Leukotriene D4 induces brain edema and enhances CysLT2 receptor-mediated aquaporin 4 expression.
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) (1ng in 0.5mul 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 24h) 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.
Wang
Meng-Ling
ML
Department of Pharmacology and Institute of Neuroscience, School of Medicine, Zhejiang University, 388, Yu Hang Tang Road, Hangzhou 310058, China.
Huang
Xiao-Jia
XJ
Fang
San-Hua
SH
Yuan
Yu-Mei
YM
Zhang
Wei-Ping
WP
Lu
Yu-Bi
YB
Ding
Qian
Q
Wei
Er-Qing
EQ
D000818:Animals; D051401:Aquaporin 4 / Q000096:biosynthesis*; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects; D001929:Brain Edema / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D017998:Leukotriene D4 / Q000633:toxicity*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018077:Receptors, Leukotriene / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D051401:Aquaporin 4; D008565:Membrane Proteins; D012333:RNA, Messenger; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor