Intracerebroventricular injection of HAMI 3379, a selective cysteinyl leukotriene receptor 2 antagonist, protects against acute brain injury after focal cerebral ischemia in rats

Shi, Qiaojuan; Xiao, Li; Zhao, Bing; Zhang, Xia-Yan; Wang, Xiaorong; Xu, Dongyu; Yu, Shufei; Fang, San‐Hua; Lu, Yun-Bi; Zhang, Weiping; Xiao-ying, SA; Wei, Er-qing

doi:10.1016/j.brainres.2012.09.020

Cited by 32 publications

(26 citation statements)

References 52 publications

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“…described a cysteinyl leukotriene receptor antagonist developed by Bayer Pharmaceuticals, that targets ASC oligomerization and is described in U.S Patent application number 7,498,460 (85). Cysteinyl leukotriene receptor antagonists have been shown to block myocardial ischemia/reperfusion injury in mice (85) and are neuroprotective after brain ischemia (86) and seizures (87). …”

Section: What Therapies Can Be Used To Treat Inflammasome-related mentioning

confidence: 99%

Therapeutics targeting the inflammasome after central nervous system injury

Vaccari

Dietrich

Keane

2016

Translational Research

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Innate immunity is part of the early response of the body to deal with tissue damage and infections. Due to the early nature of the innate immune inflammatory response, this inflammatory reaction represents an attractive option as a therapeutic target. The inflammasome is a component of the innate immune response involved in the activation of caspase-1 and the processing of pro-interleukin-1β. In this article we discuss the therapeutic potential of the inflammasome after central nervous system (CNS) injury and stoke, as well as the basic knowledge we have gained so far regarding inflammasome activation in the CNS. In addition, we discuss some of the therapies available or under investigation for the treatment of brain injury, spinal cord injury and stroke.

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Section: What Therapies Can Be Used To Treat Inflammasome-related mentioning

confidence: 99%

Therapeutics targeting the inflammasome after central nervous system injury

Vaccari

Dietrich

Keane

2016

Translational Research

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“…In the present study, possible involvement of NOS mediated NO production in high glucose-induced cell toxicity was investigated. HAMI 3379, a selective antagonist of cysteinyl leukotriene receptor 2, has been suggested as a potential protective substance in the central nervous system (Shi et al, 2012). In the present study, the possible protective effect of HAMI 3379 on high glucosetreated PC12 cells was investigated as an in vitro model of diabetic neuropathy.…”

Section: Introductionmentioning

confidence: 95%

Protective effect of HAMI 3379 against high glucose-induced PC12 cell injury

Chunzhen¹,

Wang²,

Li³

2015

Res. Pharm. Biotech.

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Diabetic neuropathy is one of the most common diabetic complications, associated with long time exposure to high glucose. Hyperglycemia induces the production of reactive oxygen species (ROS) and reactive nitrogen species contributing to neuronal damage. We have previously reported that HAMI 3379, a selective antagonist of CysLT 2 receptor, is involved in neuron injury after ischemia. In this study, we investigated the protective effect of HAMI 3379 against high glucose-induced cell injury in PC12 neural cells. The PC12 cells were pretreated with various concentrations of HAMI 3379 (0.001 ~ 10 µM) for 1 h and then co-treated with HAMI 3379 and D-glucose (100 mM) for 48 h. HAMI 3379 (0.001 ~ 10 µM) protected PC12 cells against high glucose toxicity, as determined by cell viability and apoptosis after the evaluation by Hoechst 33342 staining assay. In addition, the increased nitric oxide production and nitric oxide synthase (NOS) activity in the media induced by high glucose was significantly inhibited by HAMI 3379. These results demonstrate that HAMI 3379 protected PC12 cells against high glucoseinduced neurotoxicity by inhibition of apoptosis, nitric oxide production and nitric oxide synthase activity, suggesting that CysLT 2 receptor may be a potential target for diabetic neuropathy, and its antagonist may play a crucial role in the treatment of diabetic neuropathy.

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“…We also note for the first time that KO mice show a tendency for reduced I/R damage versus WT counterparts. The reason that the difference between damage in KO and WT mice is relatively small compared with that between WT and EC mice is that basal CysLT 2 R expression in murine cardiac vasculature is low.9 However, basal human CysLT 2 R expression is higher, 8 and leukotriene production and leukotriene receptor expression are elevated in pathological states, 11,29,30 indicating that our EC model more closely represents human CysLT 2 R expression levels. Indeed, our experimental data ( Figure II in the onlineonly Data Supplement) indicate that human CYSLTR2 expression is higher than that found in our EC mice.…”

mentioning

confidence: 97%

Multiple-Site Activation of the Cysteinyl Leukotriene Receptor 2 Is Required for Exacerbation of Ischemia/Reperfusion Injury

Ballantyne

Mewburn

et al. 2014

ATVB

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Leukotrienes are potent proinflammatory lipid mediators synthesized from arachidonic acid via the actions of 5-lipoxygenase and 5-lipoxygenase-activating protein.Cysteinyl leukotrienes (cysLTs) are a subfamily of leukotriene molecules, thus termed because of a common cysteine moiety in their respective structures. The cysLTs, leukotriene C 4 , D 4 , and E 4 (LTC 4 , D 4 , and E 4 , respectively), exert their effects by binding to sequenced G-protein-coupled receptors: cysteinyl leukotriene receptor 1 (CysLT 1 R), cysteinyl leukotriene receptor 2 (CysLT 2 R), and a novel CysLT E receptor (GPR99).3 CysLT 1 R binds LTD 4 preferentially to LTC 4 , whereas CysLT 2 R binds LTD 4 and LTC 4 with equal affinity. Both receptors bind LTE 4 , the most stable and abundant cysLT, with weak affinity. 4 In contrast, GPR99 displays preferential binding affinity for LTE 4 , with weak affinity for LTC 4 and LTD 4 . Objective-Transgenic overexpression of the human cysteinyl leukotriene receptor 2 (CysLT 2 R) in murine endothelium exacerbates vascular permeability and ischemia/reperfusion injury. Here, we explore the underlying mechanisms of CysLT 2 R activation-mediated inflammation and delineate the relative contributions of endogenous murine CysLT 2 R and the transgene-derived receptor. Approach and Results-We created a novel mouse with only endothelial-expressed CysLT 2 R (endothelium-targeted overexpression mice [EC]/CysLT 2 R-knockout mice [KO]) by crossing EC with KO to dissect the role of endothelial CysLT 2 R in tissue injury. Surprisingly, we discovered that damage in EC/KO mice was not elevated (24% versus 47% EC) after ischemia/reperfusion. We examined vascular permeability and leukocyte recruitment/rolling responses in the cremaster vasculature after cysteinyl leukotriene (cysLT) stimulation. Mice possessing transgenic endothelial CysLT 2 R overexpression, whether EC or EC/KO, when stimulated with cysLTs, exhibited vascular hyperpermeability, declining leukocyte flux, and a transient increase in slow-rolling leukocyte fraction. and coronary endothelial cells. 9 CysLT 2 R research had been previously hampered by a lack of selective pharmacological agents, 10 the majority of work instead using the nonselective cysLT antagonist/partial agonist 11 or genetic models of CysLT 2 R expression modulation. 11,12 However, recent studies have characterized 2 novel CysLT 2 R-selective antagonists: HAMI3379 13 and BayCysLT 2 , [14][15][16] which are proving to be useful as tools in eicosanoid research.There is evidence linking cysLTs to cardiovascular disease and inflammation. Expression of components of the leukotriene synthesis pathway is found in human atherosclerotic lesions.17 Furthermore, genetic polymorphisms in 5-lipoxygenase pathway genes have been correlated to increased myocardial infarction and stroke risk in some populations 18 but not all. 19,20 CysLT 2 R can mediate vascular permeability, 12,21 susceptibility to gastrointestinal tract inflammation, 22 and increased vulnerability to ischemic injury in the heart 11 a...

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Intracerebroventricular injection of HAMI 3379, a selective cysteinyl leukotriene receptor 2 antagonist, protects against acute brain injury after focal cerebral ischemia in rats

Cited by 32 publications

References 52 publications

Therapeutics targeting the inflammasome after central nervous system injury

Therapeutics targeting the inflammasome after central nervous system injury

Protective effect of HAMI 3379 against high glucose-induced PC12 cell injury

Multiple-Site Activation of the Cysteinyl Leukotriene Receptor 2 Is Required for Exacerbation of Ischemia/Reperfusion Injury

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