Abstract
Objective: Cysteinyl leukotrienes (CysLTs) are potent mediators of inflammation that are associated with cerebral ischemia/reperfusion (I/R) injury. The CysLTs receptor antagonist may offer protection against ischemic injury. The present study was designed to investigate the role of zafirlukast in experimentally induced global cerebral ischemia/reperfusion (I/R) injury in mice.Methods: Global cerebral ischemia-reperfusion was induced by bilateral carotid artery occlusion for 17 min followed by 24 h reperfusion. Mice were randomly assigned to eight groups (n = 6 per group): control, sham-operated, I/R control, prednisolone treated group (5 mg/kg, p. o.) for 10 d, zafirlukast treated group (5, 10, 20 mg/kg, p. o.) for 10 d and combination group treated with zafirlukast (5 mg/kg, p. o.)+nifedipine (5 mg/kg, i. p.) for 10 d before ischemia/reperfusion. At the end of reperfusion (24 h), a blood sample was collected from retro-orbital route and mice’s brain was removed by cervical dislocation to measure serum lactate dehydrogenase (LDH), serum nitrite concentration, malondialdehyde (MDA), and cerebral infarct size.Results: Zafirlukast showed the dose-dependent neuroprotective activity by a significant decrease in lipid peroxidation, lactate dehydrogenase, serum nitrite level and cerebral infarct size. The high dose of zafirlukast (20 mg/kg, p. o.) and combination of zafirlukast (5 mg/kg, p. o.) with nifedipine (5 mg/kg, i. p.) showed the most potent neuroprotective effect against ischemic/reperfusion (I/R) group.Conclusion: This original study demonstrated the potency of zafirlukast in global cerebral ischemia/reperfusion injury. Also zafirlukast, in combination with nifedipine could represent a therapeutic approach to reduce inflammation associated with ischemia injury.
Highlights
Stroke is one of the leading causes of death and adult long-term disability worldwide, with ischemic stroke comprising more than 85% of total cases, as a consequence of a permanent or transient occlusion by either embolism or thrombosis of cerebral arteries [13]
Global cerebral ischemia of 17 min followed by 24 h reperfusion produced a significant (p = ≤0.001) increase in lactate dehydrogenase (LDH) level in I/R injury group compared to the control and sham group
Global cerebral ischemia of 17 min followed by 24 h reperfusion produced a significant (p = ≤0.001) increase in level serum total nitrate/nitrite level in I/R injury group compared to the control and sham control group
Summary
Stroke is one of the leading causes of death and adult long-term disability worldwide, with ischemic stroke comprising more than 85% of total cases, as a consequence of a permanent or transient occlusion by either embolism or thrombosis of cerebral arteries [13]. One of the main causes of global cerebral ischemia is cardiac arrest, which leads to neurological consequence to the patients [7]. The potential treatment of ischemic stroke is still lacking due to narrow therapeutic window [3]. Thrombolytic agent recombinant tissue plasminogen activator (rt-PA) mainly recommended for the treatment of ischemic stroke, the normal prognosis is unsatisfactory [13]. It is necessary to develop new therapeutic agent for the treatment of ischemic stroke
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