Interference of TRPV1 function altered the susceptibility of PTZ-induced seizures

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is widely distributed in the central nervous system (CNS) including hippocampus, and regulates the balance of excitation and inhibition in CNS, which imply its important role in epilepsy. We used both pharmacological manipulations and transgenic mice to disturb the function of TRPV1 and then studied the effects of these alterations on the susceptibility of pentylenetetrazol (PTZ)-induced seizures. Our results showed that systemic administration of TRPV1 agonist capsaicin (CAP, 40 mg/kg) directly induced tonic-clonic seizures (TCS) without PTZ induction. The severity of seizure was increased in lower doses of CAP groups (5 and 10 mg/kg), although the latency to TCS was delayed. On the other hand, systemic administration of TRPV1 antagonist capsazepine (CPZ, 0.05 and 0.5 mg/kg) and TRPV1 knockout mice exhibited delayed latency to TCS and reduced mortality. Furthermore, hippocampal administration of CPZ (10 and 33 nmol/μL/side) was firstly reported to increase the latency to TCS, decrease the maximal grade of seizure and mortality. It is worth noting that decreased susceptibility of PTZ-induced seizures was observed in hippocampal TRPV1 overexpression mice and hippocampal CAP administration (33 nmol/μL/side), which is opposite from results of systemic agonist CAP. Our findings suggest that the systemic administration of TRPV1 antagonist may be a novel therapeutic target for epilepsy, and alteration of hippocampal TRPV1 function exerts a critical role in seizure susceptibility.

Inhibition of transient potential receptor vanilloid type 1 suppresses seizure susceptibility in the genetically epilepsy‐prone rat

“…Furthermore, the severity of PTZ‐induced tonic‐clonic seizures was decreased in TRPV1‐deficient mice . Surprisingly, decreased severity of PTZ‐induced tonic‐clonic seizures was also reported in mice with an overexpression of TRPV1 channels in the hippocampus . The severity of PTZ‐induced seizures was also reduced after intrahippocampal administration of either TRPV1 channel agonist or antagonist .…”

“…11 Surprisingly, decreased severity of PTZ-induced tonic-clonic seizures was also reported in mice with an overexpression of TRPV1 channels in the hippocampus. 22 The severity of PTZ-induced seizures was also reduced after intrahippocampal administration of either TRPV1 channel agonist or antagonist. 22 Thus, it has been suggested that in mice with TRPV1 channel overexpression, PTZ administration was not able to further increase TRPV1 channel function and neuronal excitability in the hippocampus, leading to decreased seizure susceptibility 22 .…”

“…For instance, TRPV1 antagonist CPZ suppressed PTZ‐induced seizures, while the TRPV1 agonist capsaicin reduced the prevalence of maximal electroshock‐induced tonic seizures and PTZ‐induced tonic‐clonic seizures . However, inhibition of TRPV1 channels had no effect on the severity of PTZ‐induced seizures . Furthermore, the severity of PTZ‐induced tonic‐clonic seizures was decreased in TRPV1‐deficient mice .…”

“…12,21 However, inhibition of TRPV1 channels had no effect on the severity of PTZ-induced seizures. 10,22 Furthermore, the severity of PTZ-induced tonic-clonic seizures was decreased in TRPV1-deficient mice. 11 Surprisingly, decreased severity of PTZ-induced tonic-clonic seizures was also reported in mice with an overexpression of TRPV1 channels in the hippocampus.…”

Endocannabinoids

“…Another group of potential molecular targets of CBD, TRP channels, such as TRPV 1 have also been proposed as potential mediators of the antiepileptic effects of CBD (De Petrocellis and . Although the precise role of TRPV 1 in the regulation of network excitability has not yet been fully elucidated, and may depend on the experimental paradigm (Manna and Umathe 2012;Jia et al 2015;von Rüden et al 2015a), it has been suggested that TRPV 1 is phosphorylated by increased neuronal activity and that the main function of CBD (and also cannabidivarin) is to trigger TRPV 1 dephosphorylation, thereby desensitizing the ion channel and thus reducing excitability to produce an antiepileptic effect (Iannotti et al 2014). Finally, perhaps one of the most exciting recent development is the potential antagonistic effect of CBD on the recently characterized G-protein-coupled receptor GPR55 (Ryberg et al 2007).…”