title: Leukotriene receptor antagonists, LY293111 and ONO-1078, protect neurons from the sPLA2-IB-induced neuronal cell death independently of blocking their receptors.
abstract: In the ischemic brain, leukotrienes (LTs) are increased and their receptor antagonists protect neurons. However, it has not yet been sufficiently clarified how antagonists for LT receptors exhibit neuroprotective effects. In the present study, we evaluated protective effects of receptor antagonists for LTB4 (LY293111) and cysteinyl LTs (ONO-1078) in the primary culture of rat cortical neurons. The group IB secretory phospholipase A2 (sPLA2-IB)-induced neuronal cell death had been established as the in vitro model for cerebral ischemia. sPLA2-IB triggered the influx of Ca(2+) into neurons via L-type voltage-dependent calcium channel (L-VDCC). Subsequently, the enzyme produced eicosanoids including LTB4 before neuronal cell death. Neither administration of LTB4 nor cysteinyl LTs such as LTC4, LTD4 and LTE4 killed neurons. However, both LY293111 and ONO-1078 significantly prevented neurons from the neurotoxicity of sPLA2-IB, suggesting that the two LT receptor blockers protected neurons through alternative pathways beside LT receptors. An L-VDCC blocker does not only inhibit the influx of Ca(2+) into neurons but also rescues neurons from the sPLA2-IB-induced neuronal cell death. The two LT receptor antagonists also blocked the sPLA2-IB-induced Ca(2+) influx significantly. Thus, LTs exhibited no neurotoxicity, but their receptor antagonists protected neurons directly in the in vitro ischemic model. Furthermore, the suppression of L-VDCC appeared to be involved in the neuroprotective effects of LY293111 and ONO-1078 independent of blocking their receptors.
authors.affiliation: Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 2-1, kami-ohno 7-Chome, Himeji, Hyogo 670-8524, Japan. yagami@himeji-du.ac.jp
authors.forename: Tatsurou
authors.initials: T
authors.lastname: Yagami
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kohma
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology*; D005260:Female; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D054497:Phospholipases A2, Secretory / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001565:Benzoates; D002867:Chromones; C094099:LY 293111; D020024:Leukotriene Antagonists; D018696:Neuroprotective Agents; D054497:Phospholipases A2, Secretory; C047681:pranlukast
keywords: Cerebral cortex; Group IB secretory phospholipase A(2); L-type voltage-dependent calcium channel; LY293111; Neuroprotection; ONO-1078