Modulation of Sodium Channel Inactivation Gating by a Novel Lactam: Implications for Seizure Suppression in Chronic Limbic Epilepsy
Epilepsy remains a devastating neurological disorder associated with recurrent, unprovoked, spontaneous epileptic seizures. Current treatments involve seizure suppression using antiepileptic drugs (AEDs); however, many patients remain refractory to current treatments or suffer serious side effects....
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 328; no. 1; pp. 201 - 212 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.01.2009
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Subjects | |
Online Access | Get full text |
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Summary: | Epilepsy remains a devastating neurological disorder associated with recurrent, unprovoked, spontaneous epileptic seizures.
Current treatments involve seizure suppression using antiepileptic drugs (AEDs); however, many patients remain refractory
to current treatments or suffer serious side effects. In view of this continued need for more effective and safer AEDs, we
have designed a novel compound, 3-hydroxy-3-(4-methoxyphenyl)-1-methyl-1,3-dihydro-indol-2-one (YWI92), based on a lactam
structural class, and evaluated its modulation of human neuronal sodium channel isoform (hNa v )1.2 currents and hippocampal neuron action potential firing. Furthermore, we have tested its AED activity using a chronic
and acute rat seizure model. In a similar manner to lamotrigine, a clinically used AED, YWI92 exhibited tonic block of hNa v 1.2 channels and caused a hyperpolarizing shift in the steady-state inactivation curve when using a 30-s inactivating prepulse.
YWI92 also delayed the time constants of channel repriming after a 30-s inactivating prepulse and exhibited use-dependent
block at 20-Hz stimulation frequency. In membrane excitability experiments, YWI92 inhibited burst firing in CA1 neurons of
animals with temporal lobe epilepsy at concentrations that had little effect on CA1 neurons from control animals. These actions
on neuronal activity translated into AED activity in the maximal electroshock acute seizure model (ED 50 = 22.96 mg/kg), and importantly, in a chronic temporal lobe epilepsy model, in which the mean number of seizures was reduced.
Notably, YWI92 exhibited no sedative/ataxic side effects at concentrations up to 500 mg/kg. In summary, greater affinity for
inactivated sodium channels, particularly after long depolarizing prepulses, may be important for both anticonvulsant activity
and drug tolerability. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 doi:10.1124/jpet.108.144709. Address correspondence to: Dr. Manoj K. Patel, Department of Anesthesiology, University of Virginia Health Systems, 1 Hospital Dr., Old Medical School, Charlottesville, VA 22908. E-mail: mkp5u@virginia.edu This work was supported by the National Institutes of Health [Grants NIH R01 CA 105435-01, 5 T32 GM008328]; and the United Negro College Fund/Merck Science Initiative. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. ABBREVIATIONS: AED, antiepileptic drug; Nav, voltage-gated sodium; AP, action potential; MES, maximal electric shock; YWI92, 3-hydroxy-3-(4-methoxyphenyl)-1-methyl-1,3-dihydro-indol-2-one; LTG, lamotrigine; TLE, temporal lobe epilepsy; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; ACSF, artificial cerebrospinal fluid; TPE, time of peak effect. |
ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.108.144709 |