Summary
Two actions of clinically used antiepileptic drugs have been studied using mouse neurons in primary dissociated cell culture. The antiepileptic drugs phenytoin, carbamazepine and valproic acid were demonstrated to limit sustained high frequency repetitive firing of action potentials at free serum concentratons that are achieved in patients being treated for epilepsy. Furthermore, an active metabolite of carbamazepine also limited sustained high frequency repetitive firing while inactive metabolites of phenytoin and carbamazepine did not limit sustained high frequency repetitive firing. Phenobarbital and clinically used benzodiazepines limited sustained high frequency repetitive firing of action potentials, but only at concentrations achieved during the treatment of generalized tonic-clonic status epilepticus. Ethosuximide did not limit sustained high frequency repetitive firing even at concentrations four times those achieved in the serum of patients treated for generalized absence seizures. Phenobarbital and clinically used benzodiazepines enhanced postsynaptic GABA responses at concentrations achieved free in the serum during treatment of generalized tonic-clonic or generalized absence seizures. However, phenytoin, carbamazepine, valproic acid and ethosuximide did not modify postsynaptic GABA responses at therapeutic free serum concentrations. These results suggest that the ability of antiepileptic drugs to block generalized tonicclonic seizures and generalized tonic-clonic status epilepticus may be related to their ability to block high frequency repetitive firing of neurons. The mechanism underlying blockade of myoclonic seizures may be related to the ability of antiepileptic drugs to enhance GABAergic synaptic transmission. The mechanism underlying management of generalized absence seizures remains unclear.
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References
Barnes DM, Dichter MA (1984) Effects of ethosuximide and tetramethyl-succinimide on cultured cortical neurons. Neurology 34: 620–625
Chapman A, Keane PE, Meldrum BS, Simiand J, Vernieres JC (1982) Mechanisms of anticonvulsant action of valproate. Prog Neurobiol 19: 315–359
Choi D, Farb D, Fischbach B (1977) Chlordiazepoxide selectively augments GABA action in spinal cord cell cultures. Nature 269: 342–344
Godin Y, Heiner L, Mark J, Mandel P (1969) Effects of di-n-propylacetate, an anticonvulsant compound, on GABA metabolism. J Neurochem 19: 869–873
Hille B (1977) Local anesthetics: hydropholic and hydrophobic pathways for the drugreceptor reaction. J Gen Physiol 69: 497–515
Hodeghem LM, Katzung BB (1977) Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 472: 373–398
Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA (1978) Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia 19: 409–428
Macdonald RL (1983) Mechanisms of anticonvulsant drug action. In: Pedley TA, Meldrum B (eds) Recent advances in epilepsy, vol 1. Churchill, Livingstone, Edinburgh, pp 1–23
Macdonald RL, Barker JL (1978) Benzodiazepines specifically modulate GABA-mediated post-synaptic inhibition in cultured mammalian neurons. Nature 271: 563–564
Macdonald RL, Barker JL (1979a) Enhancement of GABA-mediated postsynaptic inhibition in cultured mammalian neurons: a common mode of anticonvulsant action. Brain Res 167: 323–336
Macdonald RL, Barker JL (1979b) Anticonvulsant and anesthetic barbiturates: different postsynaptic actions in cultured mammalian neurons. Neurology 29: 432–447
Macdonald RL, McLean MJ, Skerritt JH (1985) Anticonvulsant drug mechanisms of action. Fed Proc 44: 227–235
Macdonald RL, McLean MJ (1986) Anticonvulsant drugs: mechanisms of action. In: Delgado-Esqueta AV, Ward Jr AA, Woodbury DM, Porter RJ (eds) Basic mechanisms of the epilepsies, vol 44. Raven Press, New York, pp 713–736
Matsuki N, Quandt FN, Ten Eick RE, Yeh JZ (1984) Characterization of the block of sodium channels by phenytoin in mouse neuroblastoma cells. J Pharmacol Exp Ther 228: 523–530
McLean MJ, Macdonald RL (1983a) Phenytoin and carbamazepine selectively limit sustained high frequency repetitive firing of cultured mouse neurons. Soc Neurosci Abst 9: 398
McLean MJ, Macdonald RL (1983b) Multiple actions of phenytoin on mouse spinal cord neurons in cell culture. J Pharmacol Exp Ther 227: 779–789
McLean MJ, Macdonald RL (1986a) Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 237: 1001–1011
McLean MJ, Macdonald RL (1986b) Carbamazepine and 10,11-epoxy carbamazepine produced use- and voltage-dependent limitation of rapidly firing action potentials of mouse central neurons in cell cultures. J Pharmacol Exp Ther 238: 727–732
Möhler H, Okada T (1977) Demonstration of benzodiazepine receptors in the central nervous system. Science 198: 849–851
Nau H, Löscher W (1982) Valproic acid: brain and plasma levels of the drug and its metabolites, anticonvulsant effects andγ-aminobutyric acid (GABA) metabolism in the moue. J Pharmacol Exp Ther 220: 654–659
Schulz DW, Macdonald RL (1981) Barbiturate enhancement of GABA-mediated inhibition and activation of chloride ion conductance: correlation with anticonvulsant and anesthetic actions. Brain Res 209: 177–188
Skerritt JH, Macdonald RL (1984) Benzodiazepine receptor ligand actions on GABA responses: benzodiazepines, CL 218872, zopiclone. Eur J Pharmacol 101: 127–134
Skerritt JH, Rock DM, McLean MJ, Macdonald RL (1984a) Concentration-dependent effects of benzodiazepines on GABA responses and sustained high frequency repetitive firing in mouse cultured neurons. Soc Neurosci Abstr 10: 632
Skerritt JH, Werz MA, McLean MJ, Macdonald RL (1984b) Diazepam and its anomalousp-chloro-derivative Ro 5-4864: comparative effects on mouse neurons in cell culture. Brain Res 310: 99–105
Squires RF, Braestrup C (1977) Benzodiazepine receptors in rat brain. Nature 266: 732–734
Squires RF, Casida JE, Richardson M, Saederup E (1982) [35S]t-butylbicy-clophosphorothionate binds with high affinity to brain-specific sites coupled toγ-aminobutyric acid-A and ion recognition sites. Mol Pharmacol 23: 326–336
Ticku MK, Ban M, Olsen RW (1978) Binding of [3H]α-dihydropicrotoxinin, aγ-aminobutyric acid synaptic antagonist, to rat brain membranes. Mol Pharmacol 14: 391–402
Willow M, Kuenzel EA, Catterall WA (1983) Inhibition of voltage, sensitive sodium channels in neuroblastoma cells and synaptosomes by the anticonvulsant drugs diphenylhydantoin and carbamazepine. Mol Pharmacol 25: 228–234
Woodbury DM, Penry JK, Pippenger CE (1982) Antiepileptic drugs, 2nd edn. Raven Press, New York
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Macdonald, R.L. Anticonvulsant drug actions on neurons in cell culture. J. Neural Transmission 72, 173–183 (1988). https://doi.org/10.1007/BF01243417
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DOI: https://doi.org/10.1007/BF01243417