Inhibition of phosphodiesterase 4 attenuates aquaporin 4 expression and astrocyte swelling following cerebral ischemia/reperfusion injury

May 24, 2024Glia

Blocking phosphodiesterase 4 reduces water channel levels and brain cell swelling after stroke-like injury

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Abstract

Inhibition of phosphodiesterase 4 (PDE4) by Roflumilast reduced brain edema and brain water content in rats subjected to middle cerebral artery occlusion/reperfusion.

Roflumilast decreased the expression of aquaporin 4 (AQP4) in the brain.
Phosphorylated protein kinase B (Akt) and forkhead box O3a (FoxO3a) levels were increased following Roflumilast treatment.
Primary astrocytes exposed to oxygen and glucose deprivation/reoxygenation showed reduced cell volume and AQP4 expression with Roflumilast treatment.
PDE4B knockdown produced effects similar to those observed with PDE4 inhibition, while PDE4B overexpression reversed the decrease in AQP4 expression.
Roflumilast's effects on AQP4 expression and cell volume were blocked by the Akt inhibitor MK2206.
Interleukin-1β treatment in astrocytes led to decreased AQP4 and phosphorylated Akt and FoxO3a levels.

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We have previously shown that phosphodiesterase 4 (PDE4) inhibition protects against neuronal injury in rats following middle cerebral artery occlusion/reperfusion (MCAO/R). However, the effects of PDE4 on brain edema and astrocyte swelling are unknown. In this study, we showed that inhibition of PDE4 by Roflumilast (Roflu) reduced brain edema and brain water content in rats subjected to MCAO/R. Roflu decreased the expression of aquaporin 4 (AQP4), while the levels of phosphorylated protein kinase B (Akt) and forkhead box O3a (FoxO3a) were increased. In addition, Roflu reduced cell volume and the expression of AQP4 in primary astrocytes undergoing oxygen and glucose deprivation/reoxygenation (OGD/R). Consistently, PDE4B knockdown showed similar effects as PDE4 inhibition; and PDE4B overexpression rescued the inhibitory role of PDE4B knockdown on AQP4 expression. We then found that the effects of Roflu on the expression of AQP4 and cell volume were blocked by the Akt inhibitor MK2206. Since neuroinflammation and astrocyte activation are the common events that are observed in stroke, we treated primary astrocytes with interleukin-1β (IL-1β). Astrocytes treated with IL-1β showed decreased AQP4 and phosphorylated Akt and FoxO3a. Roflu significantly reduced AQP4 expression, which was accompanied by increased phosphorylation of Akt and FoxO3a. Furthermore, overexpression of FoxO3a partly reversed the effect of Roflu on AQP4 expression. Our findings suggest that PDE4 inhibition limits ischemia-induced brain edema and astrocyte swelling via the Akt/FoxO3a/AQP4 pathway. PDE4 is a promising target for the intervention of brain edema after cerebral ischemia.

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Inhibition of phosphodiesterase 4 attenuates aquaporin 4 expression and astrocyte swelling following cerebral ischemia/reperfusion injury

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