抑制磷酸二酯酶4可降低脑缺血/再灌注损伤后的水通道蛋白4表达、减轻星形胶质细胞肿胀  

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

作　　者：Kechun Chen Bingtian Xu Shuqin Qiu Lu Long Qian Zhao Jiangping Xu Haitao Wang 唐颖馨(编译) 

机构地区：[1]NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou,China [2]Key Laboratory of Mental Health of the Ministry of Education,Southern Medical University,Guangzhou,China [3]Center for Brain Science and Brain-Inspired Intelligence,Guangdong-Hong Kong-Macao Greater Bay Area,Guangzhou,China [4]不详

出　　处：《神经损伤与功能重建》2024年第6期F0003-F0003,共1页Neural Injury and Functional Reconstruction

摘　　要：我们的既往研究已显示磷酸二酯酶4(PDE4)抑制剂对大鼠中脑动脉闭塞/再灌注(MCAO/R)后的神经元损伤具有保护作用。然而,PDE4对脑水肿和星形胶质细胞肿胀的影响尚不清楚。在本研究中,我们发现通过Roflumilast(Roflu)抑制PDE4可以减轻大鼠缺血再灌注后的脑水肿、降低脑组织含水量。Roflu减少了水通道蛋白4(AQP4)的表达,而磷酸化蛋白激酶B(Akt)和叉头框蛋白O3a(FoxO3a)的水平增加。此外,Roflu减少原代星形胶质细胞在糖氧剥夺/再灌注(OGD/R)后的细胞体积和AQP4的表达。同样,PDE4B敲低显示出与PDE4抑制相似的作用;而PDE4B过表达可以减少PDE4B敲低对AQP4表达的抑制作用。本研究还发现,Roflu对AQP4表达和细胞体积的影响可以被Akt抑制剂MK2206阻断。神经炎症和星形胶质细胞激活是在卒中病理生理的机制之一,所以本研究用白细胞介素-1β(IL-1β)处理原代星形胶质细胞。结果显示,经IL-1β处理的星形胶质细胞表现出AQP4和磷酸化Akt及FoxO3a减少。Roflu显著降低了AQP4表达,这伴随着Akt和FoxO3a磷酸化的增加。此外,FoxO3a的过表达部分逆转了Roflu对AQP4表达的影响。本研究结果显示,PDE4抑制通过Akt/FoxO3a/AQP4通路限制了缺血诱导的脑水肿和星形胶质细胞肿胀。PDE4是脑缺血后脑水肿的一个有潜力的干预目标。We have previously shown that phosphodiesterase 4(PDE4)inhibition protects against neuronal inju-ry 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 Roflumi-last(Roflu)reduced brain edema and brain water content in rats subjected to MCAO/R.Roflu decreased the ex-pression 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 as-trocytes 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 vol-ume were blocked by the Akt inhibitor MK2206.Since neuroinflammation and astrocyte activation are the com-mon events that are observed in stroke,we treated primary astrocytes with interleukin-1β(IL-1β).Astrocytes treated with IL-1βshowed decreased AQP4 and phosphorylated Akt and FoxO3a.Roflu significantly reduced AQP4 expression,which was accompanied by increased phosphorylation of Akt and FoxO3a.Furthermore,over-expression 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.

关 键 词：水通道蛋白4 脑水肿 脑缺血 叉头框蛋白O3a 磷酸二酯酶4 

分 类 号：R741[医药卫生—神经病学与精神病学] R741.02[医药卫生—临床医学]