The dual-active histamine H3 receptor antagonist and acetylcholine esterase inhibitor E100 ameliorates stereotyped repetitive behavior and neuroinflammmation in sodium valproate induced autism in mice.

Abstract

Postnatal exposure to valproic acid (VPA) in rodents induces autism-like neurobehavioral defects which are comparable to the motor and cognitive deficits observed in humans with autism spectrum disorder (ASD). Histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in several cognitive disorders such as Alzheimer's disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with ASD. Therefore, the present study aimed at evaluating effect of the novel dual-active ligand E100 with high H3R antagonist affinity and balanced AChE inhibition on autistic-like repetitive behavior, anxiety parameters, locomotor activity, and neuroinflammation in a mouse model of VPA-induced ASD in C57BL/6 mice. E100 (5, 10, and 15 mg/kg) dose-dependently and significantly ameliorated repetitive and compulsive behaviors by reducing the increased percentages of nestlets shredded (all P < 0.05). Moreover, pretreatment with E100 (10 and 15 mg/kg) attenuated disturbed anxiety levels (P < 0.05) but failed to restore the hyperactivity observed in the open field test. Furthermore, pretreatment with E100 (10 mg/kg) the increased microglial activation, proinflammatory cytokines and expression of NF-κB, iNOS, and COX-2 in the cerebellum as well as the hippocampus (all P < 0.05). These results demonstrate the ameliorative effects of E100 on repetitive compulsive behaviors in a mouse model of ASD. To our knowledge, this is the first in vivo demonstration of the effectiveness of a potent dual-active H3R antagonist and AChE inhibitor against autistic-like repetitive compulsive behaviors and neuroinflammation, and provides evidence for the role of such compounds in treating ASD.

• Authors: Nermin Eissa, Sheikh Azimullah, Petrilla Jayaprakash, Richard L Jayaraj, David Reiner, Shreesh K Ojha, Rami Beiram, Holger Stark, Dorota Łażewska, Katarzyna Kieć-Kononowicz, Bassem Sadek
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 312 Pg. 108775 (Oct 01 2019) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 31369746 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Cholinesterase Inhibitors
• Cytokines
• Histamine H3 Antagonists
• Transcription Factor RelA
• Valproic Acid
• Nitric Oxide Synthase Type II

Topics

• Animals
• Autism Spectrum Disorder (chemically induced, drug therapy, pathology)
• Behavior, Animal (drug effects)
• Cholinesterase Inhibitors (pharmacology, therapeutic use)
• Cytokines (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Hippocampus (metabolism)
• Histamine H3 Antagonists (pharmacology, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Microglia (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Transcription Factor RelA (metabolism)
• Valproic Acid (toxicity)