Repression of activity-dependent c-fos and brain-derived neurotrophic factor mRNA expression by pyrethroid...

Area of Science:

• Neuroscience
• Molecular Biology
• Toxicology

Background:

• Pyrethroid insecticides, such as permethrin, are known to target neuronal sodium channels.
• Brain-derived neurotrophic factor (BDNF) and c-fos gene expression are regulated by calcium (Ca2+) influx in an activity-dependent manner.

Purpose of the Study:

• To investigate the effect of permethrin on Ca2+ signal-induced expression of BDNF and c-fos genes in neurons.

Main Methods:

• Primary culture of mouse cerebellar granule cells (CGCs) were used.
• Stimulation with veratridine or high potassium (K+) to induce membrane depolarization and Ca2+ influx.
• Treatment with permethrin and cypermethrin.
• Analysis of c-fos and BDNF mRNA expression via RT-PCR.
• Immunoblotting for c-Fos protein.
• Gel-mobility assay for AP-1 DNA-binding activity.

Main Results:

• Veratridine and high K+ induced c-fos and BDNF mRNA expression, accompanied by Ca2+ influx.
• Permethrin pretreatment repressed this gene induction dose-dependently.
• Permethrin inhibited veratridine-induced Ca2+ influx.
• Trans-permethrin was more potent than cis-permethrin.
• Type II pyrethroid cypermethrin also affected gene expression, but less effectively than permethrin.
• Reduced c-Fos synthesis and AP-1 DNA-binding activity were observed in permethrin-treated cells.

Conclusions:

• Pyrethroids, including permethrin, inhibit activity-dependent gene expression in neurons.
• This inhibition is mediated by the suppression of Ca2+ influx into neurons.
• Permethrin's neurotoxic effects may involve the disruption of neuronal activity-dependent gene regulation.