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Abstract: Cysteinyl leukotrienes (including LTC4, LTD4, and LTE4), potent inflammatory mediators, can induce brain-blood barrier (BBB) disruption and brain edema. These reactions are mediated by their receptors, CysLT1 and CysLT2 receptors. On the other hand, aquaporin 4 (AQP4) primarily modulates brain water homeostasis and edema after various injuries. Here, we aimed to determine whether AQP4 is involved in LTD4-induced brain edema. LTD4 (1ng in 0.5μl PBS) microinjection into the cortex increased endogenous IgG exudation (BBB disruption) and water content (brain edema), and enhanced AQP4 expression in mouse brain. The selective CysLT1 receptor antagonist pranlukast inhibited the IgG exudation, but not the increased water content and AQP4 expression induced by LTD4. In the cultured rat astrocytes, LTD4 (10−9–10−7 M, for 24h) similarly enhanced AQP4 expression. The enhanced AQP4 expression was inhibited by Bay u9773, a non-selective CysLT1/CysLT2 receptor antagonist, but not by pranlukast. LTD4 (10−9–10−7 M) also induced the mRNA expression of CysLT2 (not CysLT1) receptor in astrocytes. These results indicate that LTD4 modulates brain edema; CysLT1 receptor mediates vasogenic edema while CysLT2 receptor may mediate cytotoxic edema via up-regulating AQP4 expression. [Copyright &y& Elsevier]

Abstract: Cysteinyl leukotrienes are involved in ischemic brain injury, and their receptors (CysLT1 and CysLT2) have been cloned. To clarify which subtype mediates the ischemic neuronal injury, we performed permanent transfection to increase CysLT1 and CysLT2 receptor expressions in PC12 cells. Oxygen glucose deprivation (OGD)-induced cell death was detected by Hoechst 33258 and propidium iodide fluorescent staining as well as by flow cytometry. OGD induced late phase apoptosis mainly and necrosis minimally. Over-expression of CysLT1 receptor decreased and over-expression of CysLT2 receptor increased OGD-induced cell death. An agonist LTD4 (10−7 M) also induced apoptosis, especially in CysLT2 receptor over-expressing cells. A selective CysLT1 receptor antagonist montelukast did not affect OGD-induced apoptosis; while non-selective CysLT receptor antagonist Bay u9773 inhibited OGD-induced apoptosis, especially in CysLT2 receptor over-expressing cells. Thus, CysLT1 and CysLT2 receptors play distinct roles in OGD-induced PC12 cell death; CysLT1 attenuates while CysLT2 facilitates the cell death. [Copyright &y& Elsevier]