Abstract
BackgroundAquaporin-4 (AQP4) constitutes the principal water channel in the brain and is clusteredat the perivascular astrocyte endfeet. This specific distribution of AQP4 plays a major role in maintaining water homeostasis in the brain. A growing body of evidence points to a role ofthe dystroglycan complex and its interaction with perivascular laminin in the clusteringof AQP4 atperivascular astrocyte endfeet. Indeed, mice lacking components of this complex or in which laminin-dystroglycan interaction is disrupted show a delayed onset of brain edema due to a redistribution of AQP4 away from astrocyte endfeet. It is therefore important to identify inhibitory drugs of laminin-dependent AQP4 clustering which may prevent or reduce brain edema.Methodolgy/Principal FindingsIn the present study we used primary rat astrocyte cultures toscreen a library of >3,500 chemicals and identified 6 drugs that inhibit the laminin-induced clustering of dystroglycan and AQP4. Detailed analysis of the inhibitory drug, chloranil, revealed that its inhibition of the clustering is due to the metalloproteinase-2-mediated ß-dystroglycan shedding and subsequent loss of laminin interaction with dystroglycan. Furthermore, chemical variants of chloranil induced a similar effect on ß-dystroglycan and this was prevented by the antioxidant N-acetylcysteine.Conclusion/SignificanceThese findings reveal the mechanism of action of chloranil in preventing the laminin-induced clustering of dystroglycan and AQP4 and validate the use of high-throughput screening as a tool to identify drugs that modulate AQP4 clustering and that could be tested in models of brain edema.
Highlights
Cerebral edema with excess accumulation of water and cellular swelling is a common consequence of stroke, traumatic brain injury, brain tumor and meningitis
Conclusion/Significance: These findings reveal the mechanism of action of chloranil in preventing the laminin-induced clustering of dystroglycan and AQP4 and validate the use of high-throughput screening as a tool to identify drugs that modulate AQP4 clustering and that could be tested in models of brain edema
To determine whether chloranil-induced shedding of ß-DG in astrocytes is mediated by these twometalloproteinases, we investigated their activity via gelatin zymography
Summary
Cerebral edema with excess accumulation of water and cellular swelling is a common consequence of stroke, traumatic brain injury, brain tumor and meningitis. Blocking AQP4 or inhibiting its clustering around blood vessels would reduce water entry which may be beneficial in preventing cytotoxic edema at early stages of stroke. On the contrary, activating AQP4 or increasing its clustering around blood vessels would promote the extrusion of the excess water from the brain preventing thereby vasogenic edema. Aquaporin-4 (AQP4) constitutes the principal water channel in the brain and is clusteredat the perivascular astrocyte endfeet. This specific distribution of AQP4 plays a major role in maintaining water homeostasis in the brain. Methodolgy/Principal Findings: In the present study we used primary rat astrocyte cultures toscreen a library of .3,500 chemicals and identified 6 drugs that inhibit the laminin-induced clustering of dystroglycan and AQP4. Chemical variants of chloranil induced a similar effect on ß-dystroglycan and this was prevented by the antioxidant N-acetylcysteine
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