Combination therapy with bone marrow stromal cells and FK506 enhanced amelioration of ischemic brain damage in rats

AimsWe previously reported that cysteinyl leukotriene receptor 2 (CysLT₂) mediates ischemic astrocyte injury, and leukotriene D₄-activated CysLT₂ receptor up-regulates the water channel aquaporin 4 (AQP4). Here we investigated the mechanism underlying CysLT₂ receptor-mediated ischemic astrocyte injury induced by 4-h oxygen-glucose deprivation and 24-h recovery (OGD/R).Main methodsPrimary cultures of rat astrocytes were treated by OGD/R to construct the cell injury model. AQP4 expression was inhibited by small interfering RNA (siRNA). The expressions of AQP4 and CysLTs receptors, and the MAPK signaling pathway were determined.Key findingsOGD/R induced astrocyte injury, and increased expression of the CysLT₂ (but not CysLT₁) receptor and AQP4. OGD/R-induced cell injury and AQP4 up-regulation were inhibited by a CysLT₂ receptor antagonist (Bay cysLT2) and a non-selective CysLT receptor antagonist (Bay u9773), but not by a CysLT₁ receptor antagonist (montelukast). Knockdown of AQP4 by siRNA attenuated OGD/R injury. Furthermore, OGD/R increased phosphorylation of ERK1/2 and p38, whose inhibitors relieved the cell injury and AQP4 up-regulation.SignificanceThe CysLT₂ receptor mediates AQP4 up-regulation in astrocytes, and up-regulated AQP4 leads to OGD/R-induced injury, which results from activation of the ERK1/2 and p38 MAPK pathways.