Objective: The role of α 2A adrenergic receptors (α 2A ARs) in absence epilepsy is not well characterized. Therefore, we investigated the outcomes of the specific antagonism of α 2A ARs on the spike-and-wave discharges (SWDs) in genetic absence epilepsy rats from Strasbourg (GAERSs), together with its influence on the behavior and second messenger systems, which may point to the mechanisms to which a possible SWD modulation can be related. Methods: Atipamezole, an α 2A AR antagonist, was administered intracerebroventricularly to the adult GAERSs, and electroencephalography (EEG) was conducted. The cumulative duration and number of SWDs, and the mean duration of each SWD complex were counted. The relative power of the EEG frequency bands and behavioral activity after the acute application of two doses (12 and 31 μg/5 μL) of atipamezole were evaluated. The levels of cyclic adenosine monophosphate and calcium/ calmodulin-dependent kinase II (CaMKII) were measured in the cortex, thalamus, and hippocampus of naive Wistar rats and GAERSs, administered with artificial cerebrospinal fluid (aCSF) as a vehicle, or either acute or chronic atipamezole (12 μg), the latter being administered for 5 consecutive days. Results: Atipamezole significantly suppressed SWDs dose-dependently, without affecting the relative power values of EEG frequency spectrum. The stereotypic activity was significantly lower in both naive Wistar rats and GAERSs receiving the highest dose (31 μg) of atipamezole compared to GAERSs receiving aCSF. In GAERSs, CaMKII levels were found to be higher in the thalamus after the acute and chronic application of SWD-suppressing doses of atipamezole (12 and 31 μg) compared to aCSF. Significance: This study emphasizes the α 2 AR-related modulation of absence epilepsy and particularly the significance of α 2 AR antagonism in suppressing SWDs. Atipamezole's SWD-suppressive actions may be through CaMKII-mediated second messenger systems in the thalamus.

Rho/Rho-kinase (ROCK) signaling contributes to neuroinflammation, epileptogenesis, and seizures in convulsive-type epilepsies. However, this pathway has not been investigated in absence epilepsy. We investigated RhoA activity in genetic absence epilepsy rats from Strasburg (GAERS) and the effects of ROCK inhibitors Y-27632 and fasudil on spike-and-wave discharges (SWDs) of GAERS. ROCK level and activity were measured by Western blot analysis in the brain areas involved in absence seizures (i.e., cortex and thalamus) and hippocampus. Male GAERS were stereotaxically implanted with bilateral cortical electrodes for electroencephalogram (EEG) recordings and/or guide cannula into the right ventricle. ROCK inhibitors were administered by intraperitoneal injection (1-10 mg/kg for Y-27632 or fasudil) or intracerebroventricular injection (7-20 nmol/5 μl for Y-27632 or 10-100 nmol/5 μl for fasudil). EEG was recorded under freely moving conditions. Compared with Wistar rats, GAERS exhibited increased RhoA activity in the somatosensory cortex but not in the thalamus or hippocampus. The single systemic administration of Y-27632 and fasudil partially suppressed the duration and frequency of absence seizure, respectively. However, local brain administration caused a widespread suppressive effect on the total seizure duration, number of seizures, and the average individual seizure length. In summary, Rho/ROCK signaling may be involved in the pathophysiology of absence epilepsy. Furthermore, ROCK inhibitors can control the expression of absence seizure in GAERS, thus indicating that Y-27632 and fasudil have the potential to be used as novel anti-absence drugs.

BACKGROUND AND PURPOSE: The updates in the definition of absence status epilepticus raise questions about the pathophysiological aspects of absence status. Here, we propose an animal model of absence status epilepticus, induced by specific alpha 2a adrenergic receptor (α2AR) activation. EXPERIMENTAL APPROACH: An α2AR agonist, dexmedetomidine was injected intracerebroventricularly into the adult rats with genetic absence epilepsy and the electroencephalography (EEG) from animals was recorded. The total duration, number and mean duration of each spike-and-wave discharges (SWDs) were evaluated. The blocks of absence status events were classified as first and second set of absence statuses. Ethosuximide was given as a pre-treatment to another group of animals, later injected with 2.5 μg dexmedetomidine. Power spectral characteristics and coherence analysis for the absence status events and sleep were performed on the EEG. KEY RESULTS: The 2.5 µg dose of dexmedetomidine increased the total SWD duration and induced continuous SWDs up to 26 min. Following a first absence status event, sleep is induced and it was followed by the second set of absence status events. Ethosuximide pre-treatment blocked the occurrence of these events. Power spectral density analyses revealed that dexmedetomidine injection-induced absence seizures and the absence seizures following sleep had lower spectral power than typical SWDs in the frequency bands. CONCLUSIONS AND IMPLICATIONS: This study presents that activation of α2AR may induce absence status epilepticus and this can be an animal model to study the pathophysiological role of absence status. Our results strengthen the significant role of α2AR in SWD generation or termination.