Therapeutic Effects Of Cysteinyl Leukotriene Receptor-1 Antagonists On Cerebral Ischemia

Cysteinyl leukotrienes (CysLTs, including LTC4, LTD4 and LTE4) are the 5-lipoxygenase (5-LOX) metabolites of arachidonic acid. CysLTs are potent inflammatory mediators and involved in various diseases via activating their receptors (CysLT1 and CysLT2). They can induce smooth muscle spasm, microvascular leakage and other pathophysiological processes. In the central nervous system, CysLTs are also involved in pathogenesis of various diseases, such as cerebral ischemia, trauma, hemorrhage, tumor, encephalomyelitis, multiple sclerosis, epileptic seizures and aging. Production of CysLTs is increased in the ischemic brain, and the increased CysLTs are correlated to blood-brain barrier (BBB) dysfunction and brain edema. It has been reported that 5-LOX inhibitors, such as AA861, MK-886 and nordihydroguaiaretic acid, have protective effects on cerebral ischemia, and our previous studies also show the protective effect of CysLTi receptor antagonist, pranlukast (ONO-1078). Therefore, these findings suggest that intervening pathway of CysLTs may be a possible therapeutic strategy of cerebral ischemia.A lot of selective CysLTi receptor antagonists have been developed, for example pranlulukast (ONO-1078), montelukast and zafirlukast. Some of them are used for treatment of bronchial asthma clinically because of their potent anti-inflammatory effects.Recently, we found that pranlukast, a CysLT1 receptor antagonist, protects mice and rats against focal and global cerebral ischemia. In addition to protection of neurons against ischemic injury, it can also inhibit BBB dysfunction, microvascular leakage and brain edema after cerebral ischemia. However, whether the effect of pranlukast is its special effect or a common effect of CysLTi receptor antagonists is unknown. The anti-inflammatory effects of CysLTi receptor antagonists needs to be further investigated. In addition, only short-term neuroprotective effects of CysLTi antagonists have been evaluated within 24-72 h in stroke models. Whether these effects are long lasting (such as 4-10 w after ischemia) is still unknown. Since the effects of CysLTi receptor antagonists may be mediated by antagonizing CysLTi receptor in the brain, the expression and distribution of CysLTi receptor in the brain, especially after ischemia, should be clarified to explain the effects of CysLTi receptor antagonists.Therefore, the purpose this study was to further determine the neuroprortective effects of CysLTi receptor antagonists and its possible mechanisms. We evaluated the neuroprotective effect of montelukast on acute cerebral ischemia, observed the anti-inflammatory effect of pranlukast on inflammatory reactions following cerebral ischemia, and its long-term neuroprotective effect on chronic cerebral ischemia in mice, and investigated the expression of CysLTi receptor in the brain after ischemia in rats.PartiMontelukast, a cysteinyl leukotriene receptor-1 antagonist, dose- andtime-dependently protects against focal cerebral ischemia in miceWe have reported that pranlukast, a CysLTi receptor antagonist, protects rats and mice against cerebral ischemia. We, in this part, further determined the neuroprotective effect of montelukast, another CysLTi receptor antagonist, on focal cerebral ischemia in mice to confirm whether this protective effect is a common effect of CysLTi receptor antagonists. Moreover, the dose- and time-dependencies of the effect of montelukast were also assessed. Permanent focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in mice. Montelukast was injected intraperitoneally either withmultiple doses (once a day for 3 days and 30 min before MCAO) or single doses (at 30 min before, 30 min after, or 1 h after MCAO) respectively, and pranlukast and edaravone were used as controls. The neurological deficits, infarct volumes, brain edema, neuron density, and Evans blue extravasation in the brain were determined 24 h after MCAO. We found that pretreatment with multiple doses or single dose of montelukast (0.1 and 1.0 mg/kg) before MCAO significantly attenuated all...