The Neurophysiological Effects of Diphenylhydantoin and Their Relationship to Anticonvulsant Activity (original) (raw)
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Diphenylhydantoin increases cortical postsynaptic inhibition
Brain Research, 1976
In recent years much information has been acquired on the action of diphenylhydantoin (DPH) on nervous tissue. In addition to the well-known decrease of posttetanic potentiation' DPH has been found to have many other effects which might account for its action as a 'membrane stabilizer'ss. Nearly all of the studies in which the action of DPH on synaptic mechanisms were investigated suggest a decrease in synaptic activity2,8,9,11.13.15,23,26. H owever, DPH has also been found to increase presynaptic inhibition in the frog spinal cord4 and postsynaptic inhibition in crayfish stretch receptori. In this paper we report a prolongation of the postsynaptic inhibition in the mammalian motor cortex by DPH.
Brain Research, 1993
The anticonvulsant activity of delta-HCH and of a calmodulin antagonist, W-7 were investigated on convulsions induced in mice by lindane (ED100 100 mg/kg), by GABAergic antagonists PTZ (ED100 60 mg/kg) and PTX(ED100 4 mg/kg), by calcium channel agonist BAY-K-8644 (ED100 5 mg/kg), by two agonists of excitatory amino acid receptors, kainic acid (ED100 80 mg/kg) and NMDA (ED100 160 mg/kg and by the atypical benzodiazepine Ro 5-4864 (ED100 40 mg/kg). The anticonvulsant activity of a voltage-dependent calcium channel antagonist, nifedipine was also investigated on convulsions induced by Ro 5-4864, BAY-K-8644, kainic acid and NMDA. delta-HCH antagonized lindane- and BAY-K-8644-induced convulsions (ED50 231 (172-309) mg/kg and 148 (142-154) mg/kg, respectively) and at concentrations up to 300 mg/kg failed to antagonize Ro 5-4864, kainic acid and NMDA convulsions. In contrast delta-HCH potentiated PTX-induced seizures. Nifedipine antagonized BAY-K-8644- and kainic acid-induced convulsions (ED50 6.5 (4.3-9.7) mg/kg and 30 (13-70) mg/kg but at concentrations up to 20 mg/kg failed to antagonize Ro 5-4864 and 25% of protection was observed on NMDA-induced convulsions at the highest dose (20 mg/kg). The ED50 of W-7 to antagonize convulsions induced by lindane and BAY-K-8644 were 12 (8-19) mg/kg and 49 (29-85) mg/kg, respectively. Some anticonvulsant effect was observed against PTZ and NMDA but without any dose-dependent anticonvulsant activity. W-7 did not protect against PTX and kainic acid convulsions and 30% of protection was observed against convulsions at the highest dose of W-7 (75 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
Epilepsia, 1996
D-Cycloserine (DCS) is a high-efficacy partial agonist at the strychnine-insensitive glycine modulatory site within the N-methyl+-aspartate (NMDA)-receptor/ionophore complex. Previous studies demonstrated that DCS exhibits anticonvulsant activity in a variety of experimental epilepsy models. In this study, we determined the influence of DCS in subprotective doses on the anticonvulsant action of phenytoin (PHT) and carbamazepine (CBZ) in mice. Methods: Two electroconvulsive tests were used, i.e., determination of seizure threshold and maximal electroshock seizures. Antiepileptic drug-induced motor and long-term memory deficits were quantified by using the chimney test and the passive-avoidance test, respectively. In addition, plasma levels of PHT and CBZ were measured by fluorescence polarization immunoassay to exclude any pharmacokinetic interactions. Results: DCS, when used alone in doses of 80 and 160 mg/kg, significantly increased the threshold for electroconvulsive seizures. DCS in a wide range of doses (1.25-40 mg/kg) was combined with either PHT or CBZ and tested in electroconvulsive tests. DCS, at doses of 2.5 and 10 mg/kg, was the most effective in potentiating the threshold-increasing action of PHT; higher doses of DCS (20 and 40 mg/kg) were required to achieve a similar effect of CBZ. In maximal electroshock-induced seizures, DCS (10 mg/kg) augmented the protective action of PHT, but was ineffective at a dose of 40 mgikg with CBZ. DCS did not potentiate the neurotoxicity produced by PHT and CBZ in the chimney test. Both PHT and CBZ induced impairments of long-term memory; PHT-induced memory adverse effects were counteracted by DCS (10 mg/kg). There was no such effect on CBZ-induced memory impairment, and a worsening influence was observed. Any pharmacokinetic interactions were excluded by measuring total and free plasma levels of both antiepileptic drugs. Conclusion: Our results suggest that combining DCS with PHT and CBZ may be beneficial in treating epileptic seizures.
Epilepsia, 1980
In the electroshock test-taking hind-limb tonic extension as the end point-apomorphine (10 mg/kg) exerted no effect on the anticonvulsant action of phenobarbital (PB; 20 mg/kg) or diphenylhydantoin (DPH; 8 mg/kg); amantadine (25 and 100 mg/kg) decreased that of DPH, while L-DOPA (500 mg/kg) and d,I-amphetamine (10 mg/kg) potentiated the action of both anticonvulsants. Fluphenazine (4 mg/kg) had no influence on the effects of the two anticonvulsants, but haloperidol lessened that of DPH. All GABA-ergic stimulants used, i.e., y-hydroxybutyric acid (GHBNZSO mg/kg), baclofen (2.5 and 10 mg/kg) and aminooxoacetic acid (AOAA; 15 and 20 mg/kg) potentiated the action of PB; the action of DHP was unaffected by these drugs except for AOAA (20 mg/kg). The combined treatment with dopaminergic and GABAergic stimulants, being ineffective in terms of anticonvulsant activity, resulted in a marked potentiation of the action of the anticonvulsants tested in this study. The most distinct potentiation was noted in the case of PB, baclofen (1 mg/kg), and amantadine (25 mg/kg).
Evidence that antagonism at non-NMDA receptors results in anticonvulsant action
European Journal of Pharmacology, 1987
The effect of T-D-glutamylaminomethylsulphonate (T-D-GAMS) and 1-(p-bromobenzoyl)-piperazine-2,3-dicarboxylate (pBB-PzDA) on convulsions elicited by intracerebroventricular application of kainate (KA) and Nmethyl-D-aspartate (NMDA) was studied in mice. T-D-GAMS, 0.0025-1.0 /~mol, and pBB-PzDA, 0.001-0.2 /tmol, were preferentially active against myoclonic seizures induced by kainate, but had also pronounced anticonvulsant action against NMDA. Although pBB-PzDA was a more potent anticonvulsant relative to T-D-GAMS, T-D-GAMS displayed higher kainate-selectivity. T-D-GAMS, 0.025 and 0.5 /~mol, and pBB-PzDA, 0.1 #tool, blocked myoclonic seizures induced by kainate in the presence of 2-amino-7-phosphonoheptanoate, a selective antagonist at the NMDA receptor, with potency comparable to that for antagonism of seizures produced by kainate alone. These results indicate that antagonism at kainate receptors may contribute to anticonvulsant drug action. T-D-Glutamylaminomethylsulphonic acid; 1-(p-Bromobenzoyl)-piperazine-2,3-dicarboxylic acid; Excitatory amino acid antagonists; Seizures; (Mouse)
Mechanisms of Action of Antiepileptic Drugs
Current Topics in Medicinal Chemistry, 2005
Gamma-aminobutyric acid (GABA), one of the main inhibitory neurotransmitters in the brain, interacts with three types of receptors for GABA--GABA(A), GABA(B) and GABA(C). GABA(A) receptors, associated with binding sites for benzodiazepines and barbiturates in the form of a receptor complex, control opening of the chloride channel. When GABA binds to the receptor complex, the channel is opened and chloride anions enter the neuron, which is finally hyperpolarized. GABA(B) receptors are metabotropic, linked to a cascade of second messengers whilst the physiological meaning of ionotropic GABA(C) receptors, mainly located in the retina, is generally unknown. Novel antiepileptic drugs acting selectively through the GABA-ergic system are tiagabine and vigabatrin. The former inhibits neuronal and glial uptake of GABA whilst the latter increases the synaptic concentration of GABA by inhibition of GABA-aminotransferase. Gabapentin, designed as a precursor of GABA easily entering the brain, was shown to increase brain synaptic GABA. This antiepileptic drug also decreases influx of calcium ions into neurons via a specific subunit of voltage-dependent calcium channels. Conventional antiepileptics generally inhibit sodium currents (carbamazepine, phenobarbital, phenytoin, valproate) or enhance GABA-ergic inhibition (benzodiazepines, phenobarbital, valproate). Ethosuximide, mainly controlling absences, reduces calcium currents via T-type calcium channels. Novel antiepileptic drugs, mainly associated with an inhibition of voltage-dependent sodium channels are lamotrigine and oxcarbazepine. Since glutamate-mediated excitation is involved in the generation of seizure activity, some antiepileptics are targeting glutamatergic receptors--for instance, felbamate, phenobarbital, and topiramate. Besides, they also inhibit sodium currents. Zonisamide, apparently sharing this common mechanism, also reduces the concentration of free radicals. Novel antiepileptic drugs are better tolerated by epileptic patients and practically are devoid of important pharmacokinetic drug interactions.