Deltamethrin, a Pyrethroid Insecticide, Is a Potent Inducer for the Activity-Dependent Gene Expression of Brain-Derived Neurotrophic Factor in Neurons

Abstract

The mRNA expression of brain-derived neurotrophic factor (BDNF) is controlled in an activity-dependent manner through Ca 2ϩ influx into neurons. Pyrethroids are widely used insecticides of low acute toxicity in mammals, but their effects on sodium channels are known to lead to hyperexcitation in neuronal cells of insects. In this study, we found that deltamethrin, a type II pyrethroid insecticide, was highly effective in inducing BDNF expression in culture and in the rat brain. Addition of deltamethrin to rat cortical cells in culture markedly increased the expression of BDNF exon III-V mRNA and protein, dependent upon the neuronal activity accompanying the influx of Ca 2ϩ into neurons and the Ca 2ϩ influx-dependent phosphorylation of extracellular signal-regulated kinases 1/2. The elevated expression was maintained for at least 48 h, even after deltamethrin was withdrawn from the culture medium. Comparison of the effects of selected pyrethroids on the expression revealed that type II but not type I pyrethroids effectively induced BDNF mRNA expression. In addition, administration of deltamethrin to rats increased the level of BDNF protein in the cerebral cortex and hippocampus. These results indicate that deltamethrin is a potent inducer of BDNF expression in neurons and that it may induce neuronal hyperexcitation if it reaches the brain.

Mechanisms of Pyrethroid Insecticide-Induced Stimulation of Calcium Influx in Neocortical Neurons

“…In rat primary cortical cultures, pyrethroids, including fenvalarate, cypermethrin, cyfluthrin, and deltamethrin, differentially increase BDNF mRNA expression levels by 15-to 150-fold over control (Imamura et al, 2006). This effect was thought to be triggered primarily through Ca 2ϩ influx associated with the activation of TTX-sensitive VGSCs (Imamura et al, 2006). The present results are consistent with this mode of action for activation of BDNF expression.…”

“…The rank order of efficacy for Ca 2ϩ influx was similar to that for sodium influx (Cao et al, 2009) with the exception of S-bioallethrin, which is the least efficacious compound on Ca 2ϩ influx. In rat primary cortical cultures, pyrethroids, including fenvalarate, cypermethrin, cyfluthrin, and deltamethrin, differentially increase BDNF mRNA expression levels by 15-to 150-fold over control (Imamura et al, 2006). This effect was thought to be triggered primarily through Ca 2ϩ influx associated with the activation of TTX-sensitive VGSCs (Imamura et al, 2006).…”

Effects of early life permethrin exposure on spatial working memory and on monoamine levels in different brain areas of pre-senescent rats

“…The biological effects of pyrethroid are in part caused by their ability to alter neuronal activity since they interact with specific binding sites of voltage-gated sodium channel (VGSC) slowing the rate of VGSC closing, prolonging the inward sodium conductance and then shifting the membrane to more polarized potentials (Narahashi, 1996). A secondary consequence to cell membrane depolarization is an increased Ca +2 influx into the neurons through voltage-gated calcium channel (VGCC) that contributes to impact neuronal synaptic plasticity of neurons (Imamura et al, 2006). These changes in synaptic transmission may alter neuronal function and may contribute to excitotoxicity and neurodegenerative pathology (Gomez-Villafuertes et al, 2007).…”

Antibody to Varicella-Zoster Virus Immediate-Early Protein 62 Augments Allodynia in Zoster via Brain-Derived Neurotrophic Factor

“…Although the transcriptions of Bdnf and arc were baseline in rat cortical neurons without BDNF, BDNF alone enhanced the transcription of Bdnf and arc. The combination of BDNF with anti-IE62 MAb significantly augmented their transcription (15,34), whereas anti-IE62 MAb alone had no effect (Fig. 3E).…”

“…Primary cortical neuron cultures were prepared from the cerebral cortices of SpragueDawley rat embryos (Japan SLC, Shizuoka, Japan) on the 17th day of gestation (34). Total cellular RNA was extracted by the acid guanidine phenol-chloroform method with Isogen (Nippon Gene, Japan) (15). The quantitative PCR amplification of rat BDNF exons IV to IX (1), arc cDNA, and ␤-actin cDNA was performed after DNase treatment using arc (sense, (5Ј-CGCTGGAAGAAGT CCATCAA-3Ј; antisense, 5Ј-GGGCTAACAGTGTAGTCGTA-3Ј) and ␤-actin (sense, 5Ј-TTTGAGACCTTCAACACCCC-3Ј; antisense, (5Ј-ACGATTTCCCT CTCAGCTGT-3Ј) primers, and the expression level of each mRNA was normalized using the level of ␤-actin mRNA.…”