The Neuroprotective Effects of Histamine H3 Receptor Antagonist E177 on Pilocarpine-Induced Status Epilepticus in Rats

Abstract

Epilepsy is a multifaceted neurological disorder which severely affects neuronal function. Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, necessitating an immediate intervention. The potential of histamine H3 receptors in several neuropsychiatric diseases including epilepsy is well recognized. In the current study, we aimed to explore the effect of H3R antagonist E177 on prevention and termination of pilocarpine (PLC)-induced SE in rats as well as evaluating the effects of E177 on the levels of oxidative stress in hippocampus tissues. The results showed that the survival rate of animals pretreated with E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) was significantly increased during the first hour of observation, and animals were protected from SE incidence and showed a prolonged average of latency to the first seizure when compared with animals pretreated with PLC (400 mg/kg, i.p.). Moreover, the protective effect of E177 (10 mg/kg) on SE was partially reversed when rats were co- administered with H3R agonist R-(α)-methylhistamine (RAM) and with the H2R antagonist zolantidine (ZOL), but not with the H1R antagonist pyrilamine (PYR). Furthermore, pretreatment with E177 (5 and 10 mg/kg) significantly decreased the abnormal levels of malondialdehyde (MDA), and increased levels of glutathione (GSH) in the hippocampal tissues of the treated rats. However, E177 failed to modulate the levels of catalase (CAT), superoxide dismutase (SOD), or acetylcholine esterase activity (AChE). Our findings suggest that the newly developed H3R antagonist E177 provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the therapeutic management of SE.

Antagonism of Histamine H3 receptors Alleviates Pentylenetetrazole-Induced Kindling and Associated Memory Deficits by Mitigating Oxidative Stress, Central Neurotransmitters, and c-Fos Protein Expression in Rats

“…Importantly, our results indicated that H3R antagonist E177 (5 and 10 mg/kg) restored disturbed levels of AChE in the hippocampus, with no significant difference noted in the modulating effect between the two doses used ( Figure 5). The H3R antagonist E177 was not confirmed in its in vitro profile of having AChE inhibitory effects [38,39]. However, the modulatory effect of H3R antagonist E177 on AChE levels may be due to its provided anticonvulsant effect which resulted in an inhibition of the AChE overexpression and/or preventing of the notable alternation of cholinergic transmission.…”

“…The H3R antagonist E177, namely [1-(6-(naphthalen-2-yloxy)hexyl)azepane] which belongs to the non-imidazole class of novel H3R antagonists, and with high antagonist affinity (K i = 69.40 nM) and high in vitro selectivity towards H3Rs [37], was selected for the current series of experiments, as previous experiments indicated its promising anticonvulsant effect in different acute seizure models, e.g., MES-and PTZ-induced seizure models [27]. Moreover, E177 has recently shown a dose-dependent procognitive effect in DIZ-induced amnesia without modulation of anxiety-like behaviors [32], and neuroprotective effects on pilocarpine-induced status epilepticus in rodents [38].…”

Simultaneous Blockade of Histamine H3 Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of Autism

“…Initially in 1983 it was found that histamine H 3 receptor (H 3 R) negatively regulate HA synthesis and release with high constitutive activity, acting presynaptically as auto-receptors [ 16 , 17 ]. In addition, the functioning of H 3 hetero-receptors (H 3 Rs) modulate the release of different neurotransmitters (e.g., ACh, serotonin (5-HT), dopamine (DA), γ-aminobutyric acid (GABA), noradrenaline (NA) and glutamate (Glu) in various regions of the brain [ 18 , 19 , 20 , 21 , 22 ]. Moreover and in the central nervous system (CNS), H 3 Rs are chiefly expressed on the histaminergic neurons.…”

Lrp4 in hippocampal astrocytes serves as a negative feedback factor in seizures

“…Animal seizures model has been widely employed to evaluate the progression of seizures, and used to study how seizures regulate gene expression in brain [ 15 , 16 ]. It has been reported that pilocarpine treated rodents provokes a rapid and prolonged seizure, and leads to several molecular and cellular changes in hippocampus [ 17 , 18 ]. We found that high released glutamate in seizures induced by pilocarpine down-regulated astrocytic Lrp4 expression through increasing miR-351-5p expression level in hippocampal astrocytes via activating astrocytic NMDA receptor.…”