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Martin P, Maurice T, Gammaitoni A, et al. Fenfluramine modulates the anti-amnesic effects induced by sigma-1 receptor agonists and neuro(active)steroids in vivo. Epilepsy Behav. 2022;127:108526doi: 10.1016/j.yebeh.2021.108526.
Martin, P., Maurice, T., Gammaitoni, A., Farfel, G., Boyd, B., & Galer, B. (2022). Fenfluramine modulates the anti-amnesic effects induced by sigma-1 receptor agonists and neuro(active)steroids in vivo. Epilepsy & behavior : E&B, 127108526. https://doi.org/10.1016/j.yebeh.2021.108526
Martin, Parthena, et al. "Fenfluramine modulates the anti-amnesic effects induced by sigma-1 receptor agonists and neuro(active)steroids in vivo." Epilepsy & behavior : E&B vol. 127 (2022): 108526. doi: https://doi.org/10.1016/j.yebeh.2021.108526
Martin P, Maurice T, Gammaitoni A, Farfel G, Boyd B, Galer B. Fenfluramine modulates the anti-amnesic effects induced by sigma-1 receptor agonists and neuro(active)steroids in vivo. Epilepsy Behav. 2022 Jan 07;127:108526. doi: 10.1016/j.yebeh.2021.108526. Epub 2022 Jan 07. PMID: 35007961.
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Epilepsy Behav. 2022 Jan 07;127:108526. doi: 10.1016/j.yebeh.2021.108526. Epub 2022 Jan 07.

Fenfluramine modulates the anti-amnesic effects induced by sigma-1 receptor agonists and neuro(active)steroids in vivo.

Epilepsy & behavior : E&B

Parthena Martin, Tangui Maurice, Arnold Gammaitoni, Gail Farfel, Brooks Boyd, Bradley Galer

Affiliations

  1. Zogenix Inc., Emeryville, CA, USA. Electronic address: [email protected].
  2. MMDN, Univ Montpellier, EPHE, INSERM, Montpellier, France. Electronic address: [email protected].
  3. Zogenix Inc., Emeryville, CA, USA. Electronic address: [email protected].
  4. Zogenix Inc., Emeryville, CA, USA. Electronic address: [email protected].
  5. Zogenix Inc., Emeryville, CA, USA. Electronic address: [email protected].
  6. Zogenix Inc., Emeryville, CA, USA. Electronic address: [email protected].

PMID: 35007961 DOI: 10.1016/j.yebeh.2021.108526

Abstract

Fenfluramine (N-ethyl-α-methl-3-(trifluoromethyl)phenethylamine) is an anti-seizure medication (ASM) particularly effective in patients with Dravet syndrome, a severe treatment-resistant epileptic encephalopathy. Fenfluramine acts not only as neuronal serotonin (5-HT) releaser but also as a positive modulator of the sigma-1 receptor (S1R). We here examined the modulatory activity of Fenfluramine on the S1R-mediated anti-amnesic response in mice using combination analyses. Fenfluramine and Norfenfluramine, racemate and isomers, were combined with either the S1R agonist (PRE-084) or the S1R-acting neuro(active)steroids, pregnenolone sulfate (PREGS), Dehydroepiandrosterone sulfate (DHEAS), or progesterone. We report that Fenfluramine racemate or (+)-Fenfluramine, in the 0.1-1 mg/kg dose range, attenuated the dizocilpine-induced learning deficits in spontaneous alternation and passive avoidance, and showed low-dose synergies in combination with PRE-084. These effects were blocked by the S1R antagonist NE-100. Dehydroepiandrosterone sulfate or PREGS attenuated dizocilpine-induced learning deficits in the 5-20 mg/kg dose range. Co-treatments at low dose between steroids and Fenfluramine or (+)-Fenfluramine were synergistic. Progesterone blocked Fenfluramine effect. Finally, Fenfluramine and (+)-Fenfluramine effects were prevented by the 5-HT

Copyright © 2021 Elsevier Inc. All rights reserved.

Keywords: Fenfluramine; Learning and memory; Neuro(active)steroids; Positive modulator; Sigma-1 receptor

Conflict of interest statement

Declaration of Competing Interest P. Martin, A. Gammaitoni, B. Boyd, G. Farfel, and B. Galer are employees of, and/or own stock in, Zogenix, Inc. T. Maurice received consultancy fees from Zogenix.

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