Anticonvulsant Effect Of Phenobarbital Research Articles

Early life status epilepticus and stress have distinct and sex-specific effects on learning, subsequent seizure outcomes, including anticonvulsant response to phenobarbital.

Neonatal status epilepticus (SE) is often associated with adverse cognitive and epilepsy outcomes. We investigate the effects of three episodes of kainic acid-induced SE (3KA-SE) and maternal separation in immature rats on subsequent learning, seizure susceptibility, and consequences, and the anticonvulsant effects of phenobarbital, according to sex, type, and age at early life (EL) event. 3KA-SE or maternal separation was induced on postnatal days (PN) 4-6 or 14-16. Rats were tested on Barnes maze (PN16-19), or lithium-pilocarpine SE (PN19) or flurothyl seizures (PN32). The anticonvulsant effects of phenobarbital (20 or 40 mg/kg/rat, intraperitoneally) pretreatment were tested on flurothyl seizures. FluoroJadeB staining assessed hippocampal injury. 3KA-SE or separation on PN4-6 caused more transient learning delays in males and did not alter lithium-pilocarpine SE latencies, but aggravated its outcomes in females. Anticonvulsant effects of phenobarbital were preserved and potentiated in specific groups depending on sex, type, and age at EL event. Early life 3KA-SE and maternal separation cause more but transient cognitive deficits in males but aggravate the consequences of subsequent lithium-pilocarpine SE in females. In contrast, on flurothyl seizures, EL events showed either beneficial or no effect, depending on gender, type, and age at EL events.

Inter-individual variation in the anticonvulsant effect of phenobarbital in the pilocarpine rat model of temporal lobe epilepsy

Despite a large therapeutic arsenal of old and new antiepileptic drugs (AEDs), there remains a substantial unmet need for the patients with refractory (AED-resistant) epilepsy. Animal models of refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory seizures. It is only incompletely understood why two patients with seemingly identical types of epilepsy and seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we tested whether epileptic rats from the same epilepsy model respond differently to AEDs and previously discovered phenobarbital (PB) responsive and resistant animals in groups of rats in which epilepsy had been induced by sustained electrical stimulation of the basolateral amygdala (BLA). In the present study, we used the same approach for the widely used pilocarpine model of temporal lobe epilepsy. Epileptic rats from this model were continuously video/EEG monitored over seven consecutive weeks, starting with a predrug control period of two weeks, then two weeks of daily treatment with PB at maximum tolerated doses, and finally a postdrug control period of three weeks. In those rats that were included in response selection, 50% did not adequately respond to PB, whereas PB significantly decreased seizure frequency and severity in another 50% of the animals. Responders and nonresponders did not differ in predrug seizure frequency, PB plasma levels or hippocampal neurodegeneration, but behavioral differences were observed in anxiety models. These findings demonstrate that in the pilocarpine model, similar to epilepsy patients, epileptic rats differ in their response to an AED, which is most likely due to as yet unknown genetic factors.

Pharmacodynamics of Tolerance Development to the Anesthetic and Anticonvulsant Effects of Phenobarbital in Rats

In this study, the potential development of tolerance towards the anesthetic and anticonvulsant effects of phenobarbital after chronic administration to rats was investigated, differentiating between dispositional and functional tolerance. Chronic exposure to phenobarbital by daily ip injections of 20 or 100 mg/kg for 14 days caused a 30% increase in clearance within 1 week. No changes occurred in the total amounts of phenobarbital and para-hydroxyphenobarbital excreted into urine and feces. Pharmacodynamic effects were quantitated after 2 weeks of treatment. The anesthetic effect was measured by slow iv infusion of phenobarbital until onset of loss of righting reflex (LRR), followed by measurement of drug concentrations in serum (both total and free), brain, and cerebrospinal fluid (CSF). With a phenobarbital dose of 100 mg/kg daily, CSF concentrations at the onset of LRR significantly increased from 136 ± 12 to 176 ± 21 mg/L (p < 0.001), indicating that functional tolerance developed for the anesthetic effect. Protection of phenobarbital against convulsions induced by pentylenetetrazol (PTZ), as measured by the elevation of the PTZ plasma threshold concentration necessary to elicit seizures at the EC50 of phenobarbital, was not altered. The discrepancy observed in the development of functional adaptation of the CNS demonstrates that different mechanisms of action are reflected in the different measures of the anesthetic and anticonvulsant effects of phenobarbital that were utilized.

Increased anticonvulsant effect of phenobarbital with age in mice ---A possible pharmacological index for brain aging

We have recently reported that the anticonvulsant effect of phenytoin increase with age in mice (1). Since some of the mechanisms of anticonvulsant action of phenytoin and phenobarbital may be different, the present study sought to determine whether a similar increase with age in the anticonvulsant effect of phenobarbital could also be observed. The anticonvulsant effect of phenobarbital was examined in BDF1 female mice of different ages (6, 12, 24 and 30 months old) using the abolition of the tonic hindlimb extensor component of maximal electro-shock seizure as the index. The minimal effective concentration (MEC) values of phenobarbital in plasma and brain were significantly lower in aged (24 and 30 month old) mice compared with the respective values in the youngest animal group (6 month old). Series using nearly two-fold different intensities of electroshock (30 and 55 mA) showed almost identical MEC values in 24 month-old mice. It was concluded that the brain of aged mice is more sensitive to phenobarbital, as it is to phenytoin.

Dependence of anticonvulsant drug action on central monoamines

In mice, the influence of receptor blocking drugs and variations in the central levels and metabolism of noradrenaline, dopamine and 5-hydroxytryptamine (5-HT) on the effect of certain anticonvulsant drugs was studied. The effect of phenobarbital against electro-convulsions was antagonized by treatments lowering central 5-HT or noradrenaline, as well as by cyproheptadine and phentolamine. 5-Hydroxytryptophan (5-HTP) and l-DOPA had a synergistic effect. These results point to an important participation of 5-HT and noradrenaline in the anticonvulsant effect of phenobarbital. The anticonvulsant activity of diphenylhydantoin in the maximal electroshock seizure test decreased after treatmentwithα-methyltyrosine and disulfiram, and noradrenaline seems thus to play a role for the effect of the drug. A participation of 5-HT remains doubtful since only p-chlorophenylalanine had a weak antagonistic action but cyproheptadine and 5-HTP were without influence on the ED 50. In the pentetrazole seizure threshold test, phenobarbital was antagonized by p-chlorophenylalanine and cyproheptadine whereas 5-HTP had a synergistic effect. A participation of 5-HT in the mediation of the anticonvulsant action of the drug therefore seems obvious, but indications for a role also of noradrenaline were less convincing. Results with ethosuximide were similar regarding the role of 5-HT, but experiments on the role of catecholamines gave conflicting results. A comparison of the present results with those of a previous study on the importance of the central monoamines for convulsive thresholds shows that changes in anticonvulsant ED 50 values induced by interferences with the central monoamines do not merely follow the simultaneous changes in convulsive threshold.

A hitherto undescribed feature in the anticonvulsant effect of phenobarbital.

In mice the ED50 of phenobarbital in the maximal electro-shock test was determined for time intervals of 1 to 24 h after oral application. When the concentration of phenobarbital in serum a