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Peter De Witte - One of the best experts on this subject based on the ideXlab platform.
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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, 2020Co-Authors: Daniëlle Copmans, Michèle Partoens, Borbála Hunyadi, Walter Luyten, Peter De WitteAbstract: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...
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Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B
Marine drugs, 2019Co-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 WitteAbstract: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.
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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, 2011Co-Authors: Stephen I. Deutsch, Jessica A. Burket, William R. Cannon, Luis F. JacomeAbstract: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.
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an epigenetic intervention interacts with genetic strain differences to modulate the stress induced reduction of flurazepam s Antiseizure efficacy in the mouse
European Neuropsychopharmacology, 2009Co-Authors: Stephen I. Deutsch, John Mastropaolo, Jessica A. Burket, Richard B RosseAbstract: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.
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The Antiseizure efficacies of MK-801, phencyclidine, ketamine, and memantine are altered selectively by stress.
Pharmacology biochemistry and behavior, 1997Co-Authors: Stephen I. Deutsch, John Mastropaolo, Raine L. Riggs, Richard B RosseAbstract: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.
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interference with nitric oxide production and action potentiates the Antiseizure efficacy of flurazepam
Pharmacology Biochemistry and Behavior, 1995Co-Authors: Stephen I. Deutsch, Richard B Rosse, Cassandra Morn, Lee Koetzner, John MastropaoloAbstract:The effect of inhibiting "downstream" consequences of NMDA receptor stimulation with 7-nitroindazole, an inhibitor of the neuronal form of nitric oxide synthase (NOS), and methylene blue, an inhibitor of the nitric oxide (NO)-sensitive soluble guanylyl cyclase, on electrically precipitated tonic hindlimb extension in mice was studied. Moreover, the abilities of these compounds to potentiate the Antiseizure efficacy of flurazepam were also examined. When administered alone, 7-nitroindazole (10.0-100 mg/kg) and methylene blue (1.0-100 mg/kg) did not share the ability of MK-801 (0.1 to 1.0 mg/kg) to antagonize electrically precipitated tonic hindlimb extension. However, doses of MK-801 (0.18 mg/kg), 7-nitroindazole (100 mg/kg), and methylene blue (10.0 and 100 mg/kg) that were devoid of apparent Antiseizure efficacy by themselves potentiated the ability of flurazepam to antagonize electrically precipitated seizures. NMDA receptor antagonists cause neuronal toxicity, interfere with acquisition of spatial memory and induction of long-term potentiation in the hippocampal CA1 region, and precipitate psychoses in susceptible individuals. Thus, the development of both open-channel blockers of the NMDA receptor complex that can be administered in lower doses, and inhibitors of the "downstream" consequences of NMDA receptor-gated transient elevations of intraneuronal calcium ions as potential adjunctive Antiseizure medications should be considered. Moreover, administration of these compounds with benzodiazepines may attenuate some of the neurotoxicity that may result from NMDA receptor antagonism.
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a glycinergic intervention potentiates the Antiseizure efficacies of mk 801 flurazepam and carbamazepine
Neurochemical Research, 1994Co-Authors: Deborah O. Norris, John Mastropaolo, David A Oconnor, Joshua M Cohen, Stephen I. DeutschAbstract:Twenty four hours after mice were forced to swim for up to 10 minutes in cold water, there was a reduction in the ability of MK-801 to antagonize the electrical precipitation of tonic hindlimb extension. Milacemide, a lipophilic prodrug of glycine, restored the Antiseizure efficacy of MK-801 to the same level observed in unstressed animals treated with milacemide and MK-801. Stimulation of the glycine-gated chloride ionophore subsequent to the liberation of free glycine could explain milacemide's pharmacologic action as an adjuvant to MK-801. Consistent with this interpretation, milacemide was able to potentiate the Antiseizure effects of flurazepam, a benzodiazepine agonist, in stressed and unstressed mice and carbamazepine in unstressed animals.d-cycloserine, a partial glycine agonist with greater specificity for the strychnine-insensitive modulatory site on the NMDA receptor complex, was examined for its effect on MK-801's Antiseizure efficacy. At a high dose (320 mg/kg),d-cycloserine alone had an anticonvulsant effect. Moreover, this dose ofd-cycloserine administered with MK-801 showed a significantly greater anticonvulsant efficacy than MK-801 alone. The data support the development of glycinergic interventions as adjunctive agents in the pharmacotherapy of seizure disorders.
Daniëlle Copmans - One of the best experts on this subject based on the ideXlab platform.
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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, 2020Co-Authors: Daniëlle Copmans, Michèle Partoens, Borbála Hunyadi, Walter Luyten, Peter De WitteAbstract: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...
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Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B
Marine drugs, 2019Co-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 WitteAbstract: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.
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Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea: Pseurotin A2 and Azaspirofuran A
ACS chemical neuroscience, 2018Co-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 EbelAbstract: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...
Théo Brillatz - One of the best experts on this subject based on the ideXlab platform.
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Metabolite Profiling of Javanese Ginger Zingiber purpureum and Identification of Antiseizure Metabolites via a Low-Cost Open-Source Zebrafish Bioassay-Guided Isolation.
Journal of agricultural and food chemistry, 2020Co-Authors: Théo Brillatz, Emerson Ferreira Queiroz, Laurence Marcourt, Miwa Kubo, Shimon Takahashi, Natsumi Jozukuri, Kenshi Takechi, Pierre-marie Allard, Richard J. Fish, Kenichi HaradaAbstract:The rhizomes of Zingiber purpureum, “Bangle”, were investigated for its Antiseizure properties using a streamlined and cost-effective zebrafish screening strategy and a mouse epilepsy assay. Its he...
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metabolite profiling of javanese ginger zingiber purpureum and identification of Antiseizure metabolites via a low cost open source zebrafish bioassay guided isolation
Journal of Agricultural and Food Chemistry, 2020Co-Authors: Théo Brillatz, Emerson Ferreira Queiroz, Laurence Marcourt, Miwa Kubo, Shimon Takahashi, Natsumi Jozukuri, Kenshi Takechi, Pierre-marie Allard, Richard J. Fish, Kenichi HaradaAbstract:The rhizomes of Zingiber purpureum, "Bangle", were investigated for its Antiseizure properties using a streamlined and cost-effective zebrafish screening strategy and a mouse epilepsy assay. Its hexane extract demonstrated strong Antiseizure activity in zebrafish epilepsy assay and was, therefore, selected for bioactivity-guided fractionation. Twelve compounds (1-12) were isolated, and two bioactive phenylbutenoids, trans- (11) and cis-banglene (12), reduced up to 70% of pentylenetetrazole (PTZ)-induced seizures. These compounds showed moderate activity against PTZ-induced seizures in a mouse epilepsy assay. To understand the specificity of Z. purpureum active compounds, its chemical profile was compared to that of Z. officinale. Their composition was assessed by differential metabolite profiling visualized by a molecular network, which revealed only vanillin derivatives and terpenoids as common metabolites and gave a comprehensive view of Z. purpureum composition. This study demonstrates the efficacy of a streamlined zebrafish epilepsy assay, which is therefore suitable for routine screening in phytochemistry laboratories.
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Medicinal Plants to Treat Epilepsy: Discovery of Antiseizure Compounds by In Vivo Zebrafish Bioactivity-Guided Isolation
2020Co-Authors: Théo BrillatzAbstract:Epilepsy is a chronic neurological disorder characterized by recurrent epileptic seizures which affects 1% of the world’s population, of whom 80% live in low- and middle-income countries. Antiseizure drugs (ASDs) and therapies are available for epilepsy management but despite these possibilities, a third of epileptic patients suffer from pharmaco-resistance. There is, therefore, an urgent need for new and cost-effective treatments to manage epilepsy. Herbs used in traditional medicine remain the first-line treatment for most people with limited access to ASDs. Thus, in this thesis, three plants traditionally used to treat epilepsy and CNS-related disorders were selected and studied using a bioactivity-guided isolation protocol combined to an in vivo zebrafish epilepsy model to effectively identify compounds with significant Antiseizure activity. This work demonstrated the chemical diversity of Antiseizure constituents and their mode of action which may help to provide evidence-based data for the management of epilepsy with well-selected medicinal herbs.
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Zebrafish bioassay-guided isolation of Antiseizure compounds from the Cameroonian medicinal plant Cyperus articulatus L
Phytomedicine : international journal of phytotherapy and phytopharmacology, 2020Co-Authors: Théo Brillatz, Maxime Jacmin, Emerson Ferreira Queiroz, Laurence Marcourt, Ivan Slacanin, Charlotte Petit, Pierre-alain Carrupt, Elisabeth Ngo Bum, Paul Herrling, Alexander D. CrawfordAbstract:Abstract Background Epilepsy is a chronic neurological disorder affecting more than 50 million people worldwide, of whom 80% live in low- and middle-income countries. Due to the limited availability of Antiseizure drugs (ASDs) in these countries, medicinal plants are the first-line treatment for most epilepsy patients. In Cameroon, a decoction of Cyperus articulatus L. rhizomes is traditionally used to treat epilepsy. Purpose The aim of this study was to identify and isolate the active compounds responsible for the Antiseizure activity of C. articulatus in order to confirm both its traditional medicinal usage and previous in vivo studies on extracts of this plant in mouse epilepsy models. Methods The dried rhizomes of C. articulatus were extracted with solvents of increasing polaritie (hexane, dichloromethane, methanol and water). A traditional decoction and an essential oil were also prepared. These extracts were evaluated for Antiseizure activity using a larval zebrafish seizure model with seizures induced by the GABAA antagonist pentylenetetrazole (PTZ). The hexane extract demonstrated the highest Antiseizure activity and was therefore selected for bioassay-guided fractionation. The isolated bioactive compounds were characterized by classical spectroscopic methods. Since they were found to be volatile, they were quantified by GC-FID. In addition, the absorption of the active compounds through the gastrointestinal tract and the blood-brain barrier was evaluated using a hexadecane and a blood-brain barrier parallel artificial membrane permeability assays (HDM-PAMPA and PAMPA-BBB). Results The hexane extract of C. articulatus exhibited the highest Antiseizure activity with a reduction of 93% of PTZ-induced seizures, and was therefore subjected to bioassay-guided fractionation in order to isolate the active principles. Four sesquiterpenoids were identified as cyperotundone (1), mustakone (2), 1,2-dehydro-α-cyperone (3) and sesquichamaenol (4) and exhibited significant Antiseizure activity. These volatile compounds were quantified by GC in the hexane extract, the essential oil and the simulated traditional decoction. In addition, the constituents of the hexane extract including compounds 1 and 2 were found to cross the gastrointestinal barrier and the major compound 2 crossed the blood-brain barrier as well. Conclusion These results highlight the Antiseizure activity of various sesquiterpene compounds from a hexane extract of C. articulatus dried rhizomes and support its use as a traditional treatment for epilepsy.
John Mastropaolo - One of the best experts on this subject based on the ideXlab platform.
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an epigenetic intervention interacts with genetic strain differences to modulate the stress induced reduction of flurazepam s Antiseizure efficacy in the mouse
European Neuropsychopharmacology, 2009Co-Authors: Stephen I. Deutsch, John Mastropaolo, Jessica A. Burket, Richard B RosseAbstract: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.
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The Antiseizure efficacies of MK-801, phencyclidine, ketamine, and memantine are altered selectively by stress.
Pharmacology biochemistry and behavior, 1997Co-Authors: Stephen I. Deutsch, John Mastropaolo, Raine L. Riggs, Richard B RosseAbstract: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.
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interference with nitric oxide production and action potentiates the Antiseizure efficacy of flurazepam
Pharmacology Biochemistry and Behavior, 1995Co-Authors: Stephen I. Deutsch, Richard B Rosse, Cassandra Morn, Lee Koetzner, John MastropaoloAbstract:The effect of inhibiting "downstream" consequences of NMDA receptor stimulation with 7-nitroindazole, an inhibitor of the neuronal form of nitric oxide synthase (NOS), and methylene blue, an inhibitor of the nitric oxide (NO)-sensitive soluble guanylyl cyclase, on electrically precipitated tonic hindlimb extension in mice was studied. Moreover, the abilities of these compounds to potentiate the Antiseizure efficacy of flurazepam were also examined. When administered alone, 7-nitroindazole (10.0-100 mg/kg) and methylene blue (1.0-100 mg/kg) did not share the ability of MK-801 (0.1 to 1.0 mg/kg) to antagonize electrically precipitated tonic hindlimb extension. However, doses of MK-801 (0.18 mg/kg), 7-nitroindazole (100 mg/kg), and methylene blue (10.0 and 100 mg/kg) that were devoid of apparent Antiseizure efficacy by themselves potentiated the ability of flurazepam to antagonize electrically precipitated seizures. NMDA receptor antagonists cause neuronal toxicity, interfere with acquisition of spatial memory and induction of long-term potentiation in the hippocampal CA1 region, and precipitate psychoses in susceptible individuals. Thus, the development of both open-channel blockers of the NMDA receptor complex that can be administered in lower doses, and inhibitors of the "downstream" consequences of NMDA receptor-gated transient elevations of intraneuronal calcium ions as potential adjunctive Antiseizure medications should be considered. Moreover, administration of these compounds with benzodiazepines may attenuate some of the neurotoxicity that may result from NMDA receptor antagonism.
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a glycinergic intervention potentiates the Antiseizure efficacies of mk 801 flurazepam and carbamazepine
Neurochemical Research, 1994Co-Authors: Deborah O. Norris, John Mastropaolo, David A Oconnor, Joshua M Cohen, Stephen I. DeutschAbstract:Twenty four hours after mice were forced to swim for up to 10 minutes in cold water, there was a reduction in the ability of MK-801 to antagonize the electrical precipitation of tonic hindlimb extension. Milacemide, a lipophilic prodrug of glycine, restored the Antiseizure efficacy of MK-801 to the same level observed in unstressed animals treated with milacemide and MK-801. Stimulation of the glycine-gated chloride ionophore subsequent to the liberation of free glycine could explain milacemide's pharmacologic action as an adjuvant to MK-801. Consistent with this interpretation, milacemide was able to potentiate the Antiseizure effects of flurazepam, a benzodiazepine agonist, in stressed and unstressed mice and carbamazepine in unstressed animals.d-cycloserine, a partial glycine agonist with greater specificity for the strychnine-insensitive modulatory site on the NMDA receptor complex, was examined for its effect on MK-801's Antiseizure efficacy. At a high dose (320 mg/kg),d-cycloserine alone had an anticonvulsant effect. Moreover, this dose ofd-cycloserine administered with MK-801 showed a significantly greater anticonvulsant efficacy than MK-801 alone. The data support the development of glycinergic interventions as adjunctive agents in the pharmacotherapy of seizure disorders.
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Paradoxical effect of flurazepam.
Pharmacology biochemistry and behavior, 1992Co-Authors: Stephen I. Deutsch, Deborah O. Norris, David A. O'connor, John MastropaoloAbstract:Cold water swim stress has been shown to decrease the ability of flurazepam, a prototypic GABA-positive benzodiazepine, to antagonize the electrical precipitation of seizures in mice. This stress-induced reduction in the Antiseizure efficacy of flurazepam is not due to a reduction in the threshold voltage for seizure production. In this study, we examined the effect of treating mice with flurazepam 20 min prior to cold water swim stress on its ability to antagonize electrically precipitated seizures 24 h later. Contrary to our expectation, pretreatment with flurazepam potentiated the stress-induced reduction of its Antiseizure efficacy.
