Repression of activity-dependent c-fos and brain-derived neurotrophic factor mRNA expression by pyrethroid insecticides accompanying a decrease in Ca(2+) influx into neurons.
Permethrin, a type I pyrethroid insecticide, is known to affect sodium channels of neurons and prolong sodium currents. On the other hand, the expression of brain-derived neurotrophic factor (BDNF) and c-fos genes is activated through Ca(2+) influx into neurons, in an activity-dependent manner. In this study, therefore, we investigated whether permethrin influenced the Ca(2+) signal-induced expression of these genes. In primary culture of mouse cerebellar granule cells (CGCs), stimulation with veratridine, a potent agonist for sodium channels, which causes membrane depolarization in neurons, induced c-fos and BDNF mRNA expression accompanying the Ca(2+) influx into neurons. Pretreatment with permethrin at doses nontoxic to CGCs repressed the induction of these genes dose dependently, with trans-permethrin more potent than cis-permethrin. Consistent with this, the increase in Ca(2+) influx caused by veratridine was repressed by permethrin. The membrane depolarization induced by elevating the potassium (K(+)) concentration in medium (high K(+)) caused the activation of c-fos and BDNF genes, which was also repressed by permethrin. Immunoblotting analysis of c-Fos and a gel-mobility assay of AP-1 DNA-binding activity supported the decrease in c-Fos synthesis in permethrin-treated CGCs. The type II pyrethroid cypermethrin also affected the expression of these genes but less effectively than permethrin. Thus, pyrethroids inhibit the activity-dependent gene expression in neurons.
Imamura
L
L
Toyama Medical and Pharmaceutical University, Department of Biological Chemistry, Faculty of Pharmaceutical Sciences, Toyama, Japan.
Hasegawa
H
H
Kurashina
K
K
Hamanishi
A
A
Tabuchi
A
A
Tsuda
M
M
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects*; D007306:Insecticides / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D026023:Permethrin; D011188:Potassium / Q000494:pharmacology; D011722:Pyrethrins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014701:Veratridine / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D007306:Insecticides; D011722:Pyrethrins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D026023:Permethrin; D014701:Veratridine; D004247:DNA; D011188:Potassium; D002118:Calcium