Alpha2 Adrenergic Modulation of Spike-Wave Epilepsy: Experimental Study of Pro-Epileptic and Sedative Effects of Dexmedetomidine

Abstract

In the present report, we evaluated adrenergic mechanisms of generalized spike-wave epileptic discharges (SWDs), which are the encephalographic hallmarks of idiopathic generalized epilepsies. SWDs link to a hyper-synchronization in the thalamocortical neuronal activity. We unclosed some alpha2-adrenergic mechanisms of sedation and provocation of SWDs in rats with spontaneous spike-wave epilepsy (WAG/Rij and Wistar) and in control non-epileptic rats (NEW) of both sexes. Dexmedetomidine (Dex) was a highly selective alpha-2 agonist (0.003–0.049 mg/kg, i.p.). Injections of Dex did not elicit de novo SWDs in non-epileptic rats. Dex can be used to disclose the latent form of spike-wave epilepsy. Subjects with long-lasting SWDs at baseline were at high risk of absence status after activation of alpha2- adrenergic receptors. We create the concept of alpha1- and alpha2-ARs regulation of SWDs via modulation of thalamocortical network activity. Dex induced the specific abnormal state favorable for SWDs—“alpha2 wakefulness”. Dex is regularly used in clinical practice. EEG examination in patients using low doses of Dex might help to diagnose the latent forms of absence epilepsy (or pathology of cortico-thalamo-cortical circuitry).

Alpha‐2a adrenergic receptor activation in genetic absence epilepsy: An absence status model?

“…The sedation sleep induced by DEX showed a character of deep sedation as explained previously. 24 Interestingly, the post‐sleep seizure had higher power in a delta frequency band (1–4 Hz) and attenuated power in 7‐Hz harmonics (14 and 21 Hz) than pre‐ and post‐injection seizures. Moreover, the attenuated power in beta frequencies might also indirectly indicate the dopaminergic release as stated and discussed in previous studies.…”

“… 21 In the literature, 1 to 5 times higher doses of ATI were used to recover DEX‐induced anesthesia or sedation 22 , 23 and DEX induces sedation above the doses of 3 μg and also induces high‐voltage spindles. 22 Although a study addressed that DEX can prolong SWDs via intraperitoneal route as well, 24 , 25 , 26 we picked the dose of 2.5 μg 1/5 of ATI dose as well as the doses slightly below the sedative doses in order to understand if DEX has an effect on the SWDs expressed in GAERS, as well as to antagonize ATI. In our previous study, as we established the SWD‐suppressing dose of ATI through intracerebroventricular (i.c.v.)…”

Dexmedetomidine, an alpha 2A receptor agonist, triggers seizures unilaterally in GAERS during the pre-epileptic phase: does the onset of spike-and-wave discharges occur in a focal manner?

“…Recent reports on dexmedetomidine increasing the duration of SWD activity ( 15 ) provide evidence that dexmedetomidine influences SWD duration. For instance, Sitnikova et al ( 47 , 48 ) provided preliminary results of dexmedetomidine increasing mean duration of SWDs in another model of genetic absence epilepsy Wistar Albino Glaxo/Rijswijk (WAG/Rij), and dexmedetomidine does not shorten the SWDs unlike other anesthetics ( 49 ).…”

Adrenergic receptor system as a pharmacological target in the treatment of epilepsy (Review)

“…Furthermore, dexmedetomidine significantly reduced the number of c-Fos positive cells in the rat brain ( 66 ). However, another study demonstrated a pro-epileptic effect of dexmedetomidine in spike-wave epilepsy in WAG/Rij rats ( 84 ). In previous a study on the rat hippocampus, the α2-AR antagonist was implicated in the NE-mediated anti-epileptic effect in the CA3 domain ( 85 ).…”