• 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • Studies carried out with LTRAs before the identification of


    Studies carried out with LTRAs before the identification of the CysLT2R, showed a controversial picture, as results that suggest a role for cysteinyl-LTs in the expansion of ischemic damage and in cardiac dysfunction during reperfusion [5], [68], [69] were evenly balanced by others suggesting that they have no or little effect on the progression of myocardial injury [70], [71]. The observation that several of the compounds used in these studies also possess variable activity on the CysLT2R may help to clarify the role of cysteinyl-LT in the CV setting. Furthermore, the therapeutic efficacy of commercially available LTRA in the clinical context of THZ531 msds can be reevaluated in light of the proposed model of pulmonary inflammation where CysLT1 and CysLT2 receptors are suggested to play different roles in the acute and chronic phases [72] and in consideration of the observed activity of CysLT2 as a negative regulator of CysLT1R in the inflammatory circuit involving human mast cells [73]. In conclusion, exciting findings are renewing the interest in the 5-LO/LT pathway in CV disease, and the ECs appear more and more as a critical player in the biosynthesis and the biological effects of cysteinyl-LTs in the CV system. The presence of enzymes and receptors of the LT pathway in vascular disease specimens as well as the identification of specific function involved in the regulation of the vascular wall functions provide a rationale for therapeutic intervention with agents targeting the cysteinyl-LT pathway, and the CysLT2R in particular.
    Introduction Cysteinyl leukotrienes (CysLTs, namely LTC4, LTD4 and LTE4), important inflammatory mediators, mediate many pathophysiological responses via activation of CysLT1 and CysLT2 receptors (Brink et al., 2003, Kanaoka and Boyce, 2004, Capra et al., 2007). The responses mediated by CysLT1 and CysLT2 receptors have been studied widely in peripheral organs (Brink et al., 2003, Kanaoka and Boyce, 2004, Capra et al., 2007), but less in the central nervous system. Recently, we reported that release of CysLTs increases in rat brain after focal cerebral ischemia (Zhou et al., 2006), and both CysLT1 and CysLT2 receptors are involved in ischemic brain injury in rats and mice (Zhang et al., 2002, Yu et al., 2005, Fang et al., 2006, Fang et al., 2007). In rat astrocytes, we found distinct roles of the CysLT1 and CysLT2 receptors after ischemic-like injury induced by oxygen-glucose deprivation (OGD) or exposure to their agonist LTD4 (Huang et al., 2008). The CysLT1 receptor mediates astrocyte proliferation after mild ischemic-like injury or treatment with lower concentrations of LTD4; while the CysLT2 receptor mediates astrocyte death after moderate ischemic-like injury or treatment with higher concentrations of LTD4 (Huang et al., 2008). Also, PC12 cells transfected with the CysLT2 receptor show more severe ischemic injury than those transfected with the CysLT1 receptor (Sheng et al., 2006). However, the mechanisms underlying CysLT2 receptor-mediated ischemic cell injury remain unknown. Recently, we investigated the regulatory roles of CysLT receptors in expression of the water channel aquaporin-4 (AQP4) induced by the agonist LTD4 in mouse brain and rat astrocytes. We found that activation of the CysLT2 receptor mediates cytotoxic brain edema through up-regulating AQP4, while activation of the CysLT1 receptor mediates vasogenic brain edema by disrupting the blood–brain barrier but not by regulating AQP4 (Wang et al., 2006). AQP4 plays a major role in brain water homeostasis and the development of brain edema (Verkman, 2005, Bloch et al., 2005). AQP4 mediates brain edema and neuronal damage induced by different brain injuries, such as focal cerebral ischemia, brain abscess, and water intoxication (Verkman, 2005, Bloch et al., 2005, THZ531 msds Manley et al., 2004, Manley et al., 2000). AQP4 knockout (Manley et al., 2000) or inhibition by edaravone, a free-radical scavenger (Kikuchi et al., 2009), attenuates neurological injury and edema after focal cerebral ischemia in mice or rats. In primary astrocyte cultures, AQP4 mediates cell swelling after hypoxia/reoxygenation (Fu et al., 2007) and osmotic water permeability (Solenov et al., 2004). Whether AQP4 is directly associated with ischemic astrocyte injury needs investigation.