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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

The glymphatic system regulates cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange in the brain. (A) Illustration of the main fluid compartments in the brain. (B) Diagram of fluid influx via penetrating arteries and efflux along a subset of large-caliber veins. (C) Diagram of proposed molecular mechanisms governing paravascular CSF–ISF exchange. Abbreviations: paravascular space, PVS; solute carrier, SLC; zonula occludens, ZO; connexin, CNX; Na+-K+-ATPase, NKA; intracellular fluid, ICF; aquaporin-4, AQP4. Reproduced with permission from Thrane et al. (2014).
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Figure 1: The glymphatic system regulates cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange in the brain. (A) Illustration of the main fluid compartments in the brain. (B) Diagram of fluid influx via penetrating arteries and efflux along a subset of large-caliber veins. (C) Diagram of proposed molecular mechanisms governing paravascular CSF–ISF exchange. Abbreviations: paravascular space, PVS; solute carrier, SLC; zonula occludens, ZO; connexin, CNX; Na+-K+-ATPase, NKA; intracellular fluid, ICF; aquaporin-4, AQP4. Reproduced with permission from Thrane et al. (2014).

Mentions: In the adult brain, water is distributed among various compartments that include the cerebrospinal fluid (CSF), blood, and the intracellular and interstitial components of the parenchyma. Fluid movement across vascular, ventricular and parenchymal compartments is controlled by osmotic gradients and hydrostatic pressure differences and is crucial for maintaining normal physiological function (Papadopoulos et al., 2007). The neurovascular compartment consisting of vasculature, neurons and astrocytes is critical for the control of this water movement (Badaut et al., 2011). The recently coined “glymphatic system” by Iliff and Nedergaard (reviewed in Iliff and Nedergaard, 2013), attempts to further delineate water movement facilitated via a paravascular route between glial and vascular cells that may include previously unrecognized pathways (Figure 1). In ischemic stroke, a key aggravating factor is the presence of edema. Brain volume is limited by the rigidity of the skull, so that even minute increases in volume lead to an increase in intracranial pressure and compression of neural tissue and vasculature. Edema therefore has a crucial impact on morbidity and mortality in stroke (Klatzo, 1985). Current treatment of cerebral edema is limited to osmotic agents such as mannitol and surgical decompression, but these do not address the problem at a molecular level.


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)

The glymphatic system regulates cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange in the brain. (A) Illustration of the main fluid compartments in the brain. (B) Diagram of fluid influx via penetrating arteries and efflux along a subset of large-caliber veins. (C) Diagram of proposed molecular mechanisms governing paravascular CSF–ISF exchange. Abbreviations: paravascular space, PVS; solute carrier, SLC; zonula occludens, ZO; connexin, CNX; Na+-K+-ATPase, NKA; intracellular fluid, ICF; aquaporin-4, AQP4. Reproduced with permission from Thrane et al. (2014).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: The glymphatic system regulates cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange in the brain. (A) Illustration of the main fluid compartments in the brain. (B) Diagram of fluid influx via penetrating arteries and efflux along a subset of large-caliber veins. (C) Diagram of proposed molecular mechanisms governing paravascular CSF–ISF exchange. Abbreviations: paravascular space, PVS; solute carrier, SLC; zonula occludens, ZO; connexin, CNX; Na+-K+-ATPase, NKA; intracellular fluid, ICF; aquaporin-4, AQP4. Reproduced with permission from Thrane et al. (2014).
Mentions: In the adult brain, water is distributed among various compartments that include the cerebrospinal fluid (CSF), blood, and the intracellular and interstitial components of the parenchyma. Fluid movement across vascular, ventricular and parenchymal compartments is controlled by osmotic gradients and hydrostatic pressure differences and is crucial for maintaining normal physiological function (Papadopoulos et al., 2007). The neurovascular compartment consisting of vasculature, neurons and astrocytes is critical for the control of this water movement (Badaut et al., 2011). The recently coined “glymphatic system” by Iliff and Nedergaard (reviewed in Iliff and Nedergaard, 2013), attempts to further delineate water movement facilitated via a paravascular route between glial and vascular cells that may include previously unrecognized pathways (Figure 1). In ischemic stroke, a key aggravating factor is the presence of edema. Brain volume is limited by the rigidity of the skull, so that even minute increases in volume lead to an increase in intracranial pressure and compression of neural tissue and vasculature. Edema therefore has a crucial impact on morbidity and mortality in stroke (Klatzo, 1985). Current treatment of cerebral edema is limited to osmotic agents such as mannitol and surgical decompression, but these do not address the problem at a molecular level.

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