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A novel anticonvulsant modulates voltage‐gated sodium channel inactivation and prevents kindling‐induced seizures

Here, we explore the mechanism of action of isoxylitone (ISOX), a molecule discovered in the plant , which has been shown to have anticonvulsant properties. Patch‐clamp electrophysiology assayed the activity of ISOX on voltage‐gated sodium channels (VGSCs) in both cultured neurons and brain slices i... Full description

Journal Title: Journal of Neurochemistry September 2013, Vol.126(5), pp.651-661
Main Author: Ashraf, Muhammad N.
Other Authors: Gavrilovici, Cezar , Ali Shah, Syed U. , Shaheen, Farzana , Choudhary, Muhammad I. , Rahman, Atta‐Ur , Fahnestock, Margaret , Simjee, Shabana U. , Poulter, Michael O.
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ID: ISSN: 0022-3042 ; E-ISSN: 1471-4159 ; DOI: 10.1111/jnc.12352
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title: A novel anticonvulsant modulates voltage‐gated sodium channel inactivation and prevents kindling‐induced seizures
format: Article
creator:
  • Ashraf, Muhammad N.
  • Gavrilovici, Cezar
  • Ali Shah, Syed U.
  • Shaheen, Farzana
  • Choudhary, Muhammad I.
  • Rahman, Atta‐Ur
  • Fahnestock, Margaret
  • Simjee, Shabana U.
  • Poulter, Michael O.
subjects:
  • Brain‐Derived Neurotrophic Factor
  • Electrophysiology
  • Isoxylitones []
  • Steady‐State Inactivation
ispartof: Journal of Neurochemistry, September 2013, Vol.126(5), pp.651-661
description: Here, we explore the mechanism of action of isoxylitone (ISOX), a molecule discovered in the plant , which has been shown to have anticonvulsant properties. Patch‐clamp electrophysiology assayed the activity of ISOX on voltage‐gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy (kindling model). Quantitative transcription polymerase chain reaction (qRT‐PCR) (QPCR) assessed brain‐derived neurotrophic factor (BDNF) expression in kindled rats, and kindled rats treated with ISOX. ISOX suppressed sodium current () showing an IC value of 185 nM in cultured neurons. ISOX significantly slowed the recovery from inactivation (ISOX = 18.7 ms; Control =9.4 ms; 0.001). ISOX also enhanced the development of inactivation by shifting the Boltzmann curve to more hyperpolarized potentials by −11.2 mV (0.05). In naive and electrically kindled cortical neurons, the IC for sodium current block was identical to that found in cultured neurons. ISOX prevented kindled stage 5 seizures and decreased the enhanced BDNF expression that is normally associated with kindling (
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identifier: ISSN: 0022-3042 ; E-ISSN: 1471-4159 ; DOI: 10.1111/jnc.12352
fulltext: fulltext
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  • 0022-3042
  • 00223042
  • 1471-4159
  • 14714159
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titleA novel anticonvulsant modulates voltage‐gated sodium channel inactivation and prevents kindling‐induced seizures
creatorAshraf, Muhammad N. ; Gavrilovici, Cezar ; Ali Shah, Syed U. ; Shaheen, Farzana ; Choudhary, Muhammad I. ; Rahman, Atta‐Ur ; Fahnestock, Margaret ; Simjee, Shabana U. ; Poulter, Michael O.
ispartofJournal of Neurochemistry, September 2013, Vol.126(5), pp.651-661
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subjectBrain‐Derived Neurotrophic Factor ; Electrophysiology ; Isoxylitones [] ; Steady‐State Inactivation
descriptionHere, we explore the mechanism of action of isoxylitone (ISOX), a molecule discovered in the plant , which has been shown to have anticonvulsant properties. Patch‐clamp electrophysiology assayed the activity of ISOX on voltage‐gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy (kindling model). Quantitative transcription polymerase chain reaction (qRT‐PCR) (QPCR) assessed brain‐derived neurotrophic factor (BDNF) expression in kindled rats, and kindled rats treated with ISOX. ISOX suppressed sodium current () showing an IC value of 185 nM in cultured neurons. ISOX significantly slowed the recovery from inactivation (ISOX = 18.7 ms; Control =9.4 ms; 0.001). ISOX also enhanced the development of inactivation by shifting the Boltzmann curve to more hyperpolarized potentials by −11.2 mV (0.05). In naive and electrically kindled cortical neurons, the IC for sodium current block was identical to that found in cultured neurons. ISOX prevented kindled stage 5 seizures and decreased the enhanced BDNF expression that is normally associated with kindling (<0.05). Overall, our data show that ISOX is a potent inhibitor of VGSCs that stabilizes steady‐state inactivation while slowing recovery and enhancing inactivation development. Like many other sodium channel blocker anti‐epileptic drugs, the suppression of BDNF expression that usually occurs with kindling is likely a secondary outcome that nevertheless would suppress epileptogenesis. These data show a new class of anti‐seizure compound that inhibits sodium channel function and prevents the development of epileptic seizures. Isoxylitones, isolated from Delphinium denudatum root prevent seizure induction. Activity was tested on voltage‐gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy (kindling model). Isoxylitones enhanced sodium channel inactivation with an IC of about 200 nM. Our findings suggest isoxylitones as a potential novel anticonvulsant agent. Isoxylitones, isolated from Delphinium denudatum root prevent seizure induction. Activity was tested on voltage‐gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy (kindling model). Isoxylitones enhanced sodium channel inactivation with an IC of about 200 nM. Our findings suggest isoxylitones as a potential novel anticonvulsant agent.
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titleA novel anticonvulsant modulates voltage‐gated sodium channel inactivation and prevents kindling‐induced seizures
descriptionHere, we explore the mechanism of action of isoxylitone (ISOX), a molecule discovered in the plant , which has been shown to have anticonvulsant properties. Patch‐clamp electrophysiology assayed the activity of ISOX on voltage‐gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy (kindling model). Quantitative transcription polymerase chain reaction (qRT‐PCR) (QPCR) assessed brain‐derived neurotrophic factor (BDNF) expression in kindled rats, and kindled rats treated with ISOX. ISOX suppressed sodium current () showing an IC value of 185 nM in cultured neurons. ISOX significantly slowed the recovery from inactivation (ISOX = 18.7 ms; Control =9.4 ms; 0.001). ISOX also enhanced the development of inactivation by shifting the Boltzmann curve to more hyperpolarized potentials by −11.2 mV (0.05). In naive and electrically kindled cortical neurons, the IC for sodium current block was identical to that found in cultured neurons. ISOX prevented kindled stage 5 seizures and decreased the enhanced BDNF expression that is normally associated with kindling (<0.05). Overall, our data show that ISOX is a potent inhibitor of VGSCs that stabilizes steady‐state inactivation while slowing recovery and enhancing inactivation development. Like many other sodium channel blocker anti‐epileptic drugs, the suppression of BDNF expression that usually occurs with kindling is likely a secondary outcome that nevertheless would suppress epileptogenesis. These data show a new class of anti‐seizure compound that inhibits sodium channel function and prevents the development of epileptic seizures. Isoxylitones, isolated from Delphinium denudatum root prevent seizure induction. Activity was tested on voltage‐gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy (kindling model). Isoxylitones enhanced sodium channel inactivation with an IC of about 200 nM. Our findings suggest isoxylitones as a potential novel anticonvulsant agent. Isoxylitones, isolated from Delphinium denudatum root prevent seizure induction. Activity was tested on voltage‐gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy (kindling model). Isoxylitones enhanced sodium channel inactivation with an IC of about 200 nM. Our findings suggest isoxylitones as a potential novel anticonvulsant agent.
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authorAshraf, Muhammad N. ; Gavrilovici, Cezar ; Ali Shah, Syed U. ; Shaheen, Farzana ; Choudhary, Muhammad I. ; Rahman, Atta‐Ur ; Fahnestock, Margaret ; Simjee, Shabana U. ; Poulter, Michael O.
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abstractHere, we explore the mechanism of action of isoxylitone (ISOX), a molecule discovered in the plant , which has been shown to have anticonvulsant properties. Patch‐clamp electrophysiology assayed the activity of ISOX on voltage‐gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy (kindling model). Quantitative transcription polymerase chain reaction (qRT‐PCR) (QPCR) assessed brain‐derived neurotrophic factor (BDNF) expression in kindled rats, and kindled rats treated with ISOX. ISOX suppressed sodium current () showing an IC value of 185 nM in cultured neurons. ISOX significantly slowed the recovery from inactivation (ISOX = 18.7 ms; Control =9.4 ms; 0.001). ISOX also enhanced the development of inactivation by shifting the Boltzmann curve to more hyperpolarized potentials by −11.2 mV (0.05). In naive and electrically kindled cortical neurons, the IC for sodium current block was identical to that found in cultured neurons. ISOX prevented kindled stage 5 seizures and decreased the enhanced BDNF expression that is normally associated with kindling (<0.05). Overall, our data show that ISOX is a potent inhibitor of VGSCs that stabilizes steady‐state inactivation while slowing recovery and enhancing inactivation development. Like many other sodium channel blocker anti‐epileptic drugs, the suppression of BDNF expression that usually occurs with kindling is likely a secondary outcome that nevertheless would suppress epileptogenesis. These data show a new class of anti‐seizure compound that inhibits sodium channel function and prevents the development of epileptic seizures. Isoxylitones, isolated from Delphinium denudatum root prevent seizure induction. Activity was tested on voltage‐gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy (kindling model). Isoxylitones enhanced sodium channel inactivation with an IC of about 200 nM. Our findings suggest isoxylitones as a potential novel anticonvulsant agent. Isoxylitones, isolated from Delphinium denudatum root prevent seizure induction. Activity was tested on voltage‐gated sodium channels (VGSCs) in both cultured neurons and brain slices isolated from controls and rats with experimental epilepsy (kindling model). Isoxylitones enhanced sodium channel inactivation with an IC of about 200 nM. Our findings suggest isoxylitones as a potential novel anticonvulsant agent.
doi10.1111/jnc.12352
pages651-661
date2013-09