title: Synthesis and biological evaluation of pyrethroid insecticide-derivatives as a chemical inducer for Bdnf mRNA expression in neurons.
abstract: Brain-derived neurotrophic factor (BDNF) plays a fundamental role in neuronal synaptic plasticity. A decrease of plasticity in the brain may be related to the pathogenesis of neurodegenerative or psychiatric disorders. Pyrethroid insecticides, which affect sodium channels in neurons, are widely used to control insect pests in agriculture and in the home. We previously found that deltamethrin (DM), a type II pyrethroid, increased Bdnf mRNA expression in cultured rat cortical neurons. However, the cyano group at the α-position of type II pyrethroids is likely susceptible to hydrolytic degradation and, its degraded product, hydrogen cyanide, could generate a cellular toxicity in the human body. To determine if the cyano group is required for the Bdnf exon IV-IX (Bdnf eIV-IX) mRNA expression induced by type II pyrethroids, for this study we synthesized a series of derivatives, in which the cyano group at the α-position was replaced with an ethynyl group. Then we added various substituents at the terminal position of the ethynyl group, and biologically evaluated the effects of these derivatives on Bdnf eIV-IX mRNA expression. These ethynyl derivatives induced the Bdnf eIV-IX mRNA expression in a concentration-dependent manner, at varying levels but lower levels than that evoked by DM. The mechanisms for the Bdnf induction and the morphological changes of neurons were the same whether the cyano or ethynyl group was included in the compounds.
authors.affiliation: Department of Organochemical Design and Synthesis, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsuya
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ihara
authors.forename: Mamoru
authors.initials: M
authors.lastname: Fukuchi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Honma
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Itoh
authors.forename: Akiko
authors.initials: A
authors.lastname: Tabuchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Nemoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tsuda
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007306:Insecticides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011722:Pyrethrins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015222:Sodium Channels / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007306:Insecticides; D011722:Pyrethrins; D012333:RNA, Messenger; D015222:Sodium Channels