5-aminoisoquinolinone attenuates social behavior deficits and immune abnormalities in the BTBR T+ Itpr3tf/J mouse model for autism.

Abstract

Autism spectrum disorder (ASD) is diagnosed by core symptoms including impaired social communication and the presence of repetitive and stereotypical behaviors. There is also evidence for immune dysfunction in individuals with ASD, but it is a disease that is still insufficiently controlled by current treatment strategies. The use of 5-aminoisoquinolinone (5-AIQ) ameliorates several immune-mediated symptoms including rheumatoid arthritis and colitis, and has neuroprotective properties; however, its role in ASD is not yet characterized. In this study, we investigated the effect of 5-AIQ on sociability tests, self-grooming, marble burying, and locomotor activities in BTBR T+ Itpr3tf/J (BTBR) mice, which serve as an ASD animal model. We further investigated the possible molecular mechanism of 5-AIQ administration on CXCR4-, CXCR6-, IFN-γ-, IL-22-, NOS2-, STAT1-, T-bet-, and RORγT-producing CD3+ T cells isolated from the spleens of treated mice. We also explored its effects on mRNA expression in brain tissue. Our results showed that in BTBR mice, 5-AIQ treatment significantly prevented self-grooming and marble burying behaviors and enhanced social interactions without any adverse effects on locomotor activity/anxiety level. Additionally, 5-AIQ treatment substantially decreased CXCR4-, CXCR6-, IFN-γ-, IL-22-, NOS2-, STAT1-, T-bet-, and RORγT-producing CD3+ T cells in the spleen. Furthermore, 5-AIQ treatment decreased CXCR4, IFN-γ, IL-22, STAT1, and RORγT mRNA expression levels in brain tissue. Our findings demonstrated that 5-AIQ improved behavioral and immune abnormalities associated with ASD, which supports the hypothesis that 5-AIQ has important therapeutic potential for the treatment of behavioral and neuroimmune dysfunctions in ASD.

• Authors: Sheikh F Ahmad, Mushtaq A Ansari, Ahmed Nadeem, Saleh A Bakheet, Faleh Alqahtani, Ali R Alhoshani, Fawaz Alasmari, Nasser B Alsaleh, Sabry M Attia
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 189 Pg. 172859 (02 2020) ISSN: 1873-5177 [Electronic] United States
• PMID: 31982447 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• 5-aminoisoquinolinone
• Cytokines
• ITPR3 protein, mouse
• Inositol 1,4,5-Trisphosphate Receptors
• Isoquinolines
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1

Topics

• Animals
• Autism Spectrum Disorder (drug therapy, immunology, metabolism)
• Brain (drug effects, metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Grooming (drug effects)
• Inositol 1,4,5-Trisphosphate Receptors (genetics)
• Isoquinolines (administration & dosage, pharmacology)
• Locomotion (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mutation
• Poly (ADP-Ribose) Polymerase-1 (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Social Behavior
• Stereotyped Behavior (drug effects)