Stabilization of Bioelectrical Activity Continued

Chebabo, Do-Carmo and Martins-Ferreira, Brazilian Journal of Biological and Medical Research (1988),³⁴³⁰ investigated the effects of phenytoin on the threshold concentration of K+ necessary to elicit spreading depression and on the propagation of spreading depression (SD) in strips of chick retina in vitro. SD was elicited mechanically by pricking the retina with a tungsten wire at 15-minute intervals. Two single-barreled microelectrodes were used for recording.

PHT (minimal effective concentration, 8 µM) significantly decreased the velocity of SD in an atmosphere of 95% O2 and 5% CO2 at pH 7.4. This effect was dose-dependent and persisted for at least two hours after phenytoin was removed from the medium. Under the same conditions, phenytoin (20 µM) increased the threshold concentration of K+ needed to elicit SD by 5 ± 0.8 mM/l. Phenytoin's effectiveness was influenced by ambient pH (less effective at higher pH) and by Cl- (reduced the minimal effective phenytoin concentration).

The authors conclude that phenytoin decreases the susceptibility of the chick retina preparation to spreading depression.

3430. Chebabo, S.R., Do-Carmo, R.J., and Martins-Ferreira, H., The effect of diphenylhydantoin on spreading depression, Braz. J. Med. Biol. Res., 21(3): 603-5, 1988.

Schwarz and Grigat, Epilepsia (1989),³⁴³¹ performed voltage clamp experiments in single myelinated nerve fibers of the rat to study the effects of phenytoin (PHT) and carbamazepine (CBZ) on ionic membrane currents. Both substances were effective blockers of Na channels in the nodal membrane of the rat. PHT 50 µM reduced Na currents to 30% without changing the Na equilibrium potential. The outward K currents were not affected by PHT, indicating that in mammalian nerve fibers this drug selectively blocked Na channels. Their experiments showed that the sodium channel block induced by PHT and CBZ was concentration-, potential- and frequency-dependent.

3431. Schwarz, J.R. and Grigat, G., Phenytoin and carbamezepine : potential- and frequency dependent block of Na Currents in mammalian myelinated nerve fibers, Epilepsia, 30(3): 286-94, 1989.

Birnstiel and Haas, Neuroscience Letters (1991),³⁴³² induced long-term potentiation (LTP) of population spikes in the CA1 area of rat hippocampus by tetanic stimulation of the stratum radiatum in slices kept submerged in a perfusion chamber. The addition of phenytoin or midazolam to the medium did not significantly alter this phenomenon (LTP) within 22 min after the tetanus. The early enhancement (post-tetanic potentiation, PTP) was reduced only by phenytoin. Based on their study, the authors suggest that an interaction of these drugs with N-methyl-D-aspartate (NMDA) receptors and LTP induction is unlikely.

3432. Birnstiel, S. and Haas, H.L., Anticonvulsants do not suppress long-term potentiation (LTP) in the rat hippocampus, Neurosci. Lett., 122: 61-63,1991.

Chebabo and Do Carmo, Brain Research (1991),³⁴³³ investigated the use of phenytoin to counteract spreading depression elicited by mechanical or chemical (KCl) stimulation, in isolated chick retinas. The results showed that phenytoin: (1) increases the threshold concentration of KCl to initiate the phenomenon; (2) decreases the velocity of propagation of spreading depression; (3) shortens considerably the duration of the slow potential, ionic (Ka+, Ca2+, Cl-) and volume changes of the extracellular compartment during spreading depression. The authors cite the possible relationship between spreading depression and migraine, brain ischemia, trauma and hypoglycemia. They also discuss the possible mechanisms underlying phenytoin's effect on spreading depression.

3433. Chebabo, S.R. and Do Carmo, R.J., Phenytoin and retinal spreading depression, Brain Res., 551(1-2):16-19, 1991.

Bagri, Sandner and Di Scala, Pharmacology, Biochemistry and Behavior (1992),³⁴³⁴ investigated the behavioral and motivational effects of electrical stimulation of the inferior colliculus (IC) of rats. Electrical stimulations of either the dorsal part or ventral part of the IC both elicited wild running (WR). Nevertheless, the ventral part was found more sensitive than the dorsal part, as lower intensities were needed to elicit WR. Moreover, WR differed depending on the part of the IC stimulated. It stopped as soon as the stimulation was switched off when the ventrical IC was stimulated, whereas it further persisted in a poststimulus WR when the dorsal IC was stimulated. The duration of the poststimulus WR was recorded at threshold before and 10 minutes after the administration of diazepam (1 mg/kg), phenytoin (30 mg/kg), valproic acid (200 mg/kg) and saline. The poststimulus WR was abolished by diazepam, phenytoin or sodium valproate. Since WR was similar to those behavioral responses related to aversion, the authors assessed the putative aversive effects of electrical stimulation of dorsal and ventral parts of the IC in a switch-off paradigm. These putative aversive effects were further studied in the presence of diazepam, phenytoin and sodium valproate. In an operant escape conditioning paradigm (switch-off test), only stimulation of the ventral IC readily sustained switch-off learning. Dorsal IC stimulations did not, possibly because of the poststimulus enduring effects of stimulation, as evidenced by poststimulus WR. Indeed, the drugs which abolished this poststimulus WR also permitted switch-off of dorsal IC stimulations. The authors conclude that electrical stimulation of the IC (dorsal or ventral) elicit aversive effects and that WR elicited either by ventral or dorsal stimulation may represent the overt expression of these aversive effects.

3434. Bagri, A., Sandner, G., and Di Scala, G., Wild running and switch-off behavior elicited by electrical stimulation of the inferior Colliculus: effect of anticonvulsant drugs, Pharmacol. Biochem. Behav., 39:683-688, 1992.

Tegtmeier, Wilhelm, Frankow, Thone, Vandeplassche and Peters, Journal of Cardiovascular Pharmacology (1992),³⁴³⁵ evaluated the protective effects of phenytoin (PHT) (60 æM) and Na+/Ca+ overload inhibitor R56865 (N-[1-[4-(4-fluorophenoxy)-butyl]-4-piperidinyl)-N-methyl-2-benz othiazol amine) (1æM) against ouabain (OUA) (0.04 æM) intoxication in the isolated perfused rabbit heart. Both PHT and R56865 prevented the ouabain-induced increase in left ventricular end-diastolic pressure (LVEDP), (50 in control; 0 treated); delayed the onset of arrhythmias (8.2 min and 14 min respectively); prevented the breakdown of energy-rich compounds (creatine phosphate and ATP); permitted only a slight increase in tissue lactate compared to the large increase in controls (also only one-half as much lactate was released from the treated vs. control hearts); and prevented cell degeneration (contraction bonds, necrosis, sarcolemmal changes), mitochondrial disruption and intracellular edema, and depletion of glycogen stores.

The authors conclude that the protective actions of both PHT and R56865 may be due to prevention or attenuation of mitochondrial failure caused by ouabain-induced changes in ion homeostasis.

3435. Tegtmeier, F., Wilhelm, D., Frankow, C., Thone, F., Vandeplassche, L., and Peters, T., Effects of R 56865 and phenytoin on mechanical, biochemical, and morphologic changes during oubain intoxication in isolated perfused rabbit heart, J. Cardiovasc. Pharmacol., 20:421-28, 1992.

Segal, Society for Neuroscience Abstracts (1993),³⁴³⁶ examined the effect of phenytoin on sustained depolarizations and the endogenous non-synaptic, calcium-independent plateau burst activity. For four of five excitatory rat hippocampal neurons, the addition of phenytoin to the medium, abolished the plateau burst, leaving only a non-plateau burst of action potentials (which also blocked any possible synaptic activity). The plateau burst was shortened for the fifth neuron. Vehicle (propylene/glycol/ethanol/water) alone was ineffective. The addition of phenytoin did not greatly attenuate the activity of eleven other neurons with only non-plateau action potential bursts in the synapse blocking solution.

3436. Segal, M.M., Phenytoin attenuates seizure-associated plateau bursts in solitary hipocampal neurons, Soc. Neurosci. Abstr., 19 (PT.1): 20, 1993.

Kamei, Kameyama and Nabeshima, European Journal of Pharmacology (1996),³⁴³⁷ in a study of fear-induced motor suppression in mice found that two substances that reverse this motor suppression, SKF-10,047 and dextromethorphan act through an a receptor that is regulated by phenytoin (PHT). PHT, in fact, enhances the efficacy of these agents. They further suggest that the phenytoin-regulated a site may be closely connected to dopaminergic neuronal systems involved in this stress response.

3437. Kamei, H., Kameyama, T., and Nabeshima, T., (+)-SKF-10,047 and dextromethorphan ameliorate conditioned fear stress via dopaminergic systems linked to phenytoin-regulated a1 sites, Eur. J. Pharmacol., 309:149-158, 1996.

Lee, Brown and Teyler, Brain Research Bulletin (1996),³⁴³⁸ studied the effects of phenytoin, phenobarbital, and valproic acid on N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and non-NMDA-dependent voltage-dependent calcium channel LTP. PHT (0.02 mg/ml) had no effect on NMDA-dependent LTP, but reduced VDCC-dependent LTP, while phenobarbital (0.025 mg/ml) potently blocked NMDA LTP and inhibited VDCC LTP. Valproic acid did not inhibit VDCC LTP, but abolished NMDA LTP. The authors suggest that the findings indicate that the anticonvulsant actions of these three drugs depend on different cellular mechanisms.

3438. Lee, G.Y., Brown, L.M., and Teyler, T.J., The effects of anticonvulsant drugs on long-term potentiation (LTP) in the rat hippocampus, Brain Res. Bull., 39(1):39-42, 1996.

Walker, Alavijeh, Shorvon and Patsalos, Epilepsia (1996),³⁴³⁹ report a study of the neuropharmacokinetics of phenytoin in the rat brain after acute intraperitoneal doses of 50 or 100 mg/kg as part of an effort to understand PHT's actions in status epilepticus. Microdialysis probes were implanted in the hippocampus and frontal cortex of Sprague-Dawley rats. PHT was rapidly absorbed with a time to maximum serum concentration (Tmax) of 20 minutes for serum concentration and the brain extracellular fluid (ECF) concentration. In brain ECF, PHT concentrations plateaued for 40-60 minutes despite decreasing serum concentrations. After 60 minutes the decrease in ECF concentrations parallels that in serum. The area under the brain ECF-concentration-time curve (AUC) was higher in hippocampus than frontal cortex.

3439. Walker, M.C., Alavijeh, M.S., Shorvon, S.D., and Patsalos, P.N., Microdialysis study of the neuropharmacokinetics of phenytoin in rat hippocampus and frontal cortex, Epilepsia, 37(5):421-427, 1996.

Rush and Elliott, Neuroscience Letters (1997),³⁴⁴⁰ in an effort to elucidate the mechanisms of phenytoin (PHT) and carbamazepine (CBZ) in the control of neuropathic pain, studied the effects of the agents on the heterogenous population of Na+ channels in patch-clamped small cells from adult rat dorsal root ganglia. In the preparation, the effects of PHT and CBZ were similar in inhibiting tetrodotoxin-resistant (TTX-R) currents. Fast and Type II currents were the most sensitive. Block was relieved by hyperpolarizing prepulses.

3440. Rush, A.M. and Elliott, J.R., Phenytoin and carbamazepine: differential inhibition of sodium currents in small cells from adult rat dorsal root ganglia, Neurosci. Lett., 226:95-98, 1997.

Kang, Okada and Ohmori, European Journal of Neuroscience (1998),³⁴⁴¹ as part of a study on the ionic mechanisms underlying the depolarizing afterpotential (DAP) in whole-cell voltage or current clamped rat neocortical pyramidal cells, with special emphasis on those underlying the burst afterdischarge, found that PHT (1-10 µM) suppressed the slow DAP while enhancing the plauteau-AP in the presence of TTX, most likely by blocking Ca2+-dependent cationic channels. PHT suppressed or terminated burst afterdischarge induced by the injection of K+ current pulses causing inward movement of K+.

3441. Kang, Y., Okada, T., Ohmori, H., A phenytoin-sensitive cationic current participates in generating the afterdepolarization and burst after discharge in rat neocortical pyramidal cells, Eur. J. Neurosci., 10: 1063-1375, 1998.

Samii, Chen, Wassermann and Hallett, Neurology (1998),³⁴⁴² utilized phenytoin (PHT) to study the mechanism of the postexercise facilitation of motor evoked potentials (MEP) after brief, non-fatiquing muscle activation caused by transcranial magnetic stimulation in five normal volunteers. PHT (at serum levels of 12.1 - 22.3 æg/ml) did not alter postexercise MEP facilitation or the decay of facilitation. PHT did, however, increase the mean motor threshold (p is less than 0.005). Since PHT reduces post-tetanic potentiation (PTP), but does not block long-term potentiation (LTP), the authors conclude that postexercise MEP is unlikely to be due to PTP.

3442. Samii, A., Chen, R., Wassermann, E.M., and Hallett, M., Phenytoin does not influence postexercise facilitation of motor evoked potentials, Neurology, 50:291-293, 1998.

Francis, Eubanks and McIntyre Burnham, Brain Research (2000),³⁴⁴³ examined whether phenytoin, in the presence of diazepam, [3H]phenytoin, has a brain membrane binding site that is distinct from the binding that occurs at the voltage dependant sodium channel (VDSC). The authors also examined whether the potentiated [3H]phenytoin binding activity is associated with other benzodiazepine receptor sites, either centrally or peripherally located. The data illustrated that [3H]phenytoin interacts with a novel site in brain membranes that is distinct from the voltage-dependent sodium channel and that this site is allosterically revealed by peripheral-type, but not central-type, benzodiazepine receptor agonists.

3443. Francis, J., Eubanks, J.H., and Mcintyre Burnham, W., Diazepam-potentiated [3H]phenytoin binding is associated with peripheral-type Benzodiazepine receptors and not with voltage-dependent sodium channels, Brain Res., 876:131-140, 2000.

See also Refs.

3444. Geary, W.A., Wooten, G.F., Perlin, J.B., and Lothman, E.W., In vitro and in vivo distribution and binding of phenytoin to rat brain, J. Pharmacol. Exp. Ther., 241(2):704-13, 1987.

3445. Sechi, G.P., Russo, A., Rosati, G., Mutani, R., and Monaco, F., Distribution of diphenylhydantoin in the brain during experimental status epilepticus of the cat, Epilepsy Res., 1(3):173-7, 1987.

3446. Netzer, R., Binscheck, T., and Bigalke, H., Phenytoin, baclofen, tizanidine and memantine reduce hyperexcitability of neurons in culture by interfering with different currents, Soc. Neurosci. Abstr., 15: 1301, 1989.

3447. Vivas, L., Chiaraviglio, E., and Carrer, H.F., Rat organum vasculosum laminae terminalis in vitro: responses to changes in sodium concentration, Brain Res., 519: 294-300, 1990.

3448. Leung, L.S. and Shen, B., Long-term potentiation in hippocampal CA1: effects of afterdischarges, NMDA antagonists, and anticonvulsants, Exp. Neurol., 119(2):205-214, 1993.

3449. Buritova, J., Hrabetova, S., Hrabe, J., Mares, P., and Pavlik, V., Influence of carbamezepine and phenytoin on spontaneous activity of cerebellar neurons, Physiol. Res., 43(2):113-6, 1994.

3450. Van den Berg, R.J., Versluys, C.A., De Vosa, A., and Voskuyl, R.A., Nerve fiber size-related block of action currents by phenytoin in mammalian nerve, Epilepsia, 35(6): 1279-88, 1994.

3451. Krsek, P., Haugvicova, R., and Mares, P., Age-dependent phenytoin effects on cortical stimulation in rats, Physiol. Res., 47:143-149, 1998.

3452. Ohno, K. and Higashima, M., Effects of antiepileptic drugs on afterdischarge generation in rat hippocampal slices, Brain Res., 924:39-45, 2002.

Review References

3453. De Lorenzo, R.J., Phenytoin - mechanisms of action, in: Antiepileptic Drugs, Third Edition, 143-58, Levy, R., et al, Eds., Raven Press, New York, 1989.

3454. Rho, J.M. and Sankar, R., The pharmacologic basis of antiepileptic drug action, Epilepsia, 40(11):1471-83, 1999.

3455. White, H.S., Comparative anticonvulsant and mechanistic Profile of the established and newer antiepileptic drugs, Epilepsia, 40(5):S2-S10, 1999.

3456. Moshe, S.L., Mechanisms of action of anticonvulsant agents, Neurology, 55(S1):S32-S40, 2000.