Vol. 295, Issue 3, 1175-1182, December 2000

Repression of Activity-Dependent c-fos and Brain-Derived Neurotrophic Factor mRNA Expression by Pyrethroid Insecticides Accompanying a Decrease in Ca²⁺ Influx into Neurons¹

Lisa Imamura , Hiroshi Hasegawa, Kaori Kurashina, Ayako Hamanishi, Akiko Tabuchi and Masaaki Tsuda

Toyama Medical and Pharmaceutical University, Department of Biological Chemistry, Faculty of Pharmaceutical Sciences, Toyama, Japan (L.I., H.H., K.K., A.H., A.T., M.T.); and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan (L.I., A.T., M.T.)

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 Ca²⁺ influx into neurons, in an activity-dependent manner. In this study, therefore, we investigated whether permethrin influenced the Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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.