Permethrin induces epileptic susceptibility via activation of Na+ channels and rise in glutamate

Permethrin, a common pyrethroid insecticide, is extensively used to control insect pests and has been widely detected in the environment. A growing body of epidemiological studies has revealed a substantial increase in the prevalence of epilepsy among individuals highly exposed to pesticides. However, the mechanism of action of permethrin in epilepsy remains elusive. In this study, we investigate the effects of permethrin on zebrafish and mice exposed to environmentally relevant concentrations. Acute exposure to permethrin induces dose-dependent epileptiform symptoms in zebrafish, including whirlpool-like movement, clonus-like convulsions, nystagmus and neuronal hyperactivity. Extended exposure results in neuronal hyperexcitation, impaired neurogenesis and enhanced glial cell hyperplasia in zebrafish. Additionally, pre-exposure to permethrin significantly increases susceptibility to seizures in mice. Mechanistically, the effects of permethrin are conserved across different species, promoting the activation of sodium ion channels, particularly Nav1.6. This activation increases glutamate levels, which play a critical role in epileptiform symptoms. Our findings suggest that permethrin exposure leads to the activation of sodium ion channels and disrupts the balance between excitatory versus inhibitory neurotransmitters, resulting in seizure-like symptoms and increased susceptibility to epilepsy. Sodium channels and neurotransmitter balance may be protective targets against permethrin exposure.