Immunoreactivity of Muscarinic Acetylcholine M2 and Serotonin 5-HT2B Receptors, Norepinephrine Transporter and Kir Channels in a Model of Epilepsy

Abstract

Epilepsy is characterized by an imbalance in neurotransmitter activity; an increased excitatory to an inhibitory activity. Acetylcholine (ACh), serotonin, and norepinephrine (NE) may modulate neural activity via several mechanisms, mainly through its receptors/transporter activity and alterations in the extracellular potassium (K+) concentration via K+ ion channels. Seizures may disrupt the regulation of inwardly rectifying K+ (Kir) channels and alter the receptor/transporter activity. However, there are limited data present on the immunoreactivity pattern of these neurotransmitter receptors/transporters and K+ channels in chronic models of epilepsy, which therefore was the aim of this study. Changes in the immunoreactivity of epileptogenesis-related neurotransmitter receptors/transporters (M2, 5-HT2B, and NE transporter) as well as Kir channels (Kir3.1 and Kir6.2) were determined in the cortex, hippocampus and medulla of adult Wistar rats by utilizing a Pentylenetetrazol (PTZ)-kindling chronic epilepsy model. Increased immunoreactivity of the NE transporter, M2, and 5-HT2B receptors was witnessed in the cortex and medulla. While the immunoreactivity of the 5-HT2B receptor was found increased in the cortex and medulla, it was decreased in the hippocampus, with no changes observed in the M2 receptor in this region. Kir3.1 and Kir6.2 staining showed increase immunoreactivity in the cerebral cortex, but channel contrasting findings in the hippocampus and medulla. Our results suggest that seizure kindling may result in significant changes in the neurotransmitter system which may contribute or propagate to future epileptogenesis, brain damage and potentially towards sudden unexpected death in epilepsy (SUDEP). Further studies on the pathogenic role of these changes in neurotransmitter receptors/transporters and K+ channel immunoreactivity may identify newer possible targets to treat seizures or prevent epilepsy-related comorbidities.

Impaired response to mismatch novelty in the Li2+-pilocarpine rat model of TLE: correlation with hippocampal monoaminergic inputs

“…However, these findings are in line with several studies demonstrating that inactivation of NET ameliorates seizures in animal models of epilepsy [54] and with reports that TH and NET are upregulated following seizures in animal models [55,56]. Altogether, this suggests that the ADHD-like phenotype observed in this animal model may be related to an excessive, rather than impaired, noradrenergic signalling.…”

“…Altogether, this suggests that the ADHD-like phenotype observed in this animal model may be related to an excessive, rather than impaired, noradrenergic signalling. Alternatively, the impairment in serotonergic signalling that is concomitantly observed [36,56] may be the determinant factor in this respect. This question should be further investigated but is currently beyond the scope of this paper.…”

Impaired Response to Mismatch Novelty in the Li2+-Pilocarpine Rat Model of TLE: Correlation with Hippocampal Monoaminergic Inputs

“…This is overall conflicting with previous knowledge that noradrenaline levels are decreased in the Li 2+ -pilocarpine model, and that this is related to depression-like symptoms [ 38 ]. However, these findings are in line with several studies demonstrating that inactivation of NET ameliorates seizures in animal models of epilepsy [ 56 ], and with reports that TH and NET are upregulated following seizures in animal models [ 57 , 58 ]. Altogether, this suggests that the ADHD-like phenotype observed in this animal model may be related to an excessive, rather than impaired, noradrenergic signalling.…”

Serotonin receptors in epilepsy: Novel treatment targets?

“…First, in a PTZ‐kindling rat model of chronic epilepsy increased immunoreactivity of the 5‐HT 2B receptor was found in the cortex and medulla, while it was decreased in the hippocampus. However, further behavioral/functional studies are necessary to elucidate the meaning of this immunoreactivity alteration 95 . Second, the novel ASM, CBD, reduced seizures in pilocarpine‐induced SE in rats that was attributed to both CB 1 and 5‐HT 2B receptors, 96 although 5‐HT 2B receptors are probably not involved in CBD's mechanism of action as shown by Dos Santos et al 48 and Pelz et al 97 Third, Baraban et al showed that 5‐HT 2B agonists can reduce seizures in the zebrafish DS model.…”

“…However, further behavioral/functional studies are necessary to elucidate the meaning of this immunoreactivity alteration. 95 Second, the novel ASM, CBD, reduced seizures in pilocarpine-induced SE in rats that was attributed to both CB 1 and 5-HT 2B receptors, 96 although 5-HT 2B receptors are probably not involved in CBD's mechanism of action as shown by Dos Santos et al 48 and Pelz et al 97 Third, Baraban et al showed that 5-HT 2B agonists can reduce seizures in the zebrafish DS model. Nonetheless, numerous other researchers did not observe any seizure reduction by 5-HT 2B modulation in different animal models of epilepsy.…”