Neuroprotective effect of ONO-1078, a leukotriene receptor antagonist, on transient global cerebral ischemia in rats.
OBJECTIVE
To determine whether ONO-1078 [pranlukast, 4-oxo-8-[p-(4-phenylbutyloxy)benzoyl-amono]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate], a potent leukotriene receptor antagonist, possesses a neuroprotective effect on global cerebral ischemia in rats, and to explore its possible mechanism of action.


METHODS
Transient global cerebral ischemia was induced by four-vessel occlusion for 10 min and followed by 72-h reperfusion. ONO-1078 (0.03-0.3 mg/kg) and edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one, a neuroprotective agent) 10 mg/kg were ip injected 30 min before ischemia and 1 h after reperfusion, and once a day afterward. Neurological outcome was evaluated before ischemia and 24, 48, 72 h after reperfusion. Neuron density, the expressions of N-methyl-D-aspartate (NMDA) receptor subunit proteins (NR1, NR2A, NA2B) and vascular cell adhesion molecule 1 (VCAM-1) in the cerebral cortex and hippocampus were measured at 72 h after reperfusion.


RESULTS
ONO-1078 (0.1, 0.3 mg/kg) and edaravone (10 mg/kg) improved ischemia-induced neurological deficiency and reduced neuron death. ONO-1078 (0.1, 0.3 mg/kg) significantly inhibited the enhanced expression of NMDA receptor subunit protein NR2A in the cortex and VCAM-1 in the hippocampus of ischemic rats.


CONCLUSIONS
ONO-1078 possesses a neuroprotective effect on global cerebral ischemia in rats, and its mechanism may be partly related to the inhibition of the upregulation of NR2A and VCAM-1 in different regions of the brain.
Zhang
Li-Hui
LH
Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310031, China.
Wei
Er-Qing
EQ
D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D002867:Chromones / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020024:Leukotriene Antagonists / Q000627:therapeutic use*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D002867:Chromones; D020024:Leukotriene Antagonists; C120997:NR2A NMDA receptor; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D019010:Vascular Cell Adhesion Molecule-1; C047681:pranlukast