8 results on '"Bork, Peter A. R."'
Search Results
2. Glymphatic fluid transport is suppressed by the aquaporin-4 inhibitor AER-271
- Author
-
Giannetto, Michael J, Gomolka, Ryszard S, Gahn-Martinez, Daniel, Newbold, Evan J, Bork, Peter A R, Chang, Ethan, Gresser, Michael, Thompson, Trevor, Mori, Yuki, Nedergaard, Maiken, Giannetto, Michael J, Gomolka, Ryszard S, Gahn-Martinez, Daniel, Newbold, Evan J, Bork, Peter A R, Chang, Ethan, Gresser, Michael, Thompson, Trevor, Mori, Yuki, and Nedergaard, Maiken
- Abstract
The glymphatic system transports cerebrospinal fluid (CSF) into the brain via arterial perivascular spaces and removes interstitial fluid from the brain along perivenous spaces and white matter tracts. This directional fluid flow supports the clearance of metabolic wastes produced by the brain. Glymphatic fluid transport is facilitated by aquaporin-4 (AQP4) water channels, which are enriched in the astrocytic vascular endfeet comprising the outer boundary of the perivascular space. Yet, prior studies of AQP4 function have relied on genetic models, or correlated altered AQP4 expression with glymphatic flow in disease states. Herein, we sought to pharmacologically manipulate AQP4 function with the inhibitor AER-271 to assess the contribution of AQP4 to glymphatic fluid transport in mouse brain. Administration of AER-271 inhibited glymphatic influx as measured by CSF tracer infused into the cisterna magna and inhibited increases in the interstitial fluid volume as measured by diffusion-weighted MRI. Furthermore, AER-271 inhibited glymphatic efflux as assessed by an in vivo clearance assay. Importantly, AER-271 did not affect AQP4 localization to the astrocytic endfeet, nor have any effect in AQP4 deficient mice. Since acute pharmacological inhibition of AQP4 directly decreased glymphatic flow in wild-type but not in AQP4 deficient mice, we foresee AER-271 as a new tool for manipulation of the glymphatic system in rodent brain., The glymphatic system transports cerebrospinal fluid (CSF) into the brain via arterial perivascular spaces and removes interstitial fluid from the brain along perivenous spaces and white matter tracts. This directional fluid flow supports the clearance of metabolic wastes produced by the brain. Glymphatic fluid transport is facilitated by aquaporin-4 (AQP4) water channels, which are enriched in the astrocytic vascular endfeet comprising the outer boundary of the perivascular space. Yet, prior studies of AQP4 function have relied on genetic models, or correlated altered AQP4 expression with glymphatic flow in disease states. Herein, we sought to pharmacologically manipulate AQP4 function with the inhibitor AER-271 to assess the contribution of AQP4 to glymphatic fluid transport in mouse brain. Administration of AER-271 inhibited glymphatic influx as measured by CSF tracer infused into the cisterna magna and inhibited increases in the interstitial fluid volume as measured by diffusion-weighted MRI. Furthermore, AER-271 inhibited glymphatic efflux as assessed by an in vivo clearance assay. Importantly, AER-271 did not affect AQP4 localization to the astrocytic endfeet, nor have any effect in AQP4 deficient mice. Since acute pharmacological inhibition of AQP4 directly decreased glymphatic flow in wild-type but not in AQP4 deficient mice, we foresee AER-271 as a new tool for manipulation of the glymphatic system in rodent brain.
- Published
- 2024
3. Astrocyte endfeet may theoretically act as valves to convert pressure oscillations to glymphatic flow
- Author
-
Bork, Peter A. R., primary, Ladrón-de-Guevara, Antonio, additional, Christensen, Anneline H., additional, Jensen, Kaare H., additional, Nedergaard, Maiken, additional, and Bohr, Tomas, additional
- Published
- 2023
- Full Text
- View/download PDF
4. Supplementary Information from Astrocyte endfeet may theoretically act as valves to convert pressure oscillations to glymphatic flow
- Author
-
Bork, Peter A. R., Ladrón-de-Guevara, Antonio, Christensen, Anneline H., Jensen, Kaare H., Nedergaard, Maiken, and Bohr, Tomas
- Abstract
The glymphatic system of cerebrospinal fluid transport through the perivascular spaces of the brain has been implicated in metabolic waste clearance, neurodegenerative diseases and in acute neurological disorders such as stroke and cardiac arrest. In other biological low-pressure fluid pathways such as in veins and the peripheral lymphatic system, valves play an important role in ensuring the flow direction. Though fluid pressure is low in the glymphatic system and directed bulk flow has been measured in pial and penetrating perivascular spaces, no valves have yet been identified. Valves, which asymmetrically favour forward flow to backward flow, would imply that the considerable oscillations in blood and ventricle volumes seen in magnetic resonance imaging could cause directed bulk flow. Here, we propose that astrocyte endfeet may act as such valves using a simple elastic mechanism. We combine a recent fluid mechanical model of viscous flow between elastic plates with recent measurements of in vivo elasticity of the brain to predict order of magnitude flow-characteristics of the valve. The modelled endfeet are effective at allowing forward while preventing backward flow.
- Published
- 2023
- Full Text
- View/download PDF
5. Cerebrospinal fluid is a significant fluid source for anoxic cerebral oedema
- Author
-
Du, Ting, Mestre, Humberto, Kress, Benjamin T, Liu, Guojun, Sweeney, Amanda M, Samson, Andrew J, Rasmussen, Martin Kaag, Mortensen, Kristian Nygaard, Bork, Peter A R, Peng, Weiguo, Olveda, Genaro E, Bashford, Logan, Toro, Edna R, Tithof, Jeffrey, Kelley, Douglas H, Thomas, John H, Hjorth, Poul G, Martens, Erik A, Mehta, Rupal I, Hirase, Hajime, Mori, Yuki, Nedergaard, Maiken, Du, Ting, Mestre, Humberto, Kress, Benjamin T, Liu, Guojun, Sweeney, Amanda M, Samson, Andrew J, Rasmussen, Martin Kaag, Mortensen, Kristian Nygaard, Bork, Peter A R, Peng, Weiguo, Olveda, Genaro E, Bashford, Logan, Toro, Edna R, Tithof, Jeffrey, Kelley, Douglas H, Thomas, John H, Hjorth, Poul G, Martens, Erik A, Mehta, Rupal I, Hirase, Hajime, Mori, Yuki, and Nedergaard, Maiken
- Abstract
Cerebral edema develops after anoxic brain injury. In two models of asphyxial and asystolic cardiac arrest without resuscitation, we found that edema develops shortly after anoxia secondary to terminal depolarizations and the abnormal entry of cerebrospinal fluid (CSF). Edema severity correlated with the availability of CSF with the age-dependent increase in CSF volume worsening the severity of edema. Edema was identified primarily in brain regions bordering CSF compartments in mice and humans. The degree of ex vivo tissue swelling was predicted by an osmotic model suggesting that anoxic brain tissue possesses a high intrinsic osmotic potential. This osmotic process was temperature-dependent, proposing an additional mechanism for the beneficial effect of therapeutic hypothermia. These observations show that CSF is a primary source of edema fluid in anoxic brain. This novel insight offers a mechanistic basis for the future development of alternative strategies to prevent cerebral edema formation after cardiac arrest.
- Published
- 2022
6. Cerebrospinal fluid is a significant fluid source for anoxic cerebral oedema
- Author
-
Du, Ting, primary, Mestre, Humberto, additional, Kress, Benjamin T, additional, Liu, Guojun, additional, Sweeney, Amanda M, additional, Samson, Andrew J, additional, Rasmussen, Martin Kaag, additional, Mortensen, Kristian Nygaard, additional, Bork, Peter A R, additional, Peng, Weiguo, additional, Olveda, Genaro E, additional, Bashford, Logan, additional, Toro, Edna R, additional, Tithof, Jeffrey, additional, Kelley, Douglas H, additional, Thomas, John H, additional, Hjorth, Poul G, additional, Martens, Erik A, additional, Mehta, Rupal I, additional, Hirase, Hajime, additional, Mori, Yuki, additional, and Nedergaard, Maiken, additional
- Published
- 2021
- Full Text
- View/download PDF
7. Cerebrospinal fluid is a significant fluid source for anoxic cerebral oedema.
- Author
-
Du T, Mestre H, Kress BT, Liu G, Sweeney AM, Samson AJ, Rasmussen MK, Mortensen KN, Bork PAR, Peng W, Olveda GE, Bashford L, Toro ER, Tithof J, Kelley DH, Thomas JH, Hjorth PG, Martens EA, Mehta RI, Hirase H, Mori Y, and Nedergaard M
- Subjects
- Animals, Brain, Humans, Mice, Brain Edema etiology, Heart Arrest complications, Heart Arrest therapy, Hypothermia, Induced, Hypoxia, Brain complications
- Abstract
Cerebral oedema develops after anoxic brain injury. In two models of asphyxial and asystolic cardiac arrest without resuscitation, we found that oedema develops shortly after anoxia secondary to terminal depolarizations and the abnormal entry of CSF. Oedema severity correlated with the availability of CSF with the age-dependent increase in CSF volume worsening the severity of oedema. Oedema was identified primarily in brain regions bordering CSF compartments in mice and humans. The degree of ex vivo tissue swelling was predicted by an osmotic model suggesting that anoxic brain tissue possesses a high intrinsic osmotic potential. This osmotic process was temperature-dependent, proposing an additional mechanism for the beneficial effect of therapeutic hypothermia. These observations show that CSF is a primary source of oedema fluid in anoxic brain. This novel insight offers a mechanistic basis for the future development of alternative strategies to prevent cerebral oedema formation after cardiac arrest., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
8. A network model of glymphatic flow under different experimentally-motivated parametric scenarios.
- Author
-
Tithof J, Boster KAS, Bork PAR, Nedergaard M, Thomas JH, and Kelley DH
- Abstract
Flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) in the brain delivers nutrients, clears metabolic waste, and causes edema formation. Brain-wide imaging cannot resolve PVSs, and high-resolution methods cannot access deep tissue. However, theoretical models provide valuable insight. We model the CSF pathway as a network of hydraulic resistances, using published parameter values. A few parameters (permeability of PVSs and the parenchyma, and dimensions of PVSs and astrocyte endfoot gaps) have wide uncertainties, so we focus on the limits of their ranges by analyzing different parametric scenarios. We identify low-resistance PVSs and high-resistance parenchyma as the only scenario that satisfies three essential criteria: that the flow be driven by a small pressure drop, exhibit good CSF perfusion throughout the cortex, and exhibit a substantial increase in flow during sleep. Our results point to the most important parameters, such as astrocyte endfoot gap dimensions, to be measured in future experiments., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.