α-Spinasterol, a TRPV1 receptor antagonist, elevates the seizure threshold in three acute seizure tests in mice

Abstract

α-Spinasterol is a plant-derived compound which was reported to act as a selective antagonist for the transient receptor potential vanilloid 1 (TRPV1) receptor. Several studies revealed that the TRPV1 receptors might modulate seizure activity in animal models of seizures and epilepsy. The aim of the present study was to investigate the effect of α-spinasterol on the seizure threshold in three acute models of seizures, i.e., in the intravenous (i.v.) pentylenetetrazole (PTZ) seizure test, in the maximal electroshock seizure threshold (MEST) test and in the model of psychomotor seizures induced by 6 Hz stimulation in mice. Our results revealed significant anticonvulsant effect of α-spinasterol in all the used seizure tests. In the i.v. PTZ test, statistically significant elevation was noted in case of the threshold for myoclonic twitches (doses of 0.1–1 mg/kg) and generalized clonus seizures (doses of 0.5 and 1 mg/kg) but not for tonic seizures. The studied TRPV1 antagonist also increased the threshold for tonic hindlimb extension in the MEST (doses of 0.5 and 1 mg/kg) and 6 Hz psychomotor seizure (doses of 0.1 and 0.5 mg/kg) tests in mice. Furthermore, α-spinasterol did not produce any significant impairment of motor coordination (assessed in the chimney test) and muscular strength (investigated in the grip-strength test) and it did not provoke significant changes in body temperature in mice. Based on the results of our study and the fact that α-spinasterol is characterized by good blood–brain permeability, we postulate further investigation of this compound to precisely evaluate mechanism of its anticonvulsant action and opportunity of its usage in clinical practice.

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists

“…In addition, the stimulation of TRPV1 channels induced a reduction in the release of GABA and catecholamines, neurotransmitters playing a role in the synaptic efficacy, and epilepsy . Then, epilepsy has been indicated as a new field of application for TRPV1 antagonist in therapy …”

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

“…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 .…”

“…The GEPR‐3s were first tested for AGS susceptibility prior to CPZ administration; GEPR‐3s that exhibited seizures were given an intraperitoneal (ip) CPZ injection in a volume of 0.2 mL/kg body weight at a dose of either 1, 3, or 10 mg/kg. Doses of the drug were selected from our preliminary experiments and previous studies . Subsequent testing occurred 0.5, 1, 2, and 24 hours after CPZ administration.…”

“…9 In addition, inhibition of TRPV1 channels increased the seizure threshold for clonic seizures but had no significant effect on pentylenetetrazole (PTZ)-induced tonic seizures. 10 The prevalence of PTZ-induced generalized tonic-clonic seizures was also reduced in adult mice lacking TRPV1 channels in the brain and previously subjected to a single febrile seizure episode at postnatal day 14. 11 However, activation of TRPV1 channels suppressed tonic seizures and generalized tonic-clonic seizures induced by maximal electroshock and PTZ, respectively.…”

“…In models of tonic‐clonic seizures, inhibition of TRPV1 channels prevented the development of clonic and tonic‐clonic seizures following amygdala kindling . In addition, inhibition of TRPV1 channels increased the seizure threshold for clonic seizures but had no signifi‐cant effect on pentylenetetrazole (PTZ)‐induced tonic seizures . The prevalence of PTZ‐induced generalized tonic‐clonic seizures was also reduced in adult mice lacking TRPV1 channels in the brain and previously subjected to a single febrile seizure episode at postnatal day 14 .…”