Atipamezole, a specific α_2A antagonist, suppresses spike‐and‐wave discharges and alters Ca^2⁺/calmodulin‐dependent protein kinase II in the thalamus of genetic absence epilepsy rats

Abstract

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.

Alpha-2a Adrenergic Receptor (Α2ar) Activation in Genetic Absence Epilepsy: An Absence Status Model?

“…This study once more strengthens the idea of the α 2AR being one of the main mechanisms behind the absence seizures (Sitnikova & van Luijtelaar, 2005;Yavuz et al, 2020). With our previous article (King & Burnham, 1982;Yavuz et al, 2020) and previous studies, α 2AR are discussed to underline the pathophysiology of SWD activities. In the present study, the injection of the specific agonist dexmedetomidine lengthened the mean duration of SWD events by converting the absence activity to absence status epilepticus.…”

“…On the other hand the noradrenaline is a known modulator of dopamine release, specifically by introducing specific agonists of α 2AR in VTA, α 2AR is shown to increase phasic dopamine release in the ventral tegmental area (Bernacka et al, 2022). This study once more strengthens the idea of the α 2AR being one of the main mechanisms behind the absence seizures (Sitnikova & van Luijtelaar, 2005;Yavuz et al, 2020). With our previous article (King & Burnham, 1982;Yavuz et al, 2020) and previous studies, α 2AR are discussed to underline the pathophysiology of SWD activities.…”

“…Laying the groundwork with our previous findings of alpha 2A adrenergic receptor (α 2AR ) blocker, atipamezole suppressing SWD activity (Yavuz et al, 2020), we expected the specific agonist of α 2AR dexmedetomidine might increase the SWD activity. We used the doses from the literature that possibly reverse (Dowlatshahi & Yaksh, 1997) the effective dose (12 μg) of atipamezole we found previously (Yavuz et al, 2020). As the result of the intracerebroventricular (i.c.v.)…”

“…Animals were randomly assigned to evaluate the dose-dependent effects of dexmedetomidine and number of animals were determined according to our previous studies (Yavuz et al, 2020). Groups receiving acute intracerebroventricular (i.c.v.)…”

Alpha2-Adrenergic Receptors as a Pharmacological Target for Spike-Wave Epilepsy

“…To date, a large amount of data has been accumulated on the noradrenergic modulation of spike-wave activity (e.g., [ 40 , 41 , 42 , 43 ]). Cortico-thalamo-cortical neural circuitry is known to receive dense innervations from noradrenergic neurons [ 44 , 45 , 46 ].…”