S.L. Peterson

Anticonvulsant drugs and their antagonism of kindled amygdaloid seizures in rats

Abstract The kindling phenomenon has become a useful animal model for studying the processes in the central nervous system involved in one type of epileptiform seizure response. A systematic, multipledose evaluation of 20 drugs known to have anticonvulsant properties and two new compounds (WB-CPI and SHK-I-11) is reported using a standard protocol with rats kindled by amygdaloid stimulation. Drugs which have a wide anticonvulsant spectrum of activity against various animal models of epilepsy were the most effective. The barbiturates, the benzodiazepines, a piperazine, an acetate derivative and WB-CPI (a significantly modified phenacylurea), were found to be the most effective in attenuating the induced seizures. Kindled amygdaloid seizures in the rat can be characterized as a model useful for the detection of a wide variety of anticonvulsants likely to be effective in many types of experimental seizures. The compound WB-CPI merits further neuropharmacological and psychopharmacological testing due to its activity in rats.

The anticonvulsant properties of melatonin on kindled seizures in rats.

Abstract The literature suggesting that the pineal gland and the indolamine, melatonin, have a significant role in regulating and modulating brain electrical activity is reviewed. The anticonvulsant properties of melatonin were investigated by testing acute doses of melatonin against two types of kindled Scizures in the rat. Against the electrically kindled amygdaloid Scizure, melatonin significantly reduced afterdischarge length at a non-sedative dose, but failed to modify Scizure rank scores. With larger doses of melatonin, which were associated with some sedation and ataxia, the Scizure rank score was reduced, but there was no additional reduction of afterdischarge length. Naloxone treatment (20 mg/kg, i.p.) did not reverse the sedation, ataxia, nor the anticonvulsant effects seen with the large dose of melatonin (200 mg/kg, i.p.). Additional animals were kindled with pentylenetetrazol injections (30 mg/kg, i.p.) given at 2–3 day intervals. Melatonin significantly reduced Scizure rank scores in these kindled animals at one dose (150 mg/kg, i.p.). A larger dose, associated with sedation and ataxia, did not result in any further reduction of Scizure rank scores. For comparison, large and small doses of both phenobarbital and diazepam were also tested against the pentylenetetrazol kindled Scizures. Neither phenobarbital (30 mg/kg) nor diazepam (2.5 mg/kg) induced a neurological deficit; however, both agents reduced Scizure rank to approximately the same score as did melatonin (150 mg/kg). This is the first report of a substantial anticonvulsant property of parenteral melatonin in two animal models of epilepsy. It would appear tha melatonin is most effective against the kindled pentylenetetrazol Scizure, and somewhat less effective against the electrically kindled amygdaloid Scizure. Further testing in other Scizure models and species is needed to define better the anticonvulsant profile of melatonin.

Neuropharmacology methods in epilepsy research

Electroshock, Steven L. Peterson Chemoconvulsants, H. Steve White The Kindling Model of Temporal Lobe Epilepsy, Mary Ellen Kelly Rapid Kindling: Behavioral and Electrographic, Janet L. Stringer Experimental Models of Status Epilepticus, Jeffery H. Goodman Audiogenic Seizures in Mice and Rats, Charles E. Reigel Models of Focal Epilepsy in Rodents, Charles R. Craig Evaluation of Associated Behavioral and Cognitive Deficits in Anticonvulsant Drug Testing, Piotr Wlaz and Wolfgang Loscher Gene Targeting Models of Epilepsy: Technical and Analytical Considerations, Laurence H. Tecott The Hippocampal Slice Preparation, Larry G. Stark and Timothy E. Albertson Microdialysis Techniques for Epilepsy Research, John W. Dailey and Pravin K. Mishra Methodologies for Determining Rhythmic Expression of Seizures, Thomas H. Champney Index

Cumulative after-discharge as the principal factor in the acquisition of kindled seizures

Abstract The role of after-discharge in the development of behavioral and electrographic seizures (kindling) was evaluated. Rats were stimulated (amygdala) once daily for 10 days 30 min after an intraperitoneal injection of diazepam, phenobarbital, propranolol or vehicle. Following a 10 day period to allow for drug elimination, the daily stimulations (without drug) resumed until all animals responded with fully kindled seizures. Only the lowest dosage groups of diazepam (2 mg/kg) and phenobarbital (15 mg/kg) showed a savings in the number of stimulations to kindle in the non-drug state. This suggests that little or no kindling development had occurred in the drug state with the high doses (4 or 8 mg/kg diazepam, 30 mg/kg phenobarbital). Propranolol treated rats kindled with the same number of stimulations as their control group. As an alternative measure of kindling, the number of seconds of cortical after-discharge accumulated in the drug state, the non-drug state, and the grand total required to kindle were averaged and compared between the drug and control groups. The average grand total number of seconds of after-discharge accumulated by any of the drug or control 188 and 352 sec. None of the grand totals accumulated by any of the drug or control groups differed significantly. The lowest dosage groups treated with diazepam and phenobarbital accumulated significantly less afterdischarge in both the drug and non-drug state than the total for the control. These data suggest that a specific quantity of after-discharge must be elicited to kindle (200–300 sec) and that any after-discharge elicited in the presence of phenobarbital or diazepam will contribute to that quantity.

The anticonvulsant effects of diazepam and phenobarbital in prekindled and kindled seizures in rats

Abstract The effects of various doses of diazepam (0.5–4 mg/kg) and phenobarbital (7.5–60 mg/kg) were determined on prekindled and kindled amygdaloid seizures in the same rats. Diazepam was ineffective against the prekindled focal seizures, but demonstrated profound and statistically significant control of the kindled seizures. In the kindled state, diazepam reduced the afterdischarge duration and seizure rank score to prekindled levels. Only the largest sedating dose of phenobarbital produced a reduction of both prekindled afterdischarge duration and seizure rank score. Against the kindled seizure, phenobarbital showed a marked and statistically significant increase in effectiveness in all but the smallest dose tested. The afterdischarge duration of kindled seizures was reduced to prekindled levels by 15–60 mg/kg of phenobarbital, while seizure rank score was reduced to prekindled levels by 30 and 60 mg/kg phenobarbital. The effects of two doses of diazepam (0.5 and 2.5 mg/kg) and phenobarbital (7.5 and 30 mg/kg) were tested against prekindled and kindled pentylenetetrazol (PTZ)-induced seizures. Preliminary work with 3 doses of pentylenetetrazol (30, 40 and 60 mg/kg) demonstrated that repeated doses of 30 mg/kg readily kindled seizures without the significant mortality seen with larger doses. Both diazepam and phenobarbital were less effective against seizures kindled with 30 mg/kg pentylenetetrazol compared to prekindled seizures. The comparative lack of effect that was seen with diazepam and phenobarbital against the pentylenetetrazol kindled seizure at doses associated with control of the kindled amygdaloid seizure may reflect an underlying difference in the pathogenesis of kindling between these seizure models. Further, the lack of suppression of the prekindled amygdaloid afterdischarge duration by large doses of diazepam, in contrast to large doses of phenobarbital, may also reflect differences between the mechanisms of action of these two drugs. This paradigm provides a model for testing the effectiveness of anticonvulsants during the progressive development of various epileptogenic seizures.

Intertrial intervals and kindled seizures

Abstract The effects of nonuniform intertrial intervals on the development and retention of kindled amygdaloid seizures in rats were evaluated. Six consecutive grouped trial sessions (GTSs) consisting of five stimulations with 1-h intertrial intervals each day significantly reduced the average afterdischarge duration and behavioral seizure response of rats previously kindled by single, daily stimulations. Another group was treated with 32 consecutive stimulations at 1-h intervals. The development of kindling in this group was disrupted and only half the group exhibited occasional rank 5 seizures during the hourly stimulations. When the hourly group was subsequently stimulated once daily, kindled seizures were elicited in all animals. These data demonstrate that hourly stimulations or short, massed-trial paradigms disrupt kindled seizures and produce a convulsive response that is different from that produced by a single daily stimulation, suggesting that the pattern of stimulations must be taken into account when interpreting neurophysiologic, biochemical, or pharmacologic data from animals presumably kindled by the stimulations.

Valproic acid serum levels and protection against kindled amygdaloid scizures in the rat

Abstract Valproic acid has been reported to be very effective against kindled amygdaloid Scizures in several species. In this study, the anticonvulsant effectiveness of valproic acid against kindled amygdaloid Scizures was studied in a systematic, multiple-dose evaluation in rats. A correlation at 30 min. between the degree of Scizure protection and increased serum levels of valproic acid was seen. At 30 min., the fifty percent effective dose (ED50) was found to be 200 mg/kg. Additionally, the fifty percent effective serum level (ESL50) was estimated to be 500 mg/L.

Effects of phenobarbital and SC-13504 on partially kindled hippocampal seizures in rats

Abstract The effects of three doses of SC-13504 were determined on prekindled and partially kindled hippocampal seizures in rats. A dose of phenobarbital previously shown to be anticonvulsant in rats was used for comparison. The drugs were tested for effectiveness twice during the 12 sessions, once during session 2 to determine the prekindling effectiveness and once during the last session to determine the effectiveness against kindled seizures. After 11 stimulations, the seizures showed a significant increase in afterdischarge duration, clinical seizure severity, and time to return to normal EEG and the stimulus threshold showed a nonsignificant decrease compared to the first stimulation. These results indicate that the development of progressively more severe hippocampal seizures (kindling) can occur with just 11 days of stimulation. When stimulated at the control day threshold, 3 and 300 mg/kg SC-13504 provided anticonvulsant protection against both prekindled and kindled seizures, whereas 30 mg/kg SC-13504 was less effective. Animals stimulated until seizures occurred on drug days showed a dose-dependent decrease in afterdischarge duration and an increase in voltage threshold with all three doses of SC-13504. Phenobarital provided no protection against prekindled seizures but was very effective against kindled seizures. These results may indicate that phenobarbital is a more effective anticonvulsant against developing or developed limbic system seizures than against prekindled seizures. This paradigm may provide a model for testing the effectiveness of anticonvulsants during the progressive development of epileptic seizures.

Chronic cholinesterase inhibition does not modify amygdaloid kindling

Abstract The consequences of chronic cholinesterase inhibition during kindling were examined to further evaluate the importance of cholinergic function in kindling development and maintenance. Inhibition of brain and serum cholinesterases of as much as 80% were produced by the daily administration of 0.5 or 2.0 mg/kg parathion. The degrees in inhibition attained had no significant effects upon the rate or expression of kindling.

Barbiturate serum levels and protection against kindled amygdaloid seizures in the rat

Abstract The barbiturates have been reported to be very effective against kindled amygdaloid seizures in the rat. In this study, the anticonvulsant effectiveness of pentobarbital, phenobarbital and primidone was studied in a systematic, multiple-dose evaluation. A correlation at 30 min between increased anti-convulsant protection and increased serum levels of pentobarbital and phenobarbital was seen. A possible correlation at 30 min, 2 hours and 48 hours between summed serum levels of the metabolites phenylethylmalonamide and phenobarbital was seen with the primidone treated animals. Serum primidone levels appeared to contribute little to the delayed protection against kindled amygdaloid seizures seen with primidone.