Perampanel chronic treatment does not induce tolerance and decreases tolerance to clobazam in genetically epilepsy prone rats.

Tolerance to some therapeutic effects of antiepileptic drugs may account for the development of pharmacoresistance in patients with epilepsy. In the present study, following oral acute pretreatment with the new antiepileptic drug perampanel (0.1, 0.3, 1 or 3 mg/kg), we observed that the drug significantly and dose-dependently attenuated the seizure phases (clonus and tonus) of audiogenic seizures in genetically epilepsy prone rats (GEPR-9 s), a genetic model of reflex generalized epilepsy. In addition, the GEPR-9 s were administered orally with perampanel (1 or 3 mg/kg) once daily for 10 weeks in order to study the possible development of tolerance, and when animals were subjected to auditory stimulation we observed that the ED50 values against clonus or tonus were not significantly different from those observed after single administration. Furthermore, the duration of anticonvulsant effects observed between 60 min and 9 h following oral administration of perampanel (1 mg/kg) were similar in acute and after chronic treatment. In another group of experiments, clobazam (0.75, 1.5, 3, 6, 9, 12 and 15 mg/kg) after acute administration was able to dose-dependently reduce the severity of the audiogenic seizures in GEPR-9 s. When clobazam (6 or 12 mg/kg) was administered alone for 10 consecutive weeks a clear development of tolerance to its anticonvulsant effects within approximately seven weeks was observed. In addition, we observed that when clobazam (6 mg/kg) was co-administered with perampanel (1 mg/kg), the latter drug was able to attenuate the development of tolerance to the antiseizure activity of clobazam. The present data indicate that both perampanel and clobazam are effective against audiogenic seizures, however, clobazam effects are hampered by the development of tolerance. Furthermore, concomitant treatment with perampanel slows development of tolerance to the anticonvulsant effects of clobazam in GEPR-9 s.

The Anticonvulsant Activity of a Flavonoid-Rich Extract from Orange Juice Involves both NMDA and GABA-Benzodiazepine Receptor Complexes.

The usage of dietary supplements and other natural products to treat neurological diseases has been growing over time, and accumulating evidence suggests that flavonoids possess anticonvulsant properties. The aim of this study was to examine the effects of a flavonoid-rich extract from orange juice (OJe) in some rodent models of epilepsy and to explore its possible mechanism of action. The genetically audiogenic seizures (AGS)-susceptible DBA/2 mouse, the pentylenetetrazole (PTZ)-induced seizures in ICR-CD1 mice and the WAG/Rij rat as a genetic model of absence epilepsy with comorbidity of depression were used. Our results demonstrate that OJe was able to exert anticonvulsant effects on AGS-sensible DBA/2 mice and to inhibit PTZ-induced tonic seizures, increasing their latency. Conversely, it did not have anti-absence effects on WAG/Rij rats. Our experimental findings suggest that the anti-convulsant effects of OJe are likely mediated by both an inhibition of NMDA receptors at the glycine-binding site and an agonistic activity on benzodiazepine-binding site at GABAA receptors. This study provides evidences for the antiepileptic activity of OJe, and its results could be used as scientific basis for further researches aimed to develop novel complementary therapy for the treatment of epilepsy in a context of a multitarget pharmacological strategy.

Influence of levetiracetam on the anticonvulsant efficacy of conventional antiepileptic drugs against audiogenic seizures in DBA/2 mice.

Levetiracetam (LEV, [S]-alpha-ethyl-2-oxo-1-pyrrolidine acetamide) is a new antiepileptic that has been used as adjunctive therapy to treat patients with intractable epilepsy. Systemic administration of levetiracetam (2.5-30 mg/kg, intraperitoneally (i.p.)) was able to produce a dose-dependent decrease in DBA/2 audiogenic seizure severity score. In combination with conventional antiepileptic drugs, levetiracetam, 5mg/kg, i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of some antiepileptic drugs studied against sound-induced seizures in DBA/2 mice. The degree of potentiation induced by levetiracetam was greater, approximately twice, for carbamazepine, diazepam, felbamate, topiramate, gabapentin, and valproate, less for lamotrigine, phenobarbital and phenytoin. This increase was associated with a comparable impairment in motor activity; however, the therapeutic index of combined treatment of antiepileptic drugs with levetiracetam was more favourable than the combination with saline with the exception of lamotrigine, phenytoin and phenobarbital. Since levetiracetam did not significantly influence the total and free plasma and the brain levels of antiepileptics studied. In addition, levetiracetam did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, levetiracetam showed an additive anticonvulsant effect when administered in combination with some classical anticonvulsants, most notably carbamazepine, diazepam, felbamate, gabapentin, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.