Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors.

María Rodríguez-Muñoz,Pilar Sánchez-Blázquez,Javier Garzón

doi:10.18632/oncotarget.25169

María Rodríguez-Muñoz, Pilar Sánchez-Blázquez + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.25169

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Journal: Oncotarget	Publication Date: May 4, 2018
Citations: 38	License type: cc-by

Affiliation: Instituto Cajal

Abstract

Fenfluramine exhibits antiepileptic properties and thus diminishes epileptiform discharges in experimental animal models of Dravet syndrome. Fenfluramine is metabolized into norfenfluramine in vivo, which shows greater affinity and agonist activity at serotonin 5HT2 receptors (5HT2R) than fenfluramine. In this study, we found that fenfluramine and norfenfluramine disrupted the regulatory association of the sigma 1 receptor (σ1R) with NR1 subunits of glutamate N-methyl-D-aspartate receptors (NMDAR), an effect that was also produced by σ1R antagonists such as S1RA and prevented by σ1R agonists such as PPCC. The antagonists removed σ1R bound to NMDAR NR1 subunits enabling calcium-regulated calmodulin (CaM) to bind to those subunits. As a result, CaM may inhibit calcium permeation through NMDARs. The serotoninergic activity of fenfluramine at 5HT2AR, and likely also at 5HT2CR, collaborated with its activity at σ1Rs to prevent the convulsive syndrome promoted by NMDAR overactivation. Notably, fenfluramine enhanced the inhibitory coupling of G protein-coupled receptors such as 5HT1AR and cannabinoid type 1 receptor with NMDARs, thus allowing the more effective restrain of NMDAR activity. Thus, fenfluramine circumvents the negative side effects of direct NMDAR antagonists and may improve the quality of life of subjects affected by such proconvulsant dysfunctions.

Highlights

Altered central inhibitory (e.g., γ-aminobutyric acid, or GABA) and excitatory neurotransmission is well established to play a pivotal role in the etiology of epilepsy, with excess glutamatergic transmission and the ensuing overactivation of glutamate receptors being relevant to its clinical manifestations [1,2,3]
We found that fenfluramine and norfenfluramine disrupted the regulatory association of the sigma 1 receptor (σ1R) with NR1 subunits of glutamate N-methyl-D-aspartate receptors (NMDAR), an effect that was produced by σ1R antagonists such as S1RA and prevented by σ1R agonists such as PPCC
The σ1R physically interacts with the NMDAR NR1 but not with the NR2A subunit, and the NR1 subunit only has a single σ1R binding site [43], which is located in its cytosolic C terminal regulatory region [36]

Summary

Introduction

Altered central inhibitory (e.g., γ-aminobutyric acid, or GABA) and excitatory (e.g., glutamate) neurotransmission is well established to play a pivotal role in the etiology of epilepsy, with excess glutamatergic transmission and the ensuing overactivation of glutamate receptors being relevant to its clinical manifestations [1,2,3]. In epilepsy, NMDAR stimulation escapes from these controls responsible for maintaining excitatory activity within physiological limits, and its deregulation plays a key role in the generation of seizures. NMDAR deregulation may be a consequence of upstream dysfunctions such as those that affect diverse epileptogenic manifestations, including devastating forms of childhood epilepsy that begin with prolonged seizures in the first year of life such as West [5], Dravet [6, 7] and Lennox-Gastaut syndromes [8, 9]. Because of side effects, the treatment of epilepsy with chronic selective NMDAR antagonists has mostly disappointed in clinical trials [13]

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