Histamine H3 receptor antagonist E177 attenuates amnesia induced by dizocilpine without modulation of anxiety-like behaviors in rats
Received 1 November 2018
Accepted for publication 17 January 2019
Published 20 February 2019 Volume 2019:15 Pages 531—542
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Colin Mak
Peer reviewer comments 3
Editor who approved publication: Dr Roger Pinder
Alaa Alachkar,1 Nadia Khan,1 Dorota Łażewska,2 Katarzyna Kieć-Kononowicz,2 Bassem Sadek1
1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland
Background: Alzheimer disease (AD) is the main cause of dementia in elderly people. The potential of histamine H3 receptor (H3R) antagonists as a pharmacological treatment of several neuropsychiatric diseases is well established.
Methods: The novel non-imidazole-based H3R antagonist E177 was screened for its procognitive effects on the inhibitory avoidance paradigm (IAP) and novel object recognition (NOR) task in a dizocilpine (DIZ)-induced model of amnesia in male Wistar rats. Donepezil, an acetylcholine esterase inhibitor, was used as the reference drug.
Results: Acute systemic treatment with E177 (1.25, 2.5, 5, and 10 mg/kg intraperitoneally [i.p.]) significantly attenuated the cognitive impairments induced by DIZ in the IAP (all P-values <0.05, n=7), and the protective effect of the most promising dose of E177 (5 mg/kg) was abrogated when H3R agonist R-(α)-methylhistamine (RAMH; 10 mg/kg i.p.) was co-administered (P=0.281 for DIZ-amnesia group vs DIZ + E177 + RAMH group, n=7). The discrimination index calculated for E177 (5 mg/kg, i.p.) showed a significant memory-enhancing effect on DIZ-induced short-term memory impairment in the NOR task (P<0.05, n=6), with the enhancement nullified when animals were co-administered RAMH (10 mg/kg). Moreover, the results revealed that E177 (5 and 10 mg/kg, i.p.) did not alter the anxiety levels and locomotor activity of animals naïve to the open-field test (all P-values >0.05, n=8) or the elevated plus maze test (all P-values >0.05, n=6–8), which indicated that the E177-induced enhancement of memory performance in the IAP or NOR task was unrelated to changes in emotional response or in spontaneous locomotor activity.
Conclusion: The observed results suggested a possible contribution of H3Rs in the alteration of brain neurotransmitters that accompany neurodegenerative diseases, such as AD.
Keywords: Histamine H3 receptors, antagonist, dizocilpine-induced amnesia, inhibitory avoidance paradigm, novel object recognition, elevated plus maze, open field test, memory, anxiety
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]