Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice

Wong, Jennifer C.; Dutton, Stacey B. B.; Collins, Stephen; Schachter, Steven C.; Escayg, Andrew

doi:10.3389/fphar.2016.00357

Cited by 34 publications

(37 citation statements)

References 76 publications

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“…In mammalian (rodent) DS models these channels are mainly affected in inhibitory (GABAergic) interneurons and to a lesser extent in excitatory pyramidal neurons (Dutton et al, 2013; Mistry et al, 2014). As a result, neuronal inhibition is impaired, which is assumed to cause seizures (Wong et al, 2016). Our data suggest that FA reduces epileptiform activity by stimulating 5-HT 2C and 5-HT 1D receptors, leading to enhanced GABAergic neurotransmission (as proven for 5-HT 2C receptors) (Shen and Andrade, 1998; Higgins et al, 2014), and by a σ 1 -antagonistic action that can reduce the excitatory neurotransmission by modulating NMDA responses (Rousseaux and Greene, 2015).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish

Smolders²,

et al. 2017

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Dravet syndrome (DS) is a genetic encephalopathy that is characterized by severe seizures and prominent co-morbidities (e.g., physical, intellectual disabilities). More than 85% of the DS patients carry an SCN1A mutation (sodium channel, voltage gated, type I alpha subunit). Although numerous anti-epileptic drugs have entered the market since 1990, these drugs often fail to adequately control seizures in DS patients. Nonetheless, current clinical data shows significant seizure reduction in DS patients treated with the serotonergic (5-hydroxytryptamine, 5-HT) drug fenfluramine (FA). Recent preclinical research confirmed the anti-epileptiform activity of FA in homozygous scn1a mutant zebrafish larvae that mimic DS well. Here we explored the anti-epileptiform mechanisms of FA by investigating whether selective agonists/antagonists of specific receptor subtypes were able to counteract the FA-induced inhibition of seizures and abnormal brain discharges observed in the scn1a mutants. We show that antagonists of 5-HT1D and 5-HT2C receptor subtypes were able to do so (LY 310762 and SB 242084, respectively), but notably, a 5-HT2A-antagonist (ketanserin) was not. In addition, exploring further the mechanism of action of FA beyond its serotonergic profile, we found that the anti-epileptiform brain activity of FA was significantly abolished when it was administered in combination with a σ1-agonist (PRE 084). Our study therefore provides the first evidence of an involvement of the σ1 receptor in the mechanism of FA. We further show that the level of some neurotransmitters [i.e., dopamine and noradrenaline (NAD)] in head homogenates was altered after FA treatment, whereas γ-aminobutyric acid (GABA) and glutamate levels were not. Of interest, NAD-decreasing drugs have been employed successfully in the treatment of neurological diseases; including epilepsy and this effect could contribute to the therapeutic effect of the compound. In summary, we hypothesize that the anti-epileptiform activity of FA not only originates from its 5-HT1D- and 5-HT2C-agonism, but likely also from its ability to block σ1 receptors. These findings will help in better understanding the pharmacological profile of compounds that is critical for their applicability in the treatment of DS and possibly also other drug-resistant epilepsies.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish

Smolders²,

et al. 2017

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“…Seizures were induced using the 6 Hz paradigm, as previously described 30–32 . Briefly, 30 minutes prior to seizure induction, a topical anesthetic (0.5% tetracaine hydrochloride) was applied to the cornea.…”

Section: Methodsmentioning

confidence: 99%

GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant

Giddens

Wong

Schroeder

et al. 2017

Neurobiology of Disease

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Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c.1047G>T [Lys349Asp]), an orphan G protein-coupled receptor (GPCR) expressed predominantly in the brain. In vitro studies demonstrated that the K349N substitution in GPR37L1 did not grossly alter receptor expression, surface trafficking or constitutive signaling in transfected cells. However, in vivo studies revealed that a complete loss of Gpr37L1 function in mice results in increased seizure susceptibility. Mice lacking the related receptor Gpr37 also exhibited an increase in seizure susceptibility, while genetic deletion of both receptors resulted in an even more dramatic increase in vulnerability to seizures. These findings provide evidence linking GPR37L1 and GPR37 to seizure etiology and demonstrate an association between a GPR37L1 variant and a novel progressive myoclonus epilepsy.

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“…To further assess the therapeutic potential of BIS‐001, its activity in the 6‐Hz and maximal electroshock (MES) seizure paradigms was investigated with the assistance of Dr. Andrew Escayg (Emory University) in the SCN1A R1648H/+ (RH) mouse model of generalized epilepsy with febrile seizures plus and in the SCN1A +/− model of Dravet syndrome . Acute ip administration of BIS‐001 conferred robust protection against 6‐Hz–induced seizures in the generalized epilepsy with febrile seizures plus model, with a dose of 0.5 mg/kg blocking seizures in 58% of mice and a dose of 1 mg/kg completely blocking seizures in 82% of mice.…”

Section: Bis‐001 (Huperzine A)mentioning

confidence: 99%

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development

Bialer

Johannessen

Koepp³

et al. 2018

Epilepsia

115

103

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Summary The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13‐16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from preclinical or early (phase I) clinical studies were presented. The compounds reviewed include adenosine and adenosine kinase inhibitors, BIS‐001 (huperzine A), 2‐deoxy‐d‐glucose, FV‐082, FV‐137, JNJ‐40411813, JNJ‐55511118 and analogs, ketone‐enhanced antiepileptic drugs, oxynytones, OV329, TAK‐935 (OV935), XEN901, and XEN1101. Many innovative approaches to drug development were presented. For example, some compounds are being combined with traditional antiepileptic drugs based on evidence of synergism in seizure models, some act as inhibitors of enzymes involved in modulation of neuronal activity, and some interact in novel ways with excitatory receptors or ion channels. Some of the compounds in development target the etiology of specific epilepsy syndromes (including orphan conditions) through precision medicine, and some offer hope of producing disease‐modifying effects rather than symptomatic seizure suppression. Overall, the results summarized in the report indicate that important advances are being made in the effort to develop compounds with potentially improved efficacy and safety profiles compared with existing agents.

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Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice

Cited by 34 publications

References 76 publications

Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish

Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish

GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development

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