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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Trans-2-en-valproic Acid Limits Action Potential Firing Frequency in Mouse Central Neurons in Cell Culture

Artur W. Wamil, Wolfgang Löscher and Michael J. McLean
Journal of Pharmacology and Experimental Therapeutics March 1997, 280 (3) 1349-1356;
Artur W. Wamil
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Wolfgang Löscher
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Michael J. McLean
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Abstract

Effects of the trans-isomer of 2-en-valproate (trans-2-en-NaVP; E-Δ2-en-valproate or 2-en-valproate), an unsaturated metabolite of valproic acid (VPA), on intracellularly recorded sodium-dependent action potentials of cultured mouse spinal cord and cortical neurons were compared with those of the anticonvulsant sodium valproate (NaVP). The maximal rate of rise of action potentials triggered by trains of 1-msec or 400-msec pulses declined progressively until failure to fire in both cell types during exposure to trans-2-en-NaVP or NaVP was observed. The limitation of firing by both drugs was concentration, voltage, rate and time dependent. The IC50 of trans-2-en-NaVP was 1.2 × 10−3 at ≤1 hr and 4.8 × 10−5 M at 24 to 48 hr. Trans-2-en-NaVP did not limit sustained repetitive firing in all cortical neurons. This may reflect slower rates of firing during 400-msec depolarizations in neurons of this type. In paired-pulse experiments, the absolute refractory period was 7 msec in control solution and 15 msec (P < .01 vs. control;n = 9) in solution containing 6 × 10−4 M trans-2-en-NaVP. Firing was limited in all spinal cord neurons after exposure to 0.5 mM NaVP for 24 to 48 hr; 80% were limited by 1 mM NaVP at ≤1 hr. Coincubation of the spinal cord neurons with trans-2-en-NaVP and NaVP for 24 hr showed no hyperadditive effect of these two drugs in vitro. Limitation of sustained repetitive firing was reversed by hyperpolarization in the continuing presence of either drug and incubation in drug-free medium. Limitation of sodium-dependent action potential firing rates could contribute, at least in part, to the anticonvulsant effect of trans-2-en-NaVP.

Footnotes

  • Send reprint requests to: Michael J. McLean, M.D., Ph.D., Department of Neurology, Vanderbilt University Medical Center, 2100 Pierce Avenue, 351 MCS, Nashville, TN 37212.

  • ↵1 Current address: Department of Anesthesiology, VUMC, 1161 21st Avenue South, T-4216 Medical Center North, Nashville, TN 37232-2125.

  • ↵2 Supported by a Merit Review Award from the Department of Veterans Affairs and funds received in collaboration with the Holcomb Medical Research Institute.

  • Abbreviations:
    AP
    action potential
    CSF
    cerebrospinal fluid
    Em
    resting membrane potential
    mDPBS
    modified Dulbecco’s phosphate-buffered saline
    NaVP
    sodium valproate
    Rin
    input resistance
    SRF
    sustained repetitive firing
    trans-2-en-NaVP
    trans-isomer of 2-en-valproate
    V˙max
    maximal rate of rise of action potential
    VPA
    valproic acid
    • Received March 26, 1996.
    • Accepted November 8, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 3
1 Mar 1997
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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Trans-2-en-valproic Acid Limits Action Potential Firing Frequency in Mouse Central Neurons in Cell Culture

Artur W. Wamil, Wolfgang Löscher and Michael J. McLean
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1349-1356;

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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

Trans-2-en-valproic Acid Limits Action Potential Firing Frequency in Mouse Central Neurons in Cell Culture

Artur W. Wamil, Wolfgang Löscher and Michael J. McLean
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1349-1356;
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