| Cerebral ischemia remains a major cause of death and disability worldwide. Therefore, it would be important to study the mechanisms of ischemic brain injury and its protection, and to develop new therapeutics targeting downstream events in the ischemic cascade. N-methyl-D-aspartate (NMDA) receptors play an important role in the pathological processes of ischemic neuron injury. Cerebral ischemia induces the abnormal expression and activation of NMDA receptors, and an excessive calcium influx, which further results in progressive irreversible neuronal damage and delayed cell death. On the other hand, inflammatory cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), are also involved in cerebral ischemic injury. Cerebral ischemia upregulates inflammatory cell adhesion molecules, which may induce the subsequent inflammatory reactions and neural injury. ONO-1078 {pranlukast, 4-oxo-8-[p-(4-phenylbutyloxy) benzoyl-amono]-2-(tetrazol-5-yl)-4H-l-benzopyran hemihydrate} is a potent antagonist of the recaptor for cysteinyl leukotrienes (LTC4, D4, and E4), which possesses anti-inflammatory and anti-asthma effects, and is clinically used as a therapeuticdrug of bronchial asthma. Increasing evidence has demonstrated the involvement of cysteinyl leukotrienes in cerebral ischemic injury. The production of cysteinyl leukotrienes increases in gerbil global cerebral ischemia and rat focal cerebral ischemia, and 5-lipoxygenase inhibitors and NMDA receptor antagonists inhibit both cysteinyl leukotriene production and neurological injury. These findings support the therapeutic potentials of ONO-1078 in treatment of cerebral ischemia.Models of focal cerebral ischemia in rats and mice have been established in our laboratory recently. Also, we have found that ONO-1078 is protective against ischemic brain injury in focal cerebral ischemia. To study the mechanisms and treatments of global cerebral ischemia resulting from cardiac arrest, stroke and hypoxia, we in this study established global cerebral ischemia model by four-vessel occlusion (4VO) in rats. Then, we investigated the time course of brain injury and the expression of NMDA receptors and VCAM-1 in rats with transient global cerebral ischemia. Also, we evaluated the neuroprotective effect of ONO-1078 on global cerebral ischemia. Lastly, we tried to explore the possible mechanisms of ONO-1078 by NMDA-induced injury model. Edaravone (MCI-186, 3-methyl-l-phenyl-2-pyrazolin-5-one), a novel neuroprotective agent for ischemic stroke, was used as a positive control in this study.We hoped to elucidate the pharmacological characteristics of neuroprotection by ONO-1078 and find a way to deeply research global cerebral ischemic injury and its protection mechanisms, and find effective compounds for therapeutic invention of cerebral ischemia.1 Time course of brain injury and expressions of NMDA receptors and VCAM-1 after transient global cerebral ischemia in rats1.1 Transient global cerebral ischemic model induced by 4VO in ratsGlobal cerebral ischemia was induced by 4VO method. Rats were anesthetized with chloral hydrate (350 mg / kg, ip), then fixed on a stereotaxic apparatus. An incision was made behind the occipital bone directly overlying the first two cervical vertebrae. The paraspinal muscles wereseparated from the midline, the right and left alar foramina of the first cervical vertebra were exposed. A 0.5 mm electrocautery needle was inserted through each alar foramen, and both vertebral arteries were electrocauterized and permanently occluded. Meanwhile, through a ventral midline neck incision, an atraumatic arterial clasp was loosely placed around both common carotid arteries without interrupting carotid blood flow. After these procedures, the incisions were closed, and the animals were fasted overnight.Twenty-four h later, the rats were randomly divided into groups and subjected to either global cerebral ischemia or sham operation. Global cerebral ischemia in the conscious rats was induced by tightening the carotid artery cla...
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