Leukotriene D4 induces brain edema and enhances CysLT2 receptor-mediated aquaporin 4 expression

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 (1 ng in 0.5 μl 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 24 h) 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.