The role of the Orexinergic system in temporal lobe epilepsy-induced changes in the hippocampus and hypothalamus

Author: Tsira Kapanadze
Keywords: Orexine, Temporal Lobe Epilepsy, Kainic Acid
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Epilepsy is characterized by a high prevalence among neurodegenerative diseases (Fiest et al., 2017). The complexity of the pathogenesis of the disease and the presence of forms resistant to therapy increase the need for neurobiological research in this direction. Limbic seizures, which are currently the most resistant to therapeutic treatment, affect the hippocampus (Rizzi et al., 2002). Abnormal electrical activity in epileptic neuronal networks is associated with an imbalance between the excitatory neurotransmitter glutamate and the inhibitory gamma-aminobutyric acid (GABA) (Staley, 2015). The modulating effects of the neuropeptide orexin on hippocampal glutamatergic, GABAergic, and noradrenergic transmission and related hippocampal functions—long-term potentiation of synaptic transmission, learning, and memory (Selbach et al., 2004; Yang et al., 2013) have been studied. There are controversial data in the literature about the role of orexin in epileptogenesis. Both anti-epileptic (Doreulee et al., 2009, 2010) and proconvulsant effects (Erken et al., 2012; Kortunay et al., 2012; Roundtree et al., 2016) of orexin have been observed in experiments conducted with different methodological approaches on different animal models of epilepsy. The aim of our study was to evaluate the morphological changes in the hippocampus and hypothalamus caused by status epilepticus in a rat model of temporal lobe epilepsy and to study the effect of orexin-A on the electrical activity of the hippocampal fields. We used a pharmaceutical approach, specifically a single intraperitoneal injection of kainic acid (15 mg/kg), for developing an animal model of temporal lobe epilepsy. In in vivo electrophysiological experiments, the effects of intraventricular application of Orexine-A on background neuronal activity and field potentials evoked by bipolar intrahippocampal stimulation were evaluated in the hippocampus of control and kainic acid status epilepticus (KA-SE) rats. In the morphological experiments, the structural changes caused by KA-SE in the hippocampus and hypothalamus were evaluated. An analysis of the data obtained during an electrophysiological experimental study showed that orexin-A in the CA1 field of the hippocampus of control animals causes an increase in the frequency and a decrease in the amplitude of the background neuronal activity. Orexin-A, due to the activation of orexin-1 receptors, increases the amplitude of responses evoked by intrahippocampal electrical stimulation and does not change the rate of paired facilitation, which indicates It’s postsynaptic locus of action. The effects of orexin in the hippocampal fields of control and KA-SE animals were different. Morphological Experiments in KA-SE animals showed that epilepsy alters the cytoarchitectonics of both the hippocampus and hypothalamus; In particular, the number of GAD-positive neurons decreased in the hippocampus, while the number of orexinergic neurons decreased in the hypothalamus. Thus, the morphological changes caused by epileptogenesis may explain the various effects of orexin in normal and pathophysiology.