| Cerebral ischemia, traumatic brain injury and brain tumor are common CNS diseases, which cause high mortality and disability. Exploring the mechanisms under injury/anti-injury of cerebral ischemia, traumatic brain injury and brain tumor is very important to the treatment of such diseases.Cysteinyl leukotrienes (CysLTs), include LTC4, LTD4 and LTE4, are 5-lipoxygenase (5-LO) metabolites of arachidonic acid. They are potent inflammatory mediators, which can induce hyperresponsiveness and inflammation in asthmatic airways, reduce blood flow in coronary, femoral and carotid vessels, and induce tissue edema, circulatory and respiratory dysfunctions. In the brain, CysLTs were found to be increased in brain ischemia, traumatic brain injury and brain tumors. It has been reported that CysLTs can damage blood brain barrier (BBB) and induce brain edema. Inhibitors of CysLT synthesis can reduce tissue edema and plasma exudation.Two CysLT receptors have been identified and cloned, CysLT1 and CysLT2 Both of them are classical Gq protein coupled seven transmembrane proteins. A lot of CysLT receptor antagonists were discovered, such as zafirlukast, montelukast, tomelukast, pobilukast, pranlukast (ONO-1078), and MK571. They can antagonize the constriction of bronchi induced by CysLTs. Most of these antagonists are now clinically used asanti-inflammatory and anti-asthma drugs. CysTL1 and CysLT2 were primarily identified based on their pharmacological properties whether the receptor is sensitive to the antagonists or not. CysLT1 can be antagonized by the antagonists mentioned above, whereas CysLT2 cannot. The only partial antagonist available for CysLT1 is Bay u9773. By Northern blot analysis in various human tissues, CysLT1 was found to be highly expressed in spleen, peripheral blood leukocytes, while lower expressed in brain, lung, heart, colon, pancreas, prostatic gland, kidney and liver. However, the exact location of CysLTi in the brain was unknown.ONO-1078, 4-oxo-8-[p-(4-phenylbutyloxy)benzoyl-amono]-2- (tetrazd-5-yl)-4H-l-benzopyran hemihydrate, is a potent CysLT] receptor antagonist which possesses anti-inflammatory and anti-asthma effects, now clinically used for treatment of bronchial asthma as a therapeutic drug named pranlukast. It has been reported that ONO-1078 effectively inhibited the plasma exudation induced by LTC4, LTD4, antigen, and other stimuli in the airway, heart, skin, and nose of guinea pigs and rats. In the brain, ONO-1078 inhibited subarachnoid hemorrhage-induced delayed cerebral vasospasm. But it is still unclear whether ONO-1078 or other CysLT receptor antagonists have neuroprotective effects on brain ischemia.Therefore, the purposes of this study were to establish quantitative methods for evaluating cerebral ischemia firstly, then to determine whether and how CysLTi antagonist ONO-1078 protect against brain ischemia, and to reveal the exact location of CysLTi in the CNS. These are important to discover the roles of CysLTs in the brain and new therapeutic drugs for brain ischemia, also to explore the mechanism(s) under the injury and anti-injury in the brain.1. Quantitative analysis for evaluating focal cerebral ischemia in ratsMiddle cerebral artery occlusion (MCAO) is a useful and classical ischemic model for studying the mechanism of injury and anti-injury and evaluating the drug effects on brain ischemia. Computer assisted analysis of ischemic brain injure is a more objective,qualitative and accurate method. In this experiment, focal brain ischemia was induced by MCAO, and the brain was reperfused for 24 h. Neurologic deficiency scores were assessed, infarct volume, brain hemisphere area, neuron density and albumin exudation in cortex and striatum were measured with computer assisted imaging analysis. Dexamethasone (0.1 mg/kg) and nimodipine (0.4 mg/k g) were ip injected 30 min before and 2 h after MCAO to observe their neuroprotective effects. We found that MCAO for 30 min followed by reperfusion for 24 h significantly increased neurologic deficiency scores, infarct vol...
|
PDF Full Text Request