The Mechanism of Carbamazepine Aggravation of Absence Seizures

Abstract

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 g in 4 l) 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 g in 0.2 l) into the VB (53%) but not following injection into the Rt (Ϫ9%). However, seizure aggravation was blocked when the GABA A receptor antagonist, bicuculline (BIC, 0.04 g in 0.2 l), 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 M). 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 seizures by antiepileptic drugs (AEDs) is an important clinical problem that is often overlooked in practice (Lerman, 1986;Perucca et al., 1998). The neurobiological mechanisms underlying seizure aggravation are poorly understood. One of the drugs most implicated is carbamazepine (CBZ), a major first line AED for the treatment of focal seizures. In patients with generalized epilepsy syndromes, CBZ commonly causes an increase in a variety of seizure types, including typical and atypical absence seizures, myoclonic, atonic, and tonic seizures, and also on occasions generalized tonic-clonic seizures (Perucca et al., 1998). Of these, the aggravation of absence seizures is the most predictable and, with the availability of good animal models (Snead et al., 1999), the most amenable for mechanistic studies. In agreement with human studies, CBZ has also been demonstrated by our group and others to exacerbate spontaneous absence seizures in well validated rat models, i.e., low-dose pentylenetetrazole (McLean et al., 2004) and the generalized absence epilepsy rats from Strasbourg (GAERS) (Marescaux et al., 1984;Micheletti et al., 1985;Wallengren et al., 2005).The primary neuropathological correlate of absence seizures is bursts of highly synchronized rhythmic oscillatory glutamatergic firing between neurons in the...

Carbamazepine reduces the behavioural manifestations of tinnitus following salicylate treatment in rats

“…For example, SA has been shown to reduce GABA A receptor-mediated inhibitory post-synaptic currents in the auditory cortex [17]. CBZ has been shown to cause a dose-dependent potentiation of GABA at GABA A receptors in Xenopus oocytes [18] and has also been reported to act as a GABA A receptor agonist in the reticular nucleus and the ventrobasal complex of the rat thalamus [18]. Therefore, it is conceivable that CBZ might reverse some of the effects of SA in the auditory cortex.…”

A Cav3.2 T-Type Calcium Channel Point Mutation Has Splice-Variant-Specific Effects on Function and Segregates with Seizure Expression in a Polygenic Rat Model of Absence Epilepsy

“…Seizure expression for the 90 min after injection EEG recording was quantified by visual inspection of the EEG recordings, blinded to the animal's genotype. Standard criteria described for adult GAERS were used to classify the seizures, i.e., an SWD burst of amplitude of more than three times baseline, a frequency of 7-12 Hz, and duration of longer than 0.5 s (Marescaux et al, 1992;Liu et al, 2006). The start and end of each seizure was determined by manually marking the beginning and end of each SWD on the EEG.…”

Neuropeptide Y suppresses absence seizures in a genetic rat model primarily through effects on Y2 receptors

“…Three days post-operatively, 2 nmol angiotensin II (Auspep Pty, Melbourne, Vic, Australia) was given i.c.v., and the rat's water intake observed for 30 min (both before and after injection) to ensure that the cannula had been placed correctly (McKinley et al, 2003;Stroud et al, 2005;Liu et al, 2006). If the rat failed to respond to angiotensin II (response defined as an increase of water drinking of fivefold or greater over baseline) the rat was retested the following day.…”