TY - JOUR
T1 - Alleviation of Autophagic Deficits and Neuroinflammation by Histamine H3 Receptor Antagonist E159 Ameliorates Autism-Related Behaviors in BTBR Mice
AU - Thomas, Shilu Deepa
AU - Jayaprakash, Petrilla
AU - Marwan, Nurfirzana Z.H.J.
AU - Aziz, Ezzatul A.B.A.
AU - Kuder, Kamil
AU - Łażewska, Dorota
AU - Kieć-Kononowicz, Katarzyna
AU - Sadek, Bassem
N1 - Publisher Copyright:
© 2024 by the authors.
PY - 2024/10
Y1 - 2024/10
N2 - Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social interaction difficulties, repetitive behaviors, and immune dysregulation with elevated pro-inflammatory markers. Autophagic deficiency also contributes to social behavior deficits in ASD. Histamine H3 receptor (H3R) antagonism is a potential treatment strategy for brain disorders with features overlapping ASD, such as schizophrenia and Alzheimer’s disease. Methods: This study investigated the effects of sub-chronic systemic treatment with the H3R antagonist E159 on social deficits, repetitive behaviors, neuroinflammation, and autophagic disruption in male BTBR mice. Results: E159 (2.5, 5, and 10 mg/kg, i.p.) improved stereotypic repetitive behavior by reducing self-grooming time and enhancing spontaneous alternation in addition to attenuating social deficits. It also decreased pro-inflammatory cytokines in the cerebellum and hippocampus of treated BTBR mice. In BTBR mice, reduced expression of autophagy-related proteins LC3A/B and Beclin 1 was observed, which was elevated following treatment with E159, attenuating the disruption in autophagy. The co-administration with the H3R agonist MHA (10 mg/kg, i.p.) reversed these effects, highlighting the role of histaminergic neurotransmission in observed behavioral improvements. Conclusions: These preliminary findings suggest the therapeutic potential of H3R antagonists in targeting neuroinflammation and autophagic disruption to improve ASD-like behaviors.
AB - Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social interaction difficulties, repetitive behaviors, and immune dysregulation with elevated pro-inflammatory markers. Autophagic deficiency also contributes to social behavior deficits in ASD. Histamine H3 receptor (H3R) antagonism is a potential treatment strategy for brain disorders with features overlapping ASD, such as schizophrenia and Alzheimer’s disease. Methods: This study investigated the effects of sub-chronic systemic treatment with the H3R antagonist E159 on social deficits, repetitive behaviors, neuroinflammation, and autophagic disruption in male BTBR mice. Results: E159 (2.5, 5, and 10 mg/kg, i.p.) improved stereotypic repetitive behavior by reducing self-grooming time and enhancing spontaneous alternation in addition to attenuating social deficits. It also decreased pro-inflammatory cytokines in the cerebellum and hippocampus of treated BTBR mice. In BTBR mice, reduced expression of autophagy-related proteins LC3A/B and Beclin 1 was observed, which was elevated following treatment with E159, attenuating the disruption in autophagy. The co-administration with the H3R agonist MHA (10 mg/kg, i.p.) reversed these effects, highlighting the role of histaminergic neurotransmission in observed behavioral improvements. Conclusions: These preliminary findings suggest the therapeutic potential of H3R antagonists in targeting neuroinflammation and autophagic disruption to improve ASD-like behaviors.
KW - BTBR mice
KW - H3 receptor antagonists
KW - autism spectrum disorder
KW - autophagy
KW - mTOR
KW - neuroinflammation
KW - repetitive behavior
KW - social features
UR - http://www.scopus.com/inward/record.url?scp=85207677438&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85207677438&partnerID=8YFLogxK
U2 - 10.3390/ph17101293
DO - 10.3390/ph17101293
M3 - Article
AN - SCOPUS:85207677438
SN - 1424-8247
VL - 17
JO - Pharmaceuticals
JF - Pharmaceuticals
IS - 10
M1 - 1293
ER -