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.
Highlights
Epilepsy is a multifaceted neurological disorder which severely affects neuronal function [1,2].Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, high mortality rate and comorbidities, necessitating immediate intervention with suitable pharmacological treatments [1,2,3,4,5]
The PLC-induced SE exhibit behavioral and electroencephalographic features similar to those observed in human temporal lobe epilepsy (TLE) [8,10], and it proved its effectiveness as a model to investigate the pathophysiology and development of TLE [9,11]
Supported by the behavioral and morphological outcomes as well as electroencephalographic waves observed in previous preclinical studies, the PLC-induced seizure model has been proposed as an animal model with similarity in characteristics to TLE, and numerous previous studies showed that acute systemic administration of a high dose of the muscarinic cholinergic agonist PLC (400 mg/kg) provoked behavioral alternations and convulsions in all tested animals which developed within 30 min to SE [8,9,11,48,49,50]
Summary
Epilepsy is a multifaceted neurological disorder which severely affects neuronal function [1,2].Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, high mortality rate and comorbidities, necessitating immediate intervention with suitable pharmacological treatments [1,2,3,4,5]. The treatment of SE relies on immediate seizure termination using several drugs, e.g., benzodiazepines, antiepileptic drugs, and some anesthetics, which control approximately two-thirds of seizures. To investigate prospective treatments for SE in rodents, the pilocarpine (PLC)-induced SE model is usually used [9]. The PLC-induced SE exhibit behavioral and electroencephalographic features similar to those observed in human temporal lobe epilepsy (TLE) [8,10], and it proved its effectiveness as a model to investigate the pathophysiology and development of TLE [9,11]. Previous studies indicated that the brain histamine (HA) functions as an endogenous anticonvulsant, and intracerebroventricular (i.c.v.) injection of HA was found to prevent amygdaloid-kindled seizures in tested animals [14,15]
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