The multi-targeting ligand St-2223 with histamine H3 receptor and dopamine D2/D3 receptor antagonist properties mitigates autism-like repetitive behaviors and brain oxidative stress in mice

Nermin Eissa, Karthikkumar Venkatachalam, Petrilla Jayaprakash, Markus Falkenstein, Mariam Dubiel, Annika Frank, David Reiner-Link, Holger Stark, Bassem Sadek

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H3 receptor (H3R) and dopamine D2/D3 receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data.

Original languageEnglish
Article number1947
Pages (from-to)1-21
Number of pages21
JournalInternational journal of molecular sciences
Volume22
Issue number4
DOIs
Publication statusPublished - Feb 2 2021

Keywords

  • Anxiety
  • Autistic spectrum disorder
  • BTBR mice
  • Dopamine D2/D3R antagonist
  • Histamine H3 receptor antagonist
  • Oxidative stress
  • Repetitive and restricted behavior

ASJC Scopus subject areas

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

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