Excitatory Amino Acids

Vernadakis and Woodbury, Inhibitions of the Nervous System and Gamma-aminobutyric Acid (1960),532 demonstrated that PHT enhanced the conversion of free glutarnic acid to glutarnine and GABA in rat brain.

532. Vernadakis, A. and Woodbury, D. M., Effects of diphenylhydantoin and adrenocortical steroids on free glutamic acid, glutamine, and gamma-aminobutyric acid concentrations of rat cerebral cortex, Inhibitions of the nervous system and gamma-aminobutyric acid, 242-248, Pergamon Press, Oxford, 1960.

Patsalos and Lascelles, Journal Of Neurochemistry (1981), 2851 reported that PHT (50 mg/kg), daily for ten days, reduced rat cerebellar and hypothalamic aspartate levels.

2851. Patsalos, P. N., Lascelles, P. T., Changes in regional brain levels of amino acid putative neurotransmitters after prolonged treatment with the anticonvulsant drugs diphenylhydantoin, phenobarbitone, sodium valproate, ethosuximide, and sulthiame in the rat, J. Neurochem., 36(2): 688-95, 1981.

Stone, Advances in Biochemical Psychopharmacology (1981),2983 reported that PHT reduced the response of rat somatosensory cortical neurons to iontophoretically applied glutamate and aspartate, but not acetylcholine.

2983. Stone, T. W., Studies with excitatory amino acid antagonists in rat CNS: 2-amino-5-phosphonovaleric acid, phenytoin, and benzodiazepines, Adv. Biochem. Psychopharmacol., 23: 223-30, 1981.

Gankina, Avdulov and Maisov, Farmakologiia i Toksikologiia (1982),2524 found that PHT stimulated glutamate uptake by rat brain synaptosomes, but only at very high concentrations (500 µM).

2524. Gankina, E. M., Avdulov, N. A., Maisov, N. I., Effects of different psychotropic drugs on 14C-glutamate uptake by rat brain synaptosomes, Farmakol. Toksikol., 45(6): 17-20, 1982.

Skerritt and Johnston, Clinical and Experimental Pharmacology and Physiology (1983),2961 reported that PHT (25-200 M) significantly inhibited potassium-evoked release of D-aspartate, in rat brain slices, which is consistent with its actions in reducing abnormal hyperexcitability. (See also Ref 2962.)

2961. Skerritt, J. H., Johnston, G. A., Inhibition of amino acid transmitter release from rat slices by phenytoin and related anticonvulsants, Clin. Exp. Pharmacol. Physiol., 10: 527-33, 1983.

2962. Skerritt, J. H., Johnston, G. A. Modulation of excitant amino acid release by convulsant and anticonvulsant drugs, Neurotransmitters, Seizures, and Epilepsy II, Fariello, R. G. et al., Eds., Raven Press, New York, 215-26, 1984.

Stone and Javid, Brain Research (1983),2984reported that PHT (40 mg/kg) was effective in preventing glutamate-induced seizures in mice. The authors suggest that PHT may act by reducing glutaminergic transmission.

2984. Stone, W. E., Javid, M. J., Effects of anticonvulsants and other agents on seizures induced by intracerebral L-glutamate, Brain Res., 264(1): 165-67, 1983.

Bechtereva, Nikitina, Iliuchina, Dambinova and Denisova, European Journal of Clinical Investigation (1984),2316 demonstrated the inhibitory effect of PHT on glutamate receptors in a cortical synaptic membrane preparation and suggest that this is an important mechanism by which PHT regulates neuronal excitability.

2316. Bechtereva, N. P., Nikitina, L. I., Iliuchina, V. A., Dambinova, S. A., Denisova, V. V., Dilantin: clinical and scientific experience of application, Eur. J. Clin. Invest., 14: 36, 1984.

Wamil and McLean, Journal of Pharmacology and Experimental Therapeutics (1993),3505 noting that PHT has been reported to have multiple actions, studied its effect on the responses of mouse neuron in culture to N-methyl-D-aspartate, an excitatory and potentially neurotoxic agent.

PHT (8 M) blocked responses to 10 -5 M NMDA at 2 Hz and at short, non-overlapping 2-s intervals, but less so at lower frequencies. The PHT metabolite, 5-(4-hydroxy-phenyl)-5-phenylhydantoin, does not block the response to NMDA. Based on these findings, the authors suggest that use- and frequency-dependent block of NMDA responses may contribute to the clinical effects of PHT, e.g., during sustained rapid activity along pathways excited by NMDA-preferring glutamate receptors.

3505. Wamil, A.W. and McLean, M.J., Phenytoin blocks N-methyl-D-aspartate responses of mouse central neurons, J. Pharmacol. Exp. Ther., 267(1): 218-27, 1993.

Fraser, Sills, Forrest, Thompson and Brodie, British Journal of Pharmacology (1999),3506 investigated the effects of single and repeated intraperitoneal administration of a range of established and new anti-epileptic drugs on glutamine synthetase (GS) activity in mouse brain. Male ICR mice were randomized into seven groups and, among other combinations of anti-seizure medications, were administered a combination of phenytoin, lamotrigine, topiramate, desglycinyl-remacemide - 0.3,1,3,10, 30 and 100 mg kg ),-1.

Results indicated that both single and repeated treatments with PHT significantly reduced the activity of GS at 4 hours after administration. CBZ showed similar effects on GS. Felbmate and topiramate only produced their effect after multiple doses. The authors speculate that this reduction in GS activity is not related to PHT's anti-epileptic activity, but may relate to its other effects, especially toxicity.

3506. Fraser, C.M., Sills, G.J., Forrest, G., Thompson, G.G., and Brodie, M.J., Effects of anti-epileptic drugs on glutamate synthetase activity in mouse brain, Br. J. Pharmacol., 126:1634-1638, 1999.

Lingamaneni and Hemmings, Neuroscience Letters (1999),3507 compared the effects of three conventional anti-convulsants, (PHT, carbamazepine and phenobarbital) and three novel (BW1003C87, lamotrigine and riluzole) anticonvulsants on evoked glutamate release from rat cortical synaptosomes. Glutamate release was evoked by either 20M veratridine (which requires both Na+ and Ca2+ channel activation) or 30 mM KCI (which requires Ca2+ channel, but not Na+ channel activation) to assess the involvement of Na+ and/or Ca2+ channels in the presynaptic actions of the anticonvulsants.

All six compounds inhibited veratridine-evoked glutamate release. PHT was found to significantly inhibit KCI-evoked glutamate release. The results indicated that PHT has the ability to inhibit synaptic glutamate release by preferentially blocking presynaptic Na+ channels.

3507. Lingamaneni, R. and Hemmings, H.C. Jr, Effects of anticonvulsants on vertridine- and KCL-evoked glutamate release from rat cortical synaptosomes, Neurosci. Lett., 276: 1270130, 1999.

Cunningham, Dhillon, Wood and Jones, Neuroscience (2000),3508 examined the effects of PHT on aspects of glutamate and GABA synaptic transmission, in the rat entorhinal cortex (EC) in vitro, an area highly susceptible to seizure generation. Experiments were performed on slices containing EC and hippocampus prepared from male Wistar rats.

Evoked excitatory postsynaptic potentials at glutamate synapses exhibited frequency-dependent enhancement, and PHT reduced this enhancement without altering responses evoked at low frequency. In whole-cell patch-clamp recordings, the frequency of excitatory postsynaptic currents resulting from the spontaneous release of glutamate was reduced by PHT with no change in amplitude, rise time or decay time. The results demonstrated that PHT can cause a simultaneous reduction in synaptic excitation and an increase in inhibition in cortical networks. The shift in balance in favor of inhibition could be a major factor in PHT's actions on abnormal brain excitability, including seizures.

3508. Cunningham, M.O., Dhillon, A., Wood, J., and Jones, R.S.G., Reciprocal modulation of glutamate and GABA release may underlie the anticonvulsant effect of phenytoin, Neuroscience, 95(2): 343-351, 2000.

See also Refs.

3499. Wong, P.T. and Teo, W.L., The effect of phenytoin on glutamate and GABA transport, Neurochem. Res., 11(9): 1379-82, 1986.

3509. Koh, J.Y. and Choi, D.W., Effect of anticonvulsant drugs on glutamate neurotoxicity in cortical cell culture, Neurology, 37: 319-22, 1987.

3510. Kawano, H., Sashihara, S., Mita, T., Ohno, K., Kawamura, M., and Yoshii, K., Phenytoin, an antiepileptic drug, competitively blocked non-NMDA receptors produced by xenopus oocytes, Neurosci. Lett., 166(2):183-86, 1994.

3511. Petroff, O.A.C., Rothman, D.L., Behar, K.L., Hyder, F., and Mattson, R.H., Effects of valproate and other antiepileptic drugs on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures, Seizure, 8:120-127, 1999.

3512. Churchill, J.D., Green, J.T., Voss, S.E., Manley, E., Steinmetz, J.E., and Garraghty, P.E., Discrimination reversal conditioning of an eyeblink response is impaired by NMDA receptor blockade, Integr. Physiol. Behav. Sci., 36(1): 62-74, 2001.