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Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors.
Oncotarget. 2018 May 04; 9(34):23373-23389.O

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.

Authors+Show Affiliations

Neuropharmacology, Department of Translational Neurosciences, Cajal Institute, CSIC, Madrid E-28002, Spain.Neuropharmacology, Department of Translational Neurosciences, Cajal Institute, CSIC, Madrid E-28002, Spain.Neuropharmacology, Department of Translational Neurosciences, Cajal Institute, CSIC, Madrid E-28002, Spain.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29805740

Citation

Rodríguez-Muñoz, María, et al. "Fenfluramine Diminishes NMDA Receptor-mediated Seizures Via Its Mixed Activity at Serotonin 5HT2A and Type 1 Sigma Receptors." Oncotarget, vol. 9, no. 34, 2018, pp. 23373-23389.
Rodríguez-Muñoz M, Sánchez-Blázquez P, Garzón J. Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget. 2018;9(34):23373-23389.
Rodríguez-Muñoz, M., Sánchez-Blázquez, P., & Garzón, J. (2018). Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. Oncotarget, 9(34), 23373-23389. https://doi.org/10.18632/oncotarget.25169
Rodríguez-Muñoz M, Sánchez-Blázquez P, Garzón J. Fenfluramine Diminishes NMDA Receptor-mediated Seizures Via Its Mixed Activity at Serotonin 5HT2A and Type 1 Sigma Receptors. Oncotarget. 2018 May 4;9(34):23373-23389. PubMed PMID: 29805740.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors. AU - Rodríguez-Muñoz,María, AU - Sánchez-Blázquez,Pilar, AU - Garzón,Javier, Y1 - 2018/05/04/ PY - 2018/01/04/received PY - 2018/04/03/accepted PY - 2018/5/29/entrez PY - 2018/5/29/pubmed PY - 2018/5/29/medline KW - HINT1 protein KW - fenfluramine KW - glutamate N-methyl-D-aspartate receptor KW - seizures KW - type 1 sigma receptor SP - 23373 EP - 23389 JF - Oncotarget JO - Oncotarget VL - 9 IS - 34 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/29805740/Fenfluramine_diminishes_NMDA_receptor_mediated_seizures_via_its_mixed_activity_at_serotonin_5HT2A_and_type_1_sigma_receptors_ L2 - https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.25169 DB - PRIME DP - Unbound Medicine ER -
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