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Antiseizure

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Peter De Witte – One of the best experts on this subject based on the ideXlab platform.

  • Zebrafish-Based Screening of Antiseizure Plants Used in Traditional Chinese Medicine: Magnolia officinalis Extract and Its Constituents Magnolol and Honokiol Exhibit Potent Anticonvulsant Activity in a Therapy-Resistant Epilepsy Model
    ACS chemical neuroscience, 2020
    Co-Authors: Daniëlle Copmans, Michèle Partoens, Borbála Hunyadi, Walter Luyten, Peter De Witte

    Abstract:

    With the aim to discover interesting lead compounds that could be further developed into compounds active against pharmacoresistant epilepsies, we first collected 14 medicinal plants used in traditional Chinese medicine (TCM) against epilepsy. Of the six extracts that tested positive in a pentylenetetrazole (PTZ) behavioral zebrafish model, only the ethanol and acetone extracts from Magnolia officinalis (M. officinalis) also showed effective Antiseizure activity in the ethylketopentenoate (EKP) zebrafish model. The EKP model is regarded as an interesting discovery platform to find mechanistically novel Antiseizure drugs, as it responds poorly to a large number of marketed anti-epileptics. We then demonstrated that magnolol and honokiol, two major constituents of M. officinalis, displayed an effective behavioral and electrophysiological Antiseizure activity in both the PTZ and the EKP models. Out of six structural analogues tested, only 4-O-methylhonokiol was active and to a lesser extent tetrahydromagnolo…

  • Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B
    Marine drugs, 2019
    Co-Authors: Daniëlle Copmans, Nina Dirkx, Alexander D. Crawford, Sara Kildgaard, Silas Anselm Rasmussen, Monika Ślęzak, Michèle Partoens, Camila V. Esguerra, Thomas Ostenfeld Larsen, Peter De Witte

    Abstract:

    There is a high need for the development of new and improved Antiseizure drugs (ASDs) to treat epilepsy. Despite the potential of marine natural products (MNPs), the EU marine biodiscovery consortium PharmaSea has made the only effort to date to perform ASD discovery based on large-scale screening of MNPs. To this end, the embryonic zebrafish photomotor response assay and the larval zebrafish pentylenetetrazole (PTZ) model were used to screen MNP extracts for neuroactivity and Antiseizure activity, respectively. Here we report the identification of the two known isoquinoline alkaloids TMC-120A and TMC-120B as novel Antiseizure compounds, which were isolated by bioactivity-guided purification from the marine-derived fungus Aspergillus insuetus. TMC-120A and TMC-120B were observed to significantly lower PTZ-induced seizures and epileptiform brain activity in the larval zebrafish PTZ seizure model. In addition, their structural analogues TMC-120C, penicisochroman G, and ustusorane B were isolated and also significantly lowered PTZ-induced seizures. Finally, TMC-120A and TMC-120B were investigated in a mouse model of drug-resistant focal seizures. Compound treatment significantly shortened the seizure duration, thereby confirming their Antiseizure activity. These data underscore the possibility to translate findings in zebrafish to mice in the field of epilepsy and the potential of the marine environment for ASD discovery.

Stephen I. Deutsch – One of the best experts on this subject based on the ideXlab platform.

  • Selective mGluR5 antagonism attenuates the stress-induced reduction of MK-801’s Antiseizure potency in the genetically inbred Balb/c mouse
    Epilepsy & behavior : E&B, 2011
    Co-Authors: Stephen I. Deutsch, Jessica A. Burket, William R. Cannon, Luis F. Jacome

    Abstract:

    The ability of MK-801 (dizocilpine), a noncompetitive N-methyl D-aspartate (NMDA) antagonist, to antagonize electrical seizures is reduced in stressed mice. Stress-associated alterations in seizure susceptibility and diminished efficacy of Antiseizure medications in humans have been reported [Joels, 2009; Haut et al., 2007; Moshe et al., 2008]; thus, these experimental observations implicate altered endogenous tone of NMDA receptor-mediated neurotransmission in clinically adverse effects of stress on seizure proneness and treatment. The current exploratory experiment examined the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an antagonist of mGluR5, administered prior to stress on the stress-induced reduction of MK-801’s Antiseizure effect in Swiss–Webster and Balb/c mice; the Balb/c mouse is behaviorally hypersensitive to MK-801. Interestingly, the data suggest that MPEP can attenuate the severity of the stress-induced reduction of MK-801’s Antiseizure effect in the Balb/c strain. Thus, mGluR5 could serve as a target for strategies for adjuvant treatment of seizures exacerbated by stress.

  • an epigenetic intervention interacts with genetic strain differences to modulate the stress induced reduction of flurazepam s Antiseizure efficacy in the mouse
    European Neuropsychopharmacology, 2009
    Co-Authors: Stephen I. Deutsch, John Mastropaolo, Jessica A. Burket, Richard B Rosse

    Abstract:

    Stress induces changes in the endogenous tone of both GABA and NMDA receptor-mediated neurotransmission in the intact mouse. Because changes are observed 24 h after stress, epigenetically-regulated alterations in gene expression may mediate these effects. In earlier work, sodium butyrate, a centrally-active histone deacetylase inhibitor that promotes gene expression, was shown to modulate the stress-induced reduction of the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to antagonize electrically-precipitated seizures. In the current study, we extended this work to look at sodium butyrate’s modulatory effect on stress-induced changes in the Antiseizure efficacy of flurazepam, a benzodiazepine receptor agonist, in two strains of mice. Epigenetic mechanisms, genetic strain differences and a standard stress interacted to alter flurazepam’s Antiseizure efficacy. These data support examination and development of epigenetic treatment strategies.

  • The Antiseizure efficacies of MK-801, phencyclidine, ketamine, and memantine are altered selectively by stress.
    Pharmacology biochemistry and behavior, 1997
    Co-Authors: Stephen I. Deutsch, John Mastropaolo, Raine L. Riggs, Richard B Rosse

    Abstract:

    Adaptive changes in the NMDA receptor complex occur in response to exposure to stress. We have previously shown that the ability of MK-801, an uncompetitive NMDA receptor antagonist, to antagonize electrically precipitated tonic hind-limb extension is reduced 24 h after mice are forced to swim for up to 10 min in cold water. The stress-induced reduction of the Antiseizure efficacy of MK-801 stimulated the proposal that mice exposed to swim stress may serve as “an intact animal model” of altered or diminished NMDA-mediated neural transmission. In the current investigation, the dose-dependent abilities for the antagonism of electrically precipitated seizures in mice were determined for MK-801, phencyclidine, ketamine, and memantine. Interestingly, a single session of cold water swim stress reduced the Antiseizure efficacies of MK-801 and memantine without affecting phencyclidine and ketamine when tested 24 h later. The data do not suggest that stress results in a simple reduction in the number of activated or open channels, but rather alters their size or charge characteristics.

Daniëlle Copmans – One of the best experts on this subject based on the ideXlab platform.

  • Zebrafish-Based Screening of Antiseizure Plants Used in Traditional Chinese Medicine: Magnolia officinalis Extract and Its Constituents Magnolol and Honokiol Exhibit Potent Anticonvulsant Activity in a Therapy-Resistant Epilepsy Model
    ACS chemical neuroscience, 2020
    Co-Authors: Daniëlle Copmans, Michèle Partoens, Borbála Hunyadi, Walter Luyten, Peter De Witte

    Abstract:

    With the aim to discover interesting lead compounds that could be further developed into compounds active against pharmacoresistant epilepsies, we first collected 14 medicinal plants used in traditional Chinese medicine (TCM) against epilepsy. Of the six extracts that tested positive in a pentylenetetrazole (PTZ) behavioral zebrafish model, only the ethanol and acetone extracts from Magnolia officinalis (M. officinalis) also showed effective Antiseizure activity in the ethylketopentenoate (EKP) zebrafish model. The EKP model is regarded as an interesting discovery platform to find mechanistically novel Antiseizure drugs, as it responds poorly to a large number of marketed anti-epileptics. We then demonstrated that magnolol and honokiol, two major constituents of M. officinalis, displayed an effective behavioral and electrophysiological Antiseizure activity in both the PTZ and the EKP models. Out of six structural analogues tested, only 4-O-methylhonokiol was active and to a lesser extent tetrahydromagnolo…

  • Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B
    Marine drugs, 2019
    Co-Authors: Daniëlle Copmans, Nina Dirkx, Alexander D. Crawford, Sara Kildgaard, Silas Anselm Rasmussen, Monika Ślęzak, Michèle Partoens, Camila V. Esguerra, Thomas Ostenfeld Larsen, Peter De Witte

    Abstract:

    There is a high need for the development of new and improved Antiseizure drugs (ASDs) to treat epilepsy. Despite the potential of marine natural products (MNPs), the EU marine biodiscovery consortium PharmaSea has made the only effort to date to perform ASD discovery based on large-scale screening of MNPs. To this end, the embryonic zebrafish photomotor response assay and the larval zebrafish pentylenetetrazole (PTZ) model were used to screen MNP extracts for neuroactivity and Antiseizure activity, respectively. Here we report the identification of the two known isoquinoline alkaloids TMC-120A and TMC-120B as novel Antiseizure compounds, which were isolated by bioactivity-guided purification from the marine-derived fungus Aspergillus insuetus. TMC-120A and TMC-120B were observed to significantly lower PTZ-induced seizures and epileptiform brain activity in the larval zebrafish PTZ seizure model. In addition, their structural analogues TMC-120C, penicisochroman G, and ustusorane B were isolated and also significantly lowered PTZ-induced seizures. Finally, TMC-120A and TMC-120B were investigated in a mouse model of drug-resistant focal seizures. Compound treatment significantly shortened the seizure duration, thereby confirming their Antiseizure activity. These data underscore the possibility to translate findings in zebrafish to mice in the field of epilepsy and the potential of the marine environment for ASD discovery.

  • Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea: Pseurotin A2 and Azaspirofuran A
    ACS chemical neuroscience, 2018
    Co-Authors: Daniëlle Copmans, Mostafa E. Rateb, Jioji N. Tabudravu, Mercedes Pérez-bonilla, Nina Dirkx, Riccardo Vallorani, Caridad Díaz, José Pérez Del Palacio, Alan James Smith, Rainer Ebel

    Abstract:

    In search for novel Antiseizure drugs (ASDs), the European FP7-funded PharmaSea project used zebrafish embryos and larvae as a drug discovery platform to screen marine natural products to identify promising Antiseizure hits in vivo for further development. Within the framework of this project, seven known heterospirocyclic γ-lactams, namely, pseurotin A, pseurotin A2, pseurotin F1, 11-O-methylpseurotin A, pseurotin D, azaspirofuran A, and azaspirofuran B, were isolated from the bioactive marine fungus Aspergillus fumigatus, and their Antiseizure activity was evaluated in the larval zebrafish pentylenetetrazole (PTZ) seizure model. Pseurotin A2 and azaspirofuran A were identified as Antiseizure hits, while their close chemical analogues were inactive. Besides, electrophysiological analysis from the zebrafish midbrain demonstrated that pseurotin A2 and azaspirofuran A also ameliorate PTZ-induced epileptiform discharges. Next, to determine whether these findings translate to mammalians, both compounds were a…