The mechanism of carbamazepine aggravation of absence seizures.

Carbamazepine (CBZ) aggravates many generalized seizures types, particularly absence seizures, but the mechanisms underlying this are poorly understood. GABA signaling within the reticular nucleus (Rt) and the ventrobasal complex (VB) of the thalamus is critical to the neurophysiology of absence seizures. The hypothesis that CBZ aggravates absence seizures by acting at the VB thalamus via a GABA(A) receptor-mediated mechanism was investigated in a genetic rat model, generalized absence epilepsy rats from Strasbourg (GAERS). Seizure activity was quantified by a 90-min electroencephalogram recording postdrug injection. Intracerebroventricular injections of CBZ (15 microg in 4 microl) resulted in seizure aggravation versus vehicle treatment, with a mean increase in seizure time of 40%. This indicates that CBZ acts directly, rather than via a metabolite, on the brain to aggravate seizures. Seizure aggravation also occurred following bilateral microinjection of CBZ (0.75 microg in 0.2 microl) into the VB (53%) but not following injection into the Rt (-9%). However, seizure aggravation was blocked when the GABA(A) receptor antagonist, bicuculline (BIC, 0.04 microg in 0.2 microl), was coinjected with CBZ into the VB. Injection of BIC alone (versus vehicle) into the VB also blocked seizure aggravation following systemic administration of CBZ (15 mg/kg i.p.). In vitro studies in Xenopus oocytes expressing recombinant GABA(A) receptors demonstrated that CBZ produced a dose-dependent potentiation of the GABA current at a physiological relevant concentration range (1-100 microM). These data demonstrate that CBZ acts at the VB thalamus to aggravate absence seizures in GAERS and that activation of GABA(A) receptors is critical to this effect.

Aggravation of absence seizures by carbamazepine in a genetic rat model does not induce neuronal c-Fos activation.

The mechanisms underlying carbamazepine aggravation of absence seizures are uncertain but are thought to involve enhancement of neuronal activity within the thalamocortical circuitry. We used c-Fos immunohistochemistry (cFos-ir) to examine patterns of neuronal activation and the relationship to seizure expression following administration of carbamazepine in a rat model of absence epilepsy (Genetic Absence Epilepsy Rats of Strasbourg, GAERS). Female ovariectomized GAERS implanted with extradural EEG electrodes received either 20 mg/kg carbamazepine or vehicle IP. Seizure expression was quantified by measuring the total number and duration of spike-wave discharges (SWD) and with the individual burst discharge lengths over a 90-minute EEG. This was correlated with cFos-ir in thalamocortical slices from rats killed 180 minutes after carbamazepine administration. Carbamazepine-treated rats (n = 5) had a significantly greater total duration of SWD than vehicle-treated rats (17.9% versus 8.8%, P = 0.04). Despite this aggravation of seizures, the level of cFos-ir did not differ between the treatment groups. A positive correlation was found between cFos-ir in the reticularis thalami (Rt) and the total seizure duration (R = 0.66, P = 0.04) and mean burst length (R = 0.68, P = 0.03) but not total number of seizures. The lack of difference in cFos activation patterns between carbamazepine and vehicle-treated animals suggests that the mechanism for carbamazepine aggravation of absence seizures may not involve neuronal activation but rather enhanced neuronal synchronization. The association between increased neuronal activation in the Rt and seizure burden in GAERS provides further support for the critical role of this structure in the maintenance, but not initiation, of absence seizure activity.

Neuropeptide Y suppresses absence seizures in a genetic rat model.

Evidence from studies in rodents and humans support an anti-seizure action of neuropeptide Y (NPY) in focal, acquired epilepsy. However, the effects of NPY in generalized genetic epilepsy remain unexplored. In this study, adult male Genetic Absence Epilepsy Rats of Strasbourg (GAERS) were implanted with extradural electrodes and an intracerebroventricular (icv) cannula. Six and 12 nmol NPY or vehicle was administered icv in a random order (n=6), and the effect of NPY on seizure activity quantitated from a 90-min EEG recording. A rapid onset and sustained seizure suppression was observed following NPY treatment compared to vehicle, with both 6 and 12 nmol NPY having a significantly decreased mean percentage time in seizure (5.7 +/- 1.4% and 5.0 +/- 1.7% vs. 15.8 +/- 3.4%) and mean number of seizures per minute (0.5 +/- 0.1 and 0.4 +/- 0.1 vs. 1.1 +/- 0.1). There was no significant difference between the degree of seizure suppression after 6 and 12 nmol NPY. The results of this study demonstrate that NPY suppresses absence seizures in GAERS. This suggests that NPY modulates pathological oscillatory thalamocortical activity and may represent a new therapeutic approach for the treatment of generalized epilepsies.