Cysteinyl leukotriene receptor 2 is spatiotemporally involved in neuron injury, astrocytosis and microgliosis after focal cerebral ischemia in rats

Zhao, Chun-zhen; Zhao, Bing; Zhang, X.Y.; Huang, Xueqin; Shi, Wenzhen; Liu, H.L.; Fang, San‐Hua; Ya-ping, LU; Zhang, W.P.; Tang, Fanren; Wei, Er-qing

doi:10.1016/j.neuroscience.2011.05.066

Cited by 42 publications

(45 citation statements)

References 43 publications

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“…Based on the spatiotemporal properties of the cellular responses to ischemia and reported findings [26,30] , we CysLT 1 receptors were mainly localized in neurons and neutrophils, and no immunoreactivity was found in astrocytes and microglia (Fig. 7).…”

Section: T-test)mentioning

confidence: 81%

“…Another important finding is that AQP4-KO mice have been reported in rat brain after MCAO [26,30] . However, in the present study we focused on the delayed phase (72 h) to reveal the inflammatory responses in AQP4-KO mice.…”

Section: Discussionmentioning

confidence: 91%

“…Post-ischemic inflammation involves the accumulation of inflammatory cells (resident microglia and blood-derived leukocytes) and the induction of pro-inflammatory molecules [20][21][22] . As inflammatory mediators, cysteinyl leukotrienes (CysLTs) through activating their receptors (CysLT 1 and CysLT 2 ) evoke post-ischemic inflammation [23][24][25][26] . CysLT 1 and CysLT 2 receptors are upregulated and localized in activated microglia and proliferated astrocytes in the ischemic brain in rats [24,26] .…”

Section: Introductionmentioning

confidence: 99%

“…As inflammatory mediators, cysteinyl leukotrienes (CysLTs) through activating their receptors (CysLT 1 and CysLT 2 ) evoke post-ischemic inflammation [23][24][25][26] . CysLT 1 and CysLT 2 receptors are upregulated and localized in activated microglia and proliferated astrocytes in the ischemic brain in rats [24,26] . The…”

Section: Introductionmentioning

confidence: 99%

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Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

Shi

Zhao

et al. 2012

Neurosci. Bull.

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Objective Aquaporin-4 (AQP4), the main water channel protein in the brain, plays a critical role in water homeostasis and brain edema. Here, we investigated its role in the inflammatory responses after focal cerebral ischemia. MethodsIn AQP4-knockout (KO) and wild-type mice, focal cerebral ischemia was induced by 30 min of middle cerebral arterial occlusion (MCAO). Ischemic neuronal injury and cellular inflammatory responses, as well as the expression and localization of cysteinyl leukotriene CysLT 2 and CysLT 1 receptors, were determined at 24 and 72 h after MCAO.Results AQP4-KO mice showed more neuronal loss, more severe microglial activation and neutrophil infiltration, but less astrocyte proliferation in the brain after MCAO than wild-type mice. In addition, the protein levels of both CysLT 1 and CysLT 2 receptors were up-regulated in the ischemic brain, and the up-regulation was more pronounced in AQP4-KO mice. The CysLT 1 and CysLT 2 receptors were primarily localized in neurons, microglia and neutrophils; those localized in microglia and neutrophils were enhanced in AQP4-KO mice. Conclusion AQP4 may play an inhibitory role in postischemic inflammation.

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Section: T-test)mentioning

confidence: 81%

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

Shi

Zhao

et al. 2012

Neurosci. Bull.

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“…It has been reported that the expression of CysLT 1 Rs and CysLT 2 Rs is upregulated in the brain after focal cerebral ischemia. These upregulated receptors are distributed in injured neurons in the acute phase (∼24 hours) and in activated microglia and proliferating astrocytes in the late phases (3-28 days) (Fang et al, , 2007Zhao et al, 2011). These findings suggest that CysLT 1 Rs and CysLT 2 Rs mediate acute ischemic neuronal injury and sequential microgliosis and astrocytosis in vivo.…”

Section: Introductionmentioning

confidence: 76%

HAMI 3379, a CysLT₂ Receptor Antagonist, Attenuates Ischemia-Like Neuronal Injury by Inhibiting Microglial Activation

Zhang

Wang

et al. 2013

J Pharmacol Exp Ther

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The cysteinyl leukotrienes (CysLTs) are inflammatory mediators closely associated with neuronal injury after brain ischemia through the activation of their receptors, CysLT1R and CysLT2R. Here we investigated the involvement of both receptors in oxygen-glucose deprivation/recovery (OGD/R)-induced ischemic neuronal injury and the effect of the novel CysLT2R antagonistin comparison with the CysLT1R antagonist montelukast. In primary neurons, neither the nonselective agonist leukotriene D4 (LTD4) nor the CysLT2R agonist N-methyl-leukotriene C4 (NMLTC4) induced neuronal injury, and HAMI 3379 did not affect OGD/R-induced neuronal injury. However, in addition to OGD/R, LTD4 and NMLTC4 induced cell injury and neuronal loss in mixed cultures of cortical cells, and neuronal loss and necrosis in neuron-microglial cocultures. Moreover, they induced phagocytosis and cytokine release (interleukin-1b and tumor necrosis factor-a) from primary microglia, and conditioned medium from the treated microglia induced neuronal necrosis. HAMI 3379 inhibited all of these responses, and its effects were the same as those of CysLT2R interference by CysLT2R short hairpin RNA, indicating CysLT2R dependence. In comparison, montelukast moderately inhibited OGD/R-induced primary neuronal injury and most OGD/R-and LTD4-induced (but not NMLTC4-induced) responses in mixed cultures, cocultures, and microglia. The effects of montelukast were both dependent and independent of CysLT1Rs because interference by CysLT1R small interfering RNA had limited effects on neuronal injury in neuron-microglial cocultures and on cytokine release from microglia. Our findings indicated that HAMI 3379 effectively blocked CysLT2R-mediated microglial activation, thereby indirectly attenuating ischemic neuronal injury. Therefore, CysLT2R antagonists may represent a new type of therapeutic agent in the treatment of ischemic stroke.

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The role of astrocytes in mediating exogenous cell‐based restorative therapy for stroke

Liu

Xin

et al. 2013

Glia

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Astrocytes have not been a major therapeutic target for the treatment of stroke, with most research emphasis on the neuron. Given the essential role that astrocytes play in maintaining physiological function of the central nervous system and the very rapid and sensitive reaction astrocytes have in response to cerebral injury or ischemic insult, we propose to replace the neurocentric view for treatment with a more nuanced astrocytic centered approach. In addition, after decades of effort in attempting to develop neuroprotective therapies, which target reduction of the ischemic lesion, there are no effective clinical treatments for stroke, aside from thrombolysis with tissue plasminogen activator, which is used in a small minority of patients. A more promising therapeutic approach, which may affect nearly all stroke patients, may be in promoting endogenous restorative mechanisms, which enhance neurological recovery. A focus of efforts in stimulating recovery post stroke is the use of exogenously administered cells. The present review focuses on the role of the astrocyte in mediating the brain network, brain plasticity, and neurological recovery post stroke. As a model to describe the interaction of a restorative cell-based therapy with astrocytes, which drives recovery from stroke, we specifically highlight the subacute treatment of stroke with multipotent mesenchymal stromal cell therapy.

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Cysteinyl leukotriene receptor 2 is spatiotemporally involved in neuron injury, astrocytosis and microgliosis after focal cerebral ischemia in rats

Cited by 42 publications

References 43 publications

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

HAMI 3379, a CysLT₂ Receptor Antagonist, Attenuates Ischemia-Like Neuronal Injury by Inhibiting Microglial Activation

The role of astrocytes in mediating exogenous cell‐based restorative therapy for stroke

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Cysteinyl leukotriene receptor 2 is spatiotemporally involved in neuron injury, astrocytosis and microgliosis after focal cerebral ischemia in rats

Cited by 42 publications

References 43 publications

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

Aggravated inflammation and increased expression of cysteinyl leukotriene receptors in the brain after focal cerebral ischemia in AQP4-deficient mice

HAMI 3379, a CysLT2 Receptor Antagonist, Attenuates Ischemia-Like Neuronal Injury by Inhibiting Microglial Activation

The role of astrocytes in mediating exogenous cell‐based restorative therapy for stroke

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HAMI 3379, a CysLT₂ Receptor Antagonist, Attenuates Ischemia-Like Neuronal Injury by Inhibiting Microglial Activation