through astrocyte foot processes and capillary endothelium into the blood. Extravasation of albumin protein following BBB breakdown further increases the bulk flow of water and edema in the extracellular compartment of the brain. In a series of experiments conducted in AQP4- mice, Papadopoulos and colleagues have shown strong evidence that AQP4-dependent transcellular water flux is central to the movement of edema fluid across the astrocyte cell membranes of the glia limitans into the CSF (Papadopoulos et al., 2004). These findings support earlier results by Reulen and colleagues, who demonstrated movement of edema fluid toward the ventricle (Reulen et al., 1978). There have been several reports of altered AQP4 expression in astrocytes in cases of brain edema in both human and rodent brain (reviewed in Papadopoulos and Verkman, 2013 and others). The severity of the lesion producing interstitial edema was associated with the up-regulation of AQP4 and this could potentially be a protective mechanism for countering edema accumulation (Tourdias et al., 2009). Thus, the up-regulation of AQP4 expression could be an important determinant of the overall water content on the basis of its involvement in the elimination of edema from the brain parenchyma (Figure 2A).


The central role of aquaporins in the pathophysiology of ischemic stroke.

Vella J, Zammit C, Di Giovanni G, Muscat R, Valentino M - Front Cell Neurosci (2015)

Schematic drawing depicting three distinct roles of AQP4 (green circles) in brain function. (A) Brain water balance, (B) astroglial cell migration and (C) neuronal excitation. (A) Green. Routes of edema formation in the two types of brain edema (cytotoxic – through AQP4, vasogenic – through interendothelial spaces). Orange. Edema fluid is eliminated by AQP4 through the glial limitans into subarachnoid CSF, through ependyma and sub-ependymal astroglia into ventricular CSF, and through astroglial pericapillary foot processes into blood. (B) AQP4 polarizes to the leading edge of migrating astroglia and accelerates cell migration. AQP4 facilitates water entry into lamellipodial protrusions in response to intracellular hyperosmolality produced by actin depolymerization and ion influx. (C) AQP4 deletion reduces neuroexcitation. Active neurons (neuron a) release K+ into the extracellular space (ECS). Increased extracellular [K+] depolarizes quiescent neurons (neuron b). AQP4 deletion increases ECS volume and reduces astroglial cell K+ reuptake. This buffers the increase in extracellular [K+] by active neuron a, preventing depolarization of quiescent neuron b. Reproduced with permission from Papadopoulos and Verkman (2008).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389728&req=5

Figure 2: Schematic drawing depicting three distinct roles of AQP4 (green circles) in brain function. (A) Brain water balance, (B) astroglial cell migration and (C) neuronal excitation. (A) Green. Routes of edema formation in the two types of brain edema (cytotoxic – through AQP4, vasogenic – through interendothelial spaces). Orange. Edema fluid is eliminated by AQP4 through the glial limitans into subarachnoid CSF, through ependyma and sub-ependymal astroglia into ventricular CSF, and through astroglial pericapillary foot processes into blood. (B) AQP4 polarizes to the leading edge of migrating astroglia and accelerates cell migration. AQP4 facilitates water entry into lamellipodial protrusions in response to intracellular hyperosmolality produced by actin depolymerization and ion influx. (C) AQP4 deletion reduces neuroexcitation. Active neurons (neuron a) release K+ into the extracellular space (ECS). Increased extracellular [K+] depolarizes quiescent neurons (neuron b). AQP4 deletion increases ECS volume and reduces astroglial cell K+ reuptake. This buffers the increase in extracellular [K+] by active neuron a, preventing depolarization of quiescent neuron b. Reproduced with permission from Papadopoulos and Verkman (2008).
Mentions: Vasogenic edema has traditionally been thought to be cleared primarily by bulk flow of fluid through the extracellular space, through the glia limitans into the ventricles and subarachnoid space, and to a lesser extent through astrocyte foot processes and capillary endothelium into the blood. Extravasation of albumin protein following BBB breakdown further increases the bulk flow of water and edema in the extracellular compartment of the brain. In a series of experiments conducted in AQP4- mice, Papadopoulos and colleagues have shown strong evidence that AQP4-dependent transcellular water flux is central to the movement of edema fluid across the astrocyte cell membranes of the glia limitans into the CSF (Papadopoulos et al., 2004). These findings support earlier results by Reulen and colleagues, who demonstrated movement of edema fluid toward the ventricle (Reulen et al., 1978). There have been several reports of altered AQP4 expression in astrocytes in cases of brain edema in both human and rodent brain (reviewed in Papadopoulos and Verkman, 2013 and others). The severity of the lesion producing interstitial edema was associated with the up-regulation of AQP4 and this could potentially be a protective mechanism for countering edema accumulation (Tourdias et al., 2009). Thus, the up-regulation of AQP4 expression could be an important determinant of the overall water content on the basis of its involvement in the elimination of edema from the brain parenchyma (Figure 2A).

Bottom Line: AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome.AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction.AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biochemistry, University of Malta Msida, Malta.

ABSTRACT
Stroke is a complex and devastating neurological condition with limited treatment options. Brain edema is a serious complication of stroke. Early edema formation can significantly contribute to infarct formation and thus represents a promising target. Aquaporin (AQP) water channels contribute to water homeostasis by regulating water transport and are implicated in several disease pathways. At least 7 AQP subtypes have been identified in the rodent brain and the use of transgenic mice has greatly aided our understanding of their functions. AQP4, the most abundant channel in the brain, is up-regulated around the peri-infarct border in transient cerebral ischemia and AQP4 knockout mice demonstrate significantly reduced cerebral edema and improved neurological outcome. In models of vasogenic edema, brain swelling is more pronounced in AQP4- mice than wild-type providing strong evidence of the dual role of AQP4 in the formation and resolution of both vasogenic and cytotoxic edema. AQP4 is co-localized with inwardly rectifying K(+)-channels (Kir4.1) and glial K(+) uptake is attenuated in AQP4 knockout mice compared to wild-type, indicating some form of functional interaction. AQP4- mice also exhibit a reduction in calcium signaling, suggesting that this channel may also be involved in triggering pathological downstream signaling events. Associations with the gap junction protein Cx43 possibly recapitulate its role in edema dissipation within the astroglial syncytium. Other roles ascribed to AQP4 include facilitation of astrocyte migration, glial scar formation, modulation of inflammation and signaling functions. Treatment of ischemic cerebral edema is based on the various mechanisms in which fluid content in different brain compartments can be modified. The identification of modulators and inhibitors of AQP4 offer new therapeutic avenues in the hope of reducing the extent of morbidity and mortality in stroke.

No MeSH data available.


Related in: MedlinePlus