The dual-active histamine H3 receptor antagonist and acetylcholine esterase inhibitor E100 alleviates autistic-like behaviors and oxidative stress in valproic acid induced autism in mice

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

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

The histamine H3 receptor (H3R) functions as auto-and hetero-receptors, regulating the release of brain histamine (HA) and acetylcholine (ACh), respectively. The enzyme acetylcholine esterase (AChE) is involved in the metabolism of brain ACh. Both brain HA and ACh are implicated in several cognitive disorders like Alzheimer’s disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with autistic spectrum disorder (ASD). Therefore, the novel dual-active ligand E100 with high H3R antagonist affinity (hH3R: Ki = 203 nM) and balanced AChE inhibitory effect (EeAChE: IC50 = 2 µM and EqBuChE: IC50 = 2 µM) was investigated on autistic-like sociability, repetitive/compulsive behaviour, anxiety, and oxidative stress in male C57BL/6 mice model of ASD induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, intraperitoneal (i.p.)). Subchronic systemic administration with E100 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently attenuated sociability deficits of autistic (VPA) mice in three-chamber behaviour (TCB) test (all p < 0.05). Moreover, E100 significantly improved repetitive and compulsive behaviors by reducing the increased percentage of marbles buried in marble-burying behaviour (MBB) (all p < 0.05). Furthermore, pre-treatment with E100 (10 and 15 mg/kg, i.p.) corrected decreased anxiety levels (p < 0.05), however, failed to restore hyperactivity observed in elevated plus maze (EPM) test. In addition, E100 (10 mg/kg, i.p.) mitigated oxidative stress status by increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and decreasing the elevated levels of malondialdehyde (MDA) in the cerebellar tissues (all p < 0.05). Additionally, E100 (10 mg/kg, i.p.) significantly reduced the elevated levels of AChE activity in VPA mice (p < 0.05). These results demonstrate the promising effects of E100 on in-vivo VPA-induced ASD-like features in mice, and provide evidence that a potent dual-active H3R antagonist and AChE inhibitor (AChEI) is a potential drug candidate for future therapeutic management of autistic-like behaviours.

Original languageEnglish
Article number3996
Pages (from-to)1-22
Number of pages22
JournalInternational journal of molecular sciences
Volume21
Issue number11
DOIs
Publication statusPublished - Jun 1 2020

Keywords

  • Acetylcholine esterase inhibitor
  • Antagonist
  • Anxiety histamine H3R
  • Cerebellum
  • E100
  • Mice
  • Oxidative stress
  • Repetitive behaviors
  • Sociability
  • VPA-induced autism-like behaviors

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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