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...
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MDPI AG
2017-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/19/1/46 |
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| author | Ionica Pirici Tudor Adrian Balsanu Catalin Bogdan Claudiu Margaritescu Tamir Divan Vacaras Vitalie Laurentiu Mogoanta Daniel Pirici Roxana Octavia Carare Dafin Fior Muresanu |
| author_facet | Ionica Pirici Tudor Adrian Balsanu Catalin Bogdan Claudiu Margaritescu Tamir Divan Vacaras Vitalie Laurentiu Mogoanta Daniel Pirici Roxana Octavia Carare Dafin Fior Muresanu |
| author_sort | Ionica Pirici |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T11:18:00Z |
| format | Article |
| id | doaj.art-90db9925e70f48b08b470a894811983d |
| institution | Directory Open Access Journal |
| issn | 1422-0067 |
| language | English |
| last_indexed | 2024-04-12T11:18:00Z |
| publishDate | 2017-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-90db9925e70f48b08b470a894811983d2022-12-22T03:35:27ZengMDPI AGInternational Journal of Molecular Sciences1422-00672017-12-011914610.3390/ijms19010046ijms19010046Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage PathwaysIonica Pirici0Tudor Adrian Balsanu1Catalin Bogdan2Claudiu Margaritescu3Tamir Divan4Vacaras Vitalie5Laurentiu Mogoanta6Daniel Pirici7Roxana Octavia Carare8Dafin Fior Muresanu9Department of Human Anatomy, University of Medicine and Pharmacy of Craiova, Craiova 200349, RomaniaDepartment of Physiology, University of Medicine and Pharmacy of Craiova, Craiova 200349, RomaniaDepartment of Physiology, University of Medicine and Pharmacy of Craiova, Craiova 200349, RomaniaDepartment of Pathology, University of Medicine and Pharmacy of Craiova, Craiova 200349, RomaniaDepartment of Research Methodology, University of Medicine and Pharmacy of Craiova, Petru Rares Street 2, Craiova 200349, RomaniaDepartment of Clinical Neurosciences, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca 400000, RomaniaDepartment of Histology, University of Medicine and Pharmacy of Craiova, Craiova 200349, RomaniaDepartment of Research Methodology, University of Medicine and Pharmacy of Craiova, Petru Rares Street 2, Craiova 200349, RomaniaFaculty of Medicine, University of Southampton, Southampton SO17 1BJ, UKDepartment of Clinical Neurosciences, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca 400000, RomaniaAquaporin-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.https://www.mdpi.com/1422-0067/19/1/46aquaporin-4 inhibitionischemic strokenon-reperfusion ischemiabasement membranesparavascular drainage |
| spellingShingle | Ionica Pirici Tudor Adrian Balsanu Catalin Bogdan Claudiu Margaritescu Tamir Divan Vacaras Vitalie Laurentiu Mogoanta Daniel Pirici Roxana Octavia Carare Dafin Fior Muresanu Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways International Journal of Molecular Sciences aquaporin-4 inhibition ischemic stroke non-reperfusion ischemia basement membranes paravascular drainage |
| title | Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways |
| title_full | Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways |
| title_fullStr | Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways |
| title_full_unstemmed | Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways |
| title_short | Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways |
| title_sort | inhibition of aquaporin 4 improves the outcome of ischaemic stroke and modulates brain paravascular drainage pathways |
| topic | aquaporin-4 inhibition ischemic stroke non-reperfusion ischemia basement membranes paravascular drainage |
| url | https://www.mdpi.com/1422-0067/19/1/46 |
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