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Article

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

1
Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE
2
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
3
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, Germany
4
Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
*
Author to whom correspondence should be addressed.
These authors have contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(11), 3386; https://doi.org/10.3390/ijms19113386
Received: 9 October 2018 / Revised: 24 October 2018 / Accepted: 26 October 2018 / Published: 29 October 2018
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists (116) 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. View Full-Text
Keywords: histamine H3 receptors; antagonists; anticonvulsant; maximal electroshock; pentylenetetrazole; strychnine; antiproliferative action; metabolic stability histamine H3 receptors; antagonists; anticonvulsant; maximal electroshock; pentylenetetrazole; strychnine; antiproliferative action; metabolic stability
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MDPI and ACS Style

Alachkar, A.; Łażewska, D.; Latacz, G.; Frank, A.; Siwek, A.; Lubelska, A.; Honkisz-Orzechowska, E.; Handzlik, J.; Stark, H.; Kieć-Kononowicz, K.; Sadek, B. Studies on Anticonvulsant Effects of Novel Histamine H3R Antagonists in Electrically and Chemically Induced Seizures in Rats. Int. J. Mol. Sci. 2018, 19, 3386. https://doi.org/10.3390/ijms19113386

AMA Style

Alachkar A, Łażewska D, Latacz G, Frank A, Siwek A, Lubelska A, Honkisz-Orzechowska E, Handzlik J, Stark H, Kieć-Kononowicz K, Sadek B. Studies on Anticonvulsant Effects of Novel Histamine H3R Antagonists in Electrically and Chemically Induced Seizures in Rats. International Journal of Molecular Sciences. 2018; 19(11):3386. https://doi.org/10.3390/ijms19113386

Chicago/Turabian Style

Alachkar, Alaa, Dorota Łażewska, Gniewomir Latacz, Annika Frank, Agata Siwek, Annamaria Lubelska, Ewelina Honkisz-Orzechowska, Jadwiga Handzlik, Holger Stark, Katarzyna Kieć-Kononowicz, and Bassem Sadek. 2018. "Studies on Anticonvulsant Effects of Novel Histamine H3R Antagonists in Electrically and Chemically Induced Seizures in Rats" International Journal of Molecular Sciences 19, no. 11: 3386. https://doi.org/10.3390/ijms19113386

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