The Orexin System: A Potential Player in the Pathophysiology of Absence Epilepsy

Abstract

Background: Absence epilepsy is characterized by the presence of spike-and-wave discharges (SWDs) at the EEG generated within the cortico-thalamo-cortical circuit. The molecular mechanisms involved in the pathophysiology of absence epilepsy are only partially known. WAG/Rij rats older than 2-3 months develop spontaneous SWDs, and they are sensitive to anti- absence medications. Hence, WAG/Rij rats are extensively used as a model for absence epilepsy with predictive validity.

Objective: The aim of the study was to examine the possibility that the orexin system, which supports the wake status in experimental animals and humans, plays a role in the pathophysiology of absence seizures.

Methods: The perspective grounds its method from recent literature along with measurements of orexin receptor type-1 (OX1) protein levels in the thalamus and somatosensory cortex of WAG/Rij rats and non-epileptic Wistar control rats at two ages (25 days and 6-7 months). OX1 protein levels were measured by immunoblotting.

Results: The analysis of the current literature suggests that the orexin system might be involved in the pathophysiology of absence epilepsy and might be targeted by therapeutic intervention. Experimental data are in line with this hypothesis, showing that OX1 protein levels were reduced in the thalamus and somatosensory cortex of symptomatic WAG/Rij rats (6-7 months of age) with respect to non-epileptic controls, whereas these differences were not seen in pre-symptomatic, 25 days-old WAG/Rij rats.

Conclusion: This perspective might pave the way for future studies on the involvement of the orexinergic system in the pathophysiology of SWDs associated with absence epilepsy and its comorbidities.

Keywords: Absence epilepsy; OX1; SWDs; cortico-thalamo-cortical network; orexin system; sleep disturbance.

Fig. (1)

Immunoblot analysis of OX1 receptors in the thalamus and somatosensory cortex of Wistar and WAG/Rij rats. Representative immunoblot of OX1 receptors levels in thalamus and cortex; (A) symptomatic WAG/Rij rats (6-7 months old) and (B) pre-symptomatic WAG/Rij rats (25 days old) as compared to age-matched control Wistar rats. Values are means ± S.E.M. with 4–5 animals in each group. Data points are from individual experiments. Post-hoc t-tests showed that symptomatic WAG/Rij rats differ from non-epileptic age matched controls (*: Thalamus: t = 6.27, df=7, and 95% two-tailed confidence interval for difference of means: 0.170 to 0.377; two-tailed P-value = 0.000418; Somatosensory cortex: t = 3.86, df=7, and 95% two-tailed confidence interval for difference of means: 0,0767 to 0,320; two-tailed P-value = 0,00624). There were no statistical differences detected between age-matched Wistar and pre-symptomatic WAG/Rij rats, neither in thalamus, nor in cortex (Thalamus: t = -0.956, df=7, and 95% two-tailed confidence interval for difference of means: -0,312 to 0,132; two- tailed P-value = 0,371; Somatosensory cortex: t = 1.207, df=7, and 95% two-tailed confidence interval for difference of means: -0,086 to 0,265. two-tailed P-value = 0,267). Next, and not illustrated, there was an age-dependent increase in the cortex (F=15.28, df=1,14, P-value = 0,002), but not in thalamus (F= 2.40 df = 1,14, P-value = 0,144).

Fig. (2)

Cortico-thalamo-cortical network underlying absence seizures. VB = Ventrobasal thalamic nuclei; nRT = reticular thalamic nucleus. Fig. (2) is partially adapted from Celli et al., Curr Neuropharmacol., 2017, 15(6), 918-925.