Studies on Anticonvulsant Effects of Novel Histamine H3R Antagonists in Electrically and Chemically Induced Seizures in Rats

Abstract

A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists (1–16) was evaluated in vivo for anticonvulsant effects in three different seizure models in Wistar rats. Among the novel H3R antagonists examined, H3R antagonist 4 shortened the duration of tonic hind limb extension (THLE) in a dose-dependent fashion in the maximal electroshock (MES)-induced seizure and offered full protection against pentylenetetrazole (PTZ)-induced generalized tonic-clonic seizure (GTCS), following acute systemic administration (2.5, 5, 10, and 15 mg/kg, i.p.). However, only H3R antagonist 13, without appreciable protective effects in MES- and PTZ-induced seizure, fully protected animals in the strychnine (STR)-induced GTCS following acute systemic pretreatment (10 mg/kg, i.p.). Moreover, the protective effect observed with H3R antagonist 4 in MES-induced seizure was completely abolished when animals were co-administered with the H3R agonist (R)-α-methylhistamine (RAMH, 10 mg/kg, i.p.). However, RAMH failed to abolish the full protection provided by the H3R antagonist 4 in PTZ-induced seizure and H3R antagonist 13 in STR-induced seizure. Furthermore, in vitro antiproliferative effects or possible metabolic interactions could not be observed for compound 4. Additionally, the predictive in silico, as well as in vitro, metabolic stability for the most promising H3R antagonist 4 was assessed. The obtained results show prospective effects of non-imidazole H3R antagonists as innovative antiepileptic drugs (AEDs) for potential single use against epilepsy.

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

“…However, no protective effect was observed following pretreatment with E177 (2.5 and 15 mg/kg), indicating a dose-dependent effect of E177 in PLC-induced seizure model. The latter dose-dependent effect of E177 is in agreement with previous preclinical outcomes that demonstrated a dose-dependent effect of different H3R antagonists in several animal models [23,25,30], and with our previous observation of a dose-dependent anticonvulsant effect of E177 in electrical as well as chemically induced seizure models [28]. Importantly, the protection provided by E177 (5 and 10 mg/kg) in the PLC-induced seizure model was significantly higher when compared to the higher dose (15 mg/kg, i.p.)…”

“…Moreover, numerous H3R antagonists were previously investigated on their protective effects in different acute seizure models, and the results revealed their anticonvulsant effects [23,30,42,43,44,45,46,47]. In this study and as a continuation of our previous work, the protective effect of the non-imidazole based H3R antagonist E177 with high in vitro antagonist affinity ( h H3R K i = 69.3 nM) [36,37] and excellent selectivity profile [28] towards H3Rs was investigated in the PLC-induced SE model. 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].…”

“…In a recent study, the novel histamine H3R antagonist E177, which belongs to the non-imidazole histamine H3 receptor (H3R) antagonists class, was found to provide full in vivo protection against seizures in three different seizure models in rodents, including maximal electroshock- and pentylenetetrazole-induced generalized tonic-clonic seizure, following acute systemic administration (2.5, 5, 10, and 15 mg/kg, i.p.) [28]. H3Rs are coupled to Gα i/o -proteins and are mainly expressed in the CNS presynaptically, where they function as inhibitory auto- and hetero-receptors that modulate the biosynthesis and release of HA and other neurotransmitters such as dopamine, serotonin, acetylcholine, norepinephrine, and glutamate [22,27,29,30,31].…”

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

“…In addition, we have documented the protective effect of E177, a potent non-imidazole H3R antagonist/ inverse agonist, in MES-and PTZ-induced seizure models, with E177 (10 mg/kg i.p.) showing the most promising anticonvulsant effect [31]. Also, E177 (5 mg/kg i.p.)…”

The Intestinal Perspective of COVID-19: NOS2 and AOC1 Genes as Epidemiological Factors, and a Homeopathic Approach to their Functional Improvement

“…137 Furthermore, an increase in the bioavailability of biogenic amines due to DAO or iNOS inhibition improves their vasoactive activity and they can reach the central nervous system in different possible ways to alter the nervous centres. [138][139][140][141][142] Some of the impairments are seizures and tremors through histamine H3R receptors 143 and polyamines NMDA receptors. 144 Additional pro-convulsive mechanisms for NOS2 will be discussed in next sections.…”