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

Alaa Alachkar,Ewelina Honkisz-Orzechowska,Dorota Łażewska,Bassem Sadek,Agata Siwek,Katarzyna Kieć-Kononowicz,Annika Frank,Jadwiga Handzlik,Holger Stark,Gniewomir Latacz,Annamaria Lubelska

doi:10.3390/ijms19113386

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.

Highlights

Epilepsy is considered as a brain disease characterized by repeated seizures due to different complex causes including idiopathic, symptomatic stroke, head injury, metabolic disorders, or genetic mutation of DNA sequences in genes responsible for encoding various ion channels or neurotransmitter receptors [1,2]
An additional test in the present study showed that the protection observed for H3 receptor (H3R) antagonist 4 was abolished when animals were co-administered with the central nervous system (CNS) penetrant histamine H3R agonist RAMH (10 mg/kg i.p.) (Figure 1, Table 3), proposing that the provided protective effect of H3R antagonist 4 in the maximal electroshock (MES)-induced seizure model involves, at least to some extent, H3R blockade provided by H3R antagonist 4
The in vivo anticonvulsant results revealed that H3R antagonist 4 exhibited most promising protection following acute systemic administration in MES- and PTZ-induced seizure models in rats

Summary

Introduction

Epilepsy is considered as a brain disease characterized by repeated seizures due to different complex causes including idiopathic (ion channel or protein defects), symptomatic stroke, head injury (tumors in the brain or central infectious diseases), metabolic disorders (e.g., imbalance of several electrolytes, uremia, and hyperglycemia), or genetic mutation of DNA sequences in genes responsible for encoding various ion channels or neurotransmitter receptors [1,2]. Many patients diagnosed with epilepsy show cognitive comorbid features, for example, deficiency in intellectual ability; impaired learning and memory; and behavioral neuropsychiatric disorders, such as depression, aggression, or problems in social relationships that intensify the costs for their healthcare [3]. Obtainable antiepileptic drugs (AEDs) still have a large number of non-responders with the clinical drawback that around 30% of epileptic patients do not respond to current therapies [4,5]. Numerous AEDs cause several unwanted adverse effects, with the most common ones being behavioral and cognitive deficiencies, weight gain, coordination problems, dizziness, and gait disturbance [6]. As long life drug treatment is indispensable, the search for new and more effective AEDs with improved safety profiles is an imperative therapeutic goal [5]. There is still a high therapeutic need for new medical entities

Results

Discussion

Conclusion