Leukotriene D 4 induces brain edema and enhances CysLT 2 receptor-mediated aquaporin 4 expression

Abstract

Cysteinyl leukotrienes (including LTC 4, LTD 4, and LTE 4), potent inflammatory mediators, can induce brain-blood barrier (BBB) disruption and brain edema. These reactions are mediated by their receptors, CysLT 1 and CysLT 2 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 LTD 4-induced brain edema. LTD 4 (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 CysLT 1 receptor antagonist pranlukast inhibited the IgG exudation, but not the increased water content and AQP4 expression induced by LTD 4. In the cultured rat astrocytes, LTD 4 (10 −9–10 −7 M, for 24 h) similarly enhanced AQP4 expression. The enhanced AQP4 expression was inhibited by Bay u9773, a non-selective CysLT 1/CysLT 2 receptor antagonist, but not by pranlukast. LTD 4 (10 −9–10 −7 M) also induced the mRNA expression of CysLT 2 (not CysLT 1) receptor in astrocytes. These results indicate that LTD 4 modulates brain edema; CysLT 1 receptor mediates vasogenic edema while CysLT 2 receptor may mediate cytotoxic edema via up-regulating AQP4 expression.