Elucidation of the Role of Transient Receptor Potential Vanilloid-1 (TRPV1) Channels in Epileptogenesis

Abstract

The transient receptor potential vanilloid-1 (TRPV1), previously known as the capsaicin receptor or vanilloid receptor 1 (VR1) is a nonselective cation channel that acts as an integrator of nociceptive information in sensory neurons and their sensory nerve endings with unmyelinated (C) or thin myelinated (Aδ) fibers. It is activated by capsaicin, resiniferatoxin, piperine, noxious heat (> 43ºC), protons, lipoxygenase products, and some endogenous cannabinoids. TRPV1 receptors are also expressed in the brain on neurons, glia cells and pericytes and might be involved in the modulation of epileptogenesis. TRPV1 modulates synaptic plasticity and neurotransmission, mediates long-term depression of glutamate release in the hippocampus and suppress excitatory transmission in dentate gyrus. TRPV1-knockout mice have altered susceptibility to hyperthermic seizures. Studies in vitro showed that capsaicin reduced epileptiform activity but increased neuronal discharge in excitable cells. Capsaicin given via systemic routes at low doses was shown to reduce seizures induced by kainic acid and pentylenetetrazole and to afford neuroprotection of hippocampus in vivo. These effects were associated with reduced oxidative stress and inflammation in brain. In contrast, high doses of capsaicin either elicited or enhanced seizures in animals. In addition, piperine, a TRPV1 agonist, demonstrated anti-epileptic activity in several animal models via a multiplicity of mechanisms. Moreover, non-psychotropic cannabinoids such as cannabidiol and cannabidivarin, the endocannabinoid anandamide, and acetaminophen demonstrated anti-epileptiform activity in vivo and in vitro via mechanisms that might involve TRPV1 receptors. By surveying recent research findings, this review article is intended to present the current research status on the involvement of TRPV1 receptors in epileptogenesis so as to stimulate further investigations into the detailed molecular mechanisms by which capsaicin as well as other chemical modalities impact epileptogenesis via modulating TRPV1 channels. (First online: Apr 12, 2021)