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Inhibition of aquaporin-4 improves the outcome of ischaemic stroke and modulates brain paravascular drainage pathways

Inhibition of aquaporin-4 improves the outcome of ischaemic stroke and modulates brain paravascular drainage pathways
Inhibition of aquaporin-4 improves the outcome of ischaemic stroke and modulates brain paravascular drainage pathways

Aquaporin-4 (AQP4) is the most abundant water channel in the brain, and its inhibition before inducing focal ischemia, using the AQP4 inhibitor TGN-020, has been showed to reduce oedema in imaging studies. Here, we aimed to evaluate, for the first time, the histopathological effects of a single dose of TGN-020 administered after the occlusion of the medial cerebral artery (MCAO). On a rat model of non-reperfusion ischemia, we have assessed vascular densities, albumin extravasation, gliosis, and apoptosis at 3 and 7 days after MCAO. TGN-020 significantly reduced oedema, glial scar, albumin effusion, and apoptosis, at both 3 and 7 days after MCAO. The area of GFAP-positive gliotic rim decreased, and 3D fractal analysis of astrocytic processes revealed a less complex architecture, possibly indicating water accumulating in the cytoplasm. Evaluation of the blood vessels revealed thicker basement membranes colocalizing with exudated albumin in the treated animals, suggesting that inhibition of AQP4 blocks fluid flow towards the parenchyma in the paravascular drainage pathways of the interstitial fluid. These findings suggest that a single dose of an AQP4 inhibitor can reduce brain oedema, even if administered after the onset of ischemia, and AQP4 agonists/antagonists might be effective modulators of the paravascular drainage flow.

Aquaporin-4 inhibition, Basement membranes, Ischemic stroke, Non-reperfusion ischemia, Paravascular drainage
1661-6596
Carare, Roxana Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa
Carare, Roxana Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa

Carare, Roxana Octavia (2018) Inhibition of aquaporin-4 improves the outcome of ischaemic stroke and modulates brain paravascular drainage pathways International Journal of Molecular Sciences, 19, (1) (doi:10.3390/ijms19010046).

Record type: Article

Abstract

Aquaporin-4 (AQP4) is the most abundant water channel in the brain, and its inhibition before inducing focal ischemia, using the AQP4 inhibitor TGN-020, has been showed to reduce oedema in imaging studies. Here, we aimed to evaluate, for the first time, the histopathological effects of a single dose of TGN-020 administered after the occlusion of the medial cerebral artery (MCAO). On a rat model of non-reperfusion ischemia, we have assessed vascular densities, albumin extravasation, gliosis, and apoptosis at 3 and 7 days after MCAO. TGN-020 significantly reduced oedema, glial scar, albumin effusion, and apoptosis, at both 3 and 7 days after MCAO. The area of GFAP-positive gliotic rim decreased, and 3D fractal analysis of astrocytic processes revealed a less complex architecture, possibly indicating water accumulating in the cytoplasm. Evaluation of the blood vessels revealed thicker basement membranes colocalizing with exudated albumin in the treated animals, suggesting that inhibition of AQP4 blocks fluid flow towards the parenchyma in the paravascular drainage pathways of the interstitial fluid. These findings suggest that a single dose of an AQP4 inhibitor can reduce brain oedema, even if administered after the onset of ischemia, and AQP4 agonists/antagonists might be effective modulators of the paravascular drainage flow.

Text ijms-19-00046-v2 - Version of Record
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Accepted/In Press date: 20 December 2017
e-pub ahead of print date: 23 December 2017
Published date: 1 January 2018
Keywords: Aquaporin-4 inhibition, Basement membranes, Ischemic stroke, Non-reperfusion ischemia, Paravascular drainage

Identifiers

Local EPrints ID: 417480
URI: https://eprints.soton.ac.uk/id/eprint/417480
ISSN: 1661-6596
PURE UUID: eaa8dd33-39fd-4d75-8aed-9bdea6df4aa2

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Date deposited: 01 Feb 2018 17:30
Last modified: 01 Feb 2018 17:30

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