Electroshock-induced Convulsions Research Articles

Competitive antagonist of NMDA receptors, CGP 37849 and CGP 39551, enhance the anticonvulsant activity of valproate against electroconvulsions in mice

Two novel N-methyl-D-aspartic acid (NMDA) competitive antagonist, CGP 37849 (1.25 and 2.5 mg/kg) and CGP 39551 (10 mg/kg), significantly raised the threshold for electroconvulsions in mice. CGP 37849 in doses of 0.125–1.0 mg/kg and CGP 39551 in dose of 0.625–5 mg/kg i.p. considerably potentiated the protective activity of magnesium valproate againts maximal electroshock-induced convulsions. The anticonvulsant activity of sodium valroate was potentiated by CGP 37849 (1 mg/kg) to a similar degree, which suggest that magnesium is not involved in the observed interaction. Neither CGP agent influenced the plasma level of valproate, so a pharmacokinetic interactions, in terms of total plasma levels is not probable. Furthermore the performance of mice injected with magnesium valproate (90 mg/kg) and CGP 37849 (0.25 mg/kg), which provided 50% protection againts maximal electroshock-induced convulsions, in the long-term memory test and chimney test did not differ significantly from that of the control animals. The combination of magnesium valproate and CGP 39551 had a neurotoxic potential comparable to that of valproate alone. The result suggest that a combined treatment of valproate and some competitive NMDA antagonists may be important from a clinical point of view.

Influence of flunarizine, nicardipine and nimodipine on the anticonvulsant activity of different antiepileptic drugs in mice.

Only flunarizine (40 mg/kg, i.p.) significantly raised the threshold for electroconvulsions in mice (ear-clip electrodes, 0.2 sec stimulus duration, tonic hindlimb extension as an endpoint), whilst nicardipine and nimodipine (up to 80 mg/kg) was ineffective in this respect. Further, flunarizine (10 and 20 mg/kg) potentiated the efficacy of carbamazepine and valproate against maximum electroshock (50 mA)-induced seizures and, in the dose of 20 mg/kg, enhanced that of diphenylhydantoin. In addition, this calcium channel inhibitor was without influence upon the total levels of these antiepileptics in plasma. Nicardipine (5 and 10 mg/kg) and nimodipine (10 and 20 mg/kg) increased the protective potential of carbamazepine and nimodipine (20 mg/kg) also decreased the ED50 of diphenylhydantoin against maximum electroshock. However, nicardipine distinctly increased the level of carbamazepine in plasma, whilst nimodipine did not affect the level of both antiepileptics in plasma. The combined treatment of calcium channel inhibitors and antiepileptic drugs, providing a 50% protection against maximum electroshock, did not significantly change the motor performance of mice in the chimney test, when compared with antiepileptic drugs, given alone at their ED50s, against maximum electroshock-induced convulsions. The present results give further support to the idea of the combined use of some calcium channel inhibitors and antiepileptic drugs in the treatment of human epilepsy.

The effect of antidepressant drugs on the locomotor hyperactivity induced by MK-801, a non-competitive NMDA receptor antagonist

It was found earlier that imipramine, amitriptyline and citalopram enhanced the locomotor hyperactivity induced by MK-801, a non-competitive NMDA receptor antagonist, in rats. Now, three other antidepressants: (+)-oxaprotiline, an inhibitor of the uptake of noradrenaline, (−)-oxaprotiline, an enantiomer devoid of any effect on the uptake of noradrenaline and fluoxetine, an inhibitor of the uptake of 5-hydroxytryptamine, have been examined in male Wistar rats. All those antidepressants, given in a single dose, increased the MK-801-induced locomotor hyperactivity. That increase was completely antagonized by haloperidol and partly by SCH 23390 and (±)-sulpiride; prazosin was inactive. Repeated administration of antidepressants produced a similar but more potent (than acute one) enhancement of the action of MK-801. Also, in that case haloperidol and SCH 23390 produced the strongest antagonistic effect; (±)-sulpiride and prazosin had a distinctly less potent action. Another effect of MK-801, anticonvulsant activity (electroshock-induced convulsions), was not increased by the antidepressants studied. These results indicate that antidepressants with a different pharmacological profile, increased the MK-801-induced locomotor hyperactivity, this effect being probably indirectly mediated, at least in part, by a dopamine mechanism.

Anticonvulsant activity of carbamazepine and diphenylhydantoin against maximal electroshock in mice chronically treated with aminophylline.

The anticonvulsant activities of both carbamazepine and diphenylhydantoin alone (after a single intraperitoneal administration) or combined with aminophylline were studied against maximal electroshock-induced convulsions in male mice. Aminophylline (injected acutely at 50 mg/kg) significantly increased the ED50 values of both antiepileptics. Given for three days, aminophylline (50 mg/kg, twice daily) still impaired the potency of both antiepileptics and after chronic aminophylline administration a further decrease in the protective activity of carbamazepine and diphenylhydantoin was found. Specifically, after 14 days of aminophylline treatment, ED50s for carbamazepine and diphenylhydantoin were 26 and 19 mg/kg, respectively. These ED50s were significantly elevated compared to values determined after acute aminophylline treatment (21.2 and 14.9 mg/kg, respectively). Plasma levels of both antiepileptics were unaffected by chronic aminophylline which seems to exclude a pharmacokinetic interaction in terms of total plasma levels at least. The present results clearly indicate that the aminophylline-induced impairment of the anticonvulsant activity of carbamazepine and diphenylhydantoin is enhanced over time. This may render aminophylline a hazardous drug to epileptic patients who are prescribed this smooth muscle relaxant.

Influence of MK-801 on the anticonvulsant activity of antiepileptics

MK-801 (a potent non-competitive antagonist of N-methyl-D-aspartic acid-mediated events) in subcutanteous doses of 0.1 and 0.2 mg/kg increased the threshold for electroconvulsions and in doses of 0.0031 and 0.0125 mg/kg enhanced the protective activity of valproate against maximal electroshock-induced convulsions in mice. Valproate-induced side-effects (evaluated by means of dark-avoidance acquisition and retention testing and the chimney test) at its ED 50, against maximal electroshock (i.e. 268 mg/kg) were pronounced whereas they were absent in the case of a combined treatment with MK-801 (0.0125 mg/kg) and valproate (91 mg/kg). This treatment provided 50% protection against maximal electroshock-induced seizures. Moreover. MK-801 (0.0125 and 0.05 mg/kg) potentiated the anticonvulsant action of phenobarbital, reducing phenobarbital-induced motor impairment totally at 0.05 mg/kg, but did not influence the protection offered by carbamazepine and diphenylhydantoin at 0.05 mg/kg. The N-methyl-D-aspartic acid antagonist did not affect the total plasma levels of either valproate or phenobarbital (as measured by immunofluorescence), so a pharmacokinetic interaction, in terms of total plasma levels at least, is unlikely to be involved in the observed effects. The finding that the combined treatment of MK-801 with valproate or phenobarbital, apart from the distinct potentiation of their anticonvulsant activities, is devoid of side-effects should be carefully considered.

Influence of CGS 15943 A (a nonxanthine adenosine antagonist) on the protection offered by a variety of antiepileptic drugs against maximal electroshock-induced seizures in mice

CGS 15943 A (a nonxanthine adenosine antagonist) was studied on the protective efficacy of carbamazepine (60 min prior to the convulsive test), diazepam (60 min), diphenylhydantoin (120 min), phenobarbital (120 min), and valproate (30 min) against maximal electroshock-induced convulsions in mice. Moreover, the influence of the adenosine antagonist on 2-chloroadenosine (1 mg/kg, 20 min prior to the test)- and valproate (250 mg/kg, 30 min)-induced inhibitions of locomotor activity was also studied. CGS 15943 A (1 mg/kg) was given 15 min before both tests and all the drugs were administered i.p.. The adenosine antagonist (1 mg/kg) remained without influence upon the protective activity of all studied antiepileptics, reflected by their respective ED50 values against maximal electroshock. However, both 2-chloroadenosine and valproate-induced inhibitions of locomotor activity were attenuated by CGS 15943 A, which alone did not affect this parameter. However, CGS 15943 A (5 mg/kg) diminished the protection offered by diphenylhydantoin, increasing its ED50 value from 13 to 16 mg/kg. It may be concluded that the protection provided by common antiepileptic drugs against electroconvulsions seems independent of adenosine-mediated inhibition. In the case of diphenylhydantoin, one may suggest the involvement of purinergic transmission in the final anticonvulsant effect.

Augmentation of rat brain endogenous monoamine oxidase inhibitory activity (tribulin) by electroconvulsive shock

The effects of acute and subacute supramaximal and submaximal electroshock-induced convulsions on rat brain tribulin activity were investigated. Both supramaximal and submaximal shocks induced a marked increase, as measured 30 min after the onset of convulsions, with a significantly greater effect from the former. The effects were no longer present 24 h after stimulus. Repeated electroshock for 5 and 10 days showed that submaximal stimuli produced little change, whereas supramaximal shock brought about a significant increase in tribulin activity, the effect being greater with 10-day exposure. The results are not inconsistent with the clinical observation that a single electroconvulsive therapy (ECT) shock has little clinical usefulness but that repeated shocks, spread over several days, result in therapeutic benefit due, perhaps, to an increase in brain concentrations of tribulin, an endogenous monoamine oxidase inhibitor.

Intrathecal Antiepileptic Drugs in Experimental Epilepsy

The effect of intrathecal administration of antiepileptic drugs on electroshock-induced convulsions (maximal electroshock seizure, MES test) was investigated in an experimental study in rats. Drugs tested were phenobarbital sodium (50-800 micrograms), sodium valproate (50-6,400 micrograms) and midazolam (50-250 micrograms), delivered into the cerebrospinal fluid via a catheter placed in the upper cervical intrathecal space. Control animals were tested with saline. The animals were tested in the MES test 30 min after drug administration. Phenobarbital sodium showed a dose-related protective effect on the tonic phase of the convulsion, with a 50% effect at a dose of 200 micrograms. Sodium valproate showed a less protective effect, even when reaching doses that produced neurological symptoms. Midazolam protected at a high dose but produced a severe decrease in motor activity. The results indicate the feasibility to treat experimental convulsions by means of intrathecal injection of antiepileptic drugs.

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Azuletil sodium (AZE, 100 mg/kg, p.o.) did not affect the general behaviors, spontaneous motor activity, pentobarbital-induced hypnosis and body temperature. Furthermore, it did not elicit anticonvulsant and muscle relaxant actions. However, AZE (300 mg/kg, p.o.) elicited a stiff gate and slightly inhibited the spontaneous motor activity and electroshock-induced convulsions. It had no influence on spontaneous EEG activities, even at 30 mg/kg, i.v. AZE inhibited acetic acid-induced writhing moderately at doses above 100 mg/kg. AZE at concentrations up to 10(-5) g/ml did not affect agonist-induced contractions of the isolated ileum, trachea, vas deference and uterus, but inhibited serotonin and oxytocin-induced contraction at concentrations above 3 x 10(-4) and 10(-5) g/ml, respectively; and it also depressed spontaneous movements of the ileum and uterus at concentrations above 3 x 10(-4) g/ml. AZE caused no changes in blood pressure (BP), heart rate (HR), left ventricular pressure, ECG, tracheal pressure (TP), femoral blood flow (FBF) and coronary blood flow (CBF) at doses up to 10 mg/kg, i.v. in anesthetized dogs, but it caused an increase or a decrease in BP, an increase in TP and an increase in CBF at 30 mg/kg, i.v. However, even at 300 mg/kg, p.o., it caused no changes in BP and HR in conscious rats. AZE moderately promoted the charcoal transport. AZE at doses up to 300 mg/kg, p.o. did not affect urine volume, urinary electrolyte excretion, blood glucose and prothrombin time. These results suggest that AZE at anti-ulcer doses of 10-100 mg/kg, p.o. does not have noticeable effects on general pharmacological properties, and there is no marked differences as compared with those of GAS.

Central and Cardiovascular Effects of the Alcoholic Extract of the Leaves of Carica papaya

AbstractThe central effects of an alcoholic extract of Carica papaya leaf were investigated in male rats. The extract (≥ 10 mg kg−1, i.p.) induced a dose-dependent sedative effect. The extract (≥ 5 mg kg, i.p.) also induced central muscle relaxation. The behavioral effects of the extract were associated with an initial desynchronization of the electroencephalogram (EEG) and an increased activity of the electromyogram (EMG). This was followed by a deactivating pattern in the optic chiasma while the EMG activity was diminished. The extract at doses ≥50 mg kg−1 (i.p.) completely protected the rats against pentylenetetrazol-induced seizures, while doses of 5 mg kg−1 (i.p.) gave 50% protection. The extract at doses of 100 and 200 mg kg−1 (i.p.) also gave 100% protection against maximal electroshock-induced convulsions.

Computer-assisted predictive mathematical relationship among electroshock voltage and duration and occurrence of convulsion in mice

A microcomputer program in BASIC for predicting percentage of occurrence of electroshock-induced convulsion in mice was designed. A formula published by the author to express the mathematical relationship among the drug dose, the time, and the biological response was used in this program. Analysis of the actual, and the computer-assisted predicted percentages of occurrence of convulsion has shown that the program is fairly accurate in expressing convulsion response of mice as a function of the voltage and the duration.

The interaction between zolpidem and β-CMC: a clue to the identification of receptor sites involved in the sedative effect of zolpidem

The interaction of β-CMC, an amino β-carboline recently described as a selective antagonist of the sedative effect of diazepam, with zolpidem, an imidazopyridine hypnotic, which like β-CMC binds preferentially to the ω 1 (BZ-1) site of the GABA benzodiazepine chloride channel receptor complex, was investigated. In mice, β-CMC antagonized the effect of zolpidem against isoniazid-induced convulsions without affecting its activity against convulsions induced by pentylenetetrazole or electroshock. β-CMC also antagonized the decrease in locomotor activity and the impairment in muscle strenght provoked by zolpidem. In rats trained to discriminate zolpidem, β-CMC antagonized both the interoceptive stimulus and the decrease in the rate of lever pressing produced by zolpidem. This selective antagonism, inhibition of effects of zolpidem exerted by low doses (locomotor activity and isoniazid-induced convulsions) as well as effects produced by high doses (muscle strenght) but not those provoked by intermediate doses (pentylenetetrazole and electroshock-induced convulsions), could not be explained by a receptor occupancy hypothesis. These results suggest that the anticonvulsant and sedative effects of zolpidem do not involve the same receptor subtype and that the hypnoselective properties of zolpidem may be linked to its selectivity for the ω 1 (BZ-1) site of the GABA A receptor.

Anticonvulsant activity of root and stem extracts of Calliandra portoricensis

A comparative study of the anticonvulsant properties of root and stem extracts of Calliandra portoricensis was carried out in mice. The convulsion models were pentylenetetrazole- and electroshock-induced convulsions. The results showed that the aqueous extracts of both root and stem possess anticonvulsant activity when given intraperitoneally. An alkaloidal extract did not show any anticonvulsant action up to 316 mg kg i.p.

Effect of aminophylline and enprofylline on the protective efficacy of common antiepileptic drugs against electroconvulsions in mice.

The anticonvulsant potency of phenobarbital (PB) (120 min before the test), phenytoin (PHT) (120 min), carbamazepine (CBZ) (60 min), valproate (VPA) (30 min), and acetazolamide (60 min) alone or in combination with either aminophylline (50 mg/kg, 30 min) or enprofylline (46.2 mg/kg, 30 min) was measured against maximal electroshock-induced convulsions in mice. All drugs were administered intraperitoneally (i.p.), and the protective efficacy of each drug was expressed as ED50 in milligrams per kilogram. Aminophylline decreased anticonvulsant activity of PB, PHT, CBZ, and VPA, increasing the respective ED50 values from 16 to 28 mg/kg, 7.4 to 14 mg/kg, 18 to 26 mg/kg, and 260 to 335 mg/kg. On the contrary, enprofylline in the equimolar dose did not exert such effect. Furthermore, neither aminophylline nor enprofylline affected anticonvulsant action of acetazolamide. The present data favor enprofylline as a preferable drug for treatment of obstructive lung diseases in epilepsy patients. However, accurate pharmacokinetic data in mice and men for both xanthines are necessary if one attempts to compare their cerebral and pulmonary actions.

Substantia nigra-mediated anticonvulsant actions: Role of nigral output pathways

Bilateral ablation of the superior colliculus in rats abolished the anticonvulsant effect of muscimol, a γ-aminobutyric acid (GABA) agonist, infused into the substantia nigra. Our data indicate that the ability of intranigral muscimol to protect against maximal electroshock convulsions requires the integrity of the nigrotectal pathway. We present evidence that the nigrotegmental, nigrothalamic, and nigrostriatal projections do not appear to contribute to the nigral-evoked attenuation of electroshock convulsions. Inasmuch as the nigrotectal pathway utilizes the inhibitory neurotransmitter GABA, we hypothesize that the anticonvulsant effect of nigral manipulations in the electroshock test is a result of the disinhibition of neurons in the superior colliculus, the firing of which must therefore be capable of suppressing or disrupting electroshock-induced convulsions.

Modification of electroshock and pentylenetetrazol seizure patterns in rats affer precollicular transections

Rats with precollicular transections leaving the brain stem intact were subjected to electroshock or pentylenetetrazol-induced convulsions. Animals with transections failed to display the face and forelimb clonus (with or without rearing) typically seen in sham-operated rats subjected to pentylenetetrazol- or minimal electroshock-induced convulsions elicited with corneal electrodes. Moreover, rats with transections exhibited all other components of pentylenetetrazol- and electroshock-induced seizures. These findings support the hypothesis that tonic and some types of clonic convulsions can occur independently of seizure discharge in forebrain structures, whereas clonus restricted to the face and forelimbs depends on seizure discharge emanating from structures within the forebrain for expression.

9 Hormonal regulation of epithelial and stromal cell growth in the human prostate

The present results refer to the action of three gonadal steroid antihormones, tamoxifen (TXF, an estrogen antagonist), cyproterone acetate (CYP, an antiandrogen) and mifepristone (MIF, a progesterone antagonist) on seizure phenomena in mice. TXF and CYP at their lowest protective dose in the electroconvulsive threshold test, enhanced the antiseizure efficacy of some antiepileptic drugs. TXF (20 mg/kg) potentiated the protective activity of valproate, diphenylhydantoin and clonazepam, but not that of carbamazepine or phenobarbital, against maximal electroshock-induced convulsions in female mice. CYP (40 mg/kg) enhanced the anticonvulsant action of valproate, carbamazepine, diphenylhydantoin and clonazepam, but not that of phenobarbital, against maximal electroshock in male animals. MIF failed to affect the electroconvulsive threshold or the efficacy of antiepileptic drugs in maximal electroshock. The effect of TXF or CYP upon the electroconvulsive threshold and on the action of antiepileptics was not reversed by sex steroid hormones (estradiol, testosterone, progesterone). However, the TXF-induced elevation of the electroconvulsive threshold was abolished by bicuculline, N-methyl-d-aspartic acid and kainic acid, and partially reversed by aminophylline, strychnine being ineffective in this respect. The action of CYP on the threshold for electroconvulsions was partially reversed by bicuculline and aminophylline. Both glutamatergic agonists and strychnine remained ineffective in this respect. Moreover, the action of TXF or CYP on the activity of antiepileptics was not influenced by strychnine, and reversed to various extents by the remaining convulsants. In contrast to maximal electroshock, none of the three antihormones affected the protective action of antiepileptic drugs against pentylenetetrazol-induced seizures in mice. Neither TXF nor CYP altered the free plasma levels of antiepileptic drugs, so a pharmacokinetic interaction is not probable. The combined treatment of the two antihormones with antiepileptic drugs, providing 50% protection against maximal electroshock, did not affect motor performance in mice, and did not result in significant long-term memory deficits. Our data indicate that steroid receptor-mediated events may be indirectly associated with seizure phenomena in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs.

Synthesis and properties of cyclic derivatives of succinic acid with anticonvulsant activity. Part 4.

A series of new phenylsuccinimide derivatives substituted in the aromatic ring and/or at the nitrogen atom was synthesized and tested for activity against pentetrazole- and electroshock-induced convulsions.

Evaluation of the CNS properties of SCH 29851, a potential non-sedating antihistamine.

SCH 29851 [8-chloro[6,11-dihydro-11-(1-carboethoxy-4-piperidylidene)- 5-H-benzo [5,6]cyclohepta[1,2-b]-pyridine] was discovered as part of a search for a new antihistamine without effects on the central nervous system (CHS). Antihistaminic potency and duration of action of SCH 29851 and other antihistamines were assessed by inhibition of histamine-induced lethality in guinea pigs and histamine-induced paw edema in mice. Evaluation of possible CNS effects included gross observation of mice, rats, dogs and monkeys, prevention of electroshock-induced convulsions, acetic acid-induced writhing and physostigmine-induced lethality in mice and biochemical measures related to sedative liability such as displacement of in vivo 3H-mepyramine binding in mouse brain and in vitro 3H-WB 4101 binding in guinea pig cortex. Comparisons were made to several antihistamines considered to be sedative to varying degrees, including diphenhydramine, promethazine, chlorpheniramine and azatadine and to the newer antihistamines terfenadine and astemizole which are reported to be non-sedating in man at doses that antagonize the effects of histamine peripherally. SCH 29851 had antihistamine activity in the tests used with a potency at least comparable to most standards and was devoid of activity in all the functional and biochemical models used as indices of CNS activity. It is expected that SCH 29851 should be an effective, long acting, antihistamine in man without sedative effects at therapeutic doses.

Differential effects of baclofen, γ-hydroxybutyric acid and muscimol on the protective action of phenobarbital and diphenylhydantoin against maximal electroshock-induced seizures in mice

This study was designed to compare the effects of baclofen (a GABAB agonist), muscimol (a GABAA agonist) and gamma-hydroxybutyric acid on the protective action of phenobarbital (PB) and diphenylhydantoin (DPH) against electroshock-induced convulsions. All drugs were given intraperitoneally, muscimol being also injected intraventricularly in a dose of 50 ng per mouse. It was found that both baclofen and gamma-hydroxybutyric acid potentiated the anticonvulsant activity of phenobarbital, being ineffective regarding the action of diphenylhydantoin. Conversely, muscimol injected by two different routes moderately enhanced the efficacy of diphenylhydantoin but remained without a significant effect upon the action of phenobarbital.