title: Ciproxifan, a histamine H3receptor antagonist and inverse agonist, presynaptically inhibits glutamate release in rat hippocampus.
abstract: Ciproxifan is an H3receptor antagonist and inverse agonist with antipsychotic effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus. In a synaptosomal preparation, ciproxifan reduced 4-aminopyridine (4-AP)-evoked Ca2+-dependent glutamate release and cytosolic Ca2+concentration elevation but did not affect the membrane potential. The inhibitory effect of ciproxifan on 4-AP-evoked glutamate release was prevented by the Gi/Go-protein inhibitor pertussis toxin and Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was not affected by the intracellular Ca2+-release inhibitors dantrolene and CGP37157. Furthermore, the phospholipase A2(PLA2) inhibitor OBAA, prostaglandin E2(PGE2), PGE2 subtype 2 (EP2) receptor antagonist PF04418948, and extracellular signal-regulated kinase (ERK) inhibitor FR180204 eliminated the inhibitory effect of ciproxifan on glutamate release. Ciproxifan reduced the 4-AP-evoked phosphorylation of ERK and synapsin I, a presynaptic target of ERK. The ciproxifan-mediated inhibition of glutamate release was prevented in synaptosomes from synapsin I-deficient mice. Moreover, ciproxifan reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. Our data suggest that ciproxifan, acting through the blockade of Gi/Go protein-coupled H3receptors present on hippocampal nerve terminals, reduces voltage-dependent Ca2+entry by diminishing PLA2/PGE2/EP2receptor pathway, which subsequently suppresses the ERK/synapsin I cascade to decrease the evoked glutamate release.
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan; Department of Mechanical Engineering, Yuan Ze University, Taoyuan 320, Taiwan.
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan; Department of Mechanical Engineering, Yuan Ze University, Taoyuan 320, Taiwan.
authors.forename: Tzu-Yu
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan; Department of Chemistry, Fu Jen Catholic University, No. 510, Chung-Cheng Road, Hsin-Chuang District, New Taipei City 24205, Taiwan.
authors.forename: Chia-Ying
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan.
authors.forename: Shu-Kuei
authors.initials: SK
authors.lastname: Huang
authors.affiliation: School of Medicine, Fu Jen Catholic University, No. 510, Chung-Cheng Rd., Hsin-Chuang, New Taipei 24205, Taiwan; Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan City, Taiwan. Electronic address: med0003@mail.fju.edu.tw.
authors.forename: Su-Jane
authors.initials: SJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D054828:Histamine H3 Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020864:Calcium Channels, N-Type; D018698:Glutamic Acid; D054828:Histamine H3 Antagonists; D007093:Imidazoles; C115705:ciproxifan
keywords: Ciproxifan; Gi/Go-protein/PLA(2)/PGE(2)/EP(2) pathway; Glutamate release; H(3) receptor; Hippocampus; Voltage-dependent Ca(2+) channels