Abstract
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, withtrans-permethrin more potent thancis-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.
Footnotes
-
Send reprint requests to: Masaaki Tsuda, Toyama Medical and Pharmaceutical University, Department of Biological Chemistry, Faculty of Pharmaceutical Sciences, Sugitani 2630, Toyama 930-0194, Japan. E-mail: tsuda{at}ms.toyama-mpu.ac.jp
-
↵1 This study was supported by a grant-in-aid for Core Research for Evolutional Science and Technology (CREST) from the Science and Technology Corporation of Japan.
- Abbreviations:
- BDNF
- brain-derived neurotrophic factor
- CGC
- cerebellar granule cell
- DMEM
- Dulbecco's modified Eagle's medium
- FCS
- fetal calf serum
- RT
- room temperature
- LDH
- lactate dehydrogenase
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- AP-1
- activator protein-1
- Na+-ch
- sodium channel
- L-VDCC
- L-type voltage-dependent calcium channel
- Received May 17, 2000.
- Accepted September 6, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|