Pranlukast, A Cysteinyl Leukotriene Receptor 1 Antagonist, Protects Mice Against Brain Cold Injury

Cysteinyl leukotrienes (CysLTs, including LTC₄, LTD₄ and LTE₄) are the 5-lipoxygenase metabolites of arachidonic acid. CysLTs are potent inflammatory mediators and involved in several inflammatory pathological process through two subtypes of cysteinyl leukotriene receptors (CysLT₁ and CysLT₂ receptors). In the central nervous system, CysLTs are involved in various brain injuries, such as cerebral ischemia, brain trauma and brain tumors. The pathophysiological properties of cerebral ischemia are similar to those of cerebral trauma. The level of CysLTs is increased in both the ischemic brain and traumatic brain, and the increased CysLTs are correlated to brain edema. We have reported CysLTi receptor selective antagonists, pranlukast and montelukast, protect mice and rats against both focal and global cerebral ischemia. Therefore, we propose that CysLTi receptor selective antagonists, pranlukast, may have similar protective effects on brain trauma.The purpose of this study is to establish brain cold injury model at first, and then to determine whether CysLTi receptor selective antagonists, pranlukast, has protective effects on brain cold injury, at last to investigate the mechanism of action.Brain cold injury was induced according to the reported method with somemodifications. Mice motor ability was assessed by comprehend score, and brain lesion volume and brain edema were evaluated by TTC staining. Toluidine blue staining and NeuN (a specific marker for neurons) immunostaining were used to assess neuronal injury and neuron density. The degenerative neurons were detected by Fluoro-Jade B fluorescent staining. Finally we evaluated permeability of blood-brain barrier by IgG immunostaining.The results indicated that no motor ability defect was found in mice with brain cold injury, but obvious brain injury and brain edema were found. We found that pranlukast significantly reduced cold-induced lesion volume (0.3 mg/kg) and the percentage increase in lesioned hemisphere volume (0.03-0.3 mg/kg) 24 h after injury;but it did not show any effect 72 h after injury. Pranlukast also significantly inhibited neuron loss 24 h (0.1 mg/kg) and 72 h (0.1-0.3 mg/kg) after injury, and decreased the density of degenerated neurons 24 h (0.01-0.3 mg/kg) and 72 h (0.03-0.3 mg/kg) after injury. In addition, pranlukast (0.1-0.3 mg/kg) significantly reduced endogenous IgG exudation both 24 h and 72 h after injuryTherefore, we made the following conclusions:1. CysLT! receptor selective antagonist, pranlukast, has protective effects on brain trauma.2. The protective effects of pranlukast on brain cold injury are related to the decrease in BBB permeability and accordingly attenuation of brain edema.3. CysLTi receptor selective antagonists may have a therapeutic potential in the treatment of brain injury.