The histamine H3R and dopamine D2R/D3R antagonist ST-713 ameliorates autism-like behavioral features in BTBR T+tf/J mice by multiple actions - 16/04/21
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Abstract |
Several brain neurotransmitters, including histamine (HA), acetylcholine (ACh), and dopamine (DA) are suggested to be involved in several brain disorders including cognitive deficits, depression, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with Autism spectrum disorder (ASD). Therefore, the ameliorative effects of the novel multiple-active compound ST-713 with high binding affinities at histamine H3 receptor (H3R), dopamine D2sR and D3R on ASD-like behaviors in male BTBR T+tf/J mice model were assessed. ST-713 (3-(2-chloro-10H-phenothiazin-10-yl)-N-methyl-N-(4-(3-(piperidin-1-yl)propoxy)benzyl)propan-1-amine; 2.5, 5, and 10 mg/kg, i.p.) ameliorated dose-dependently social deficits, and significantly alleviated the repetitive/compulsive behaviors of BTBR mice (all P < 0.05). Moreover, ST-713 modulated disturbed anxiety levels, but failed to obliterate increased hyperactivity of tested mice. Furthermore, ST-713 (5 mg/kg) attenuated the increased levels of hippocampal and cerebellar protein expressions of NF-κB p65, COX-2, and iNOS in BTBR mice (all P < 0.05). The ameliorative effects of ST-713 on social parameters were entirely reversed by co-administration of the H3R agonist (R)-α-methylhistamine or the anticholinergic drug scopolamine. The obtained results demonstrate the potential of multiple-active compounds for the therapeutic management of neuropsychiatric disorders, e.g. ASD.
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Highlights |
• | Effects of the multiple-active ligand ST-713 on ASD-like features were assessed. |
• | ST-713 provided ameliorative effects on social behaviors in BTBR mice. |
• | ST-713 mitigated neuroinflammation and stereo-typed repetitive behaviors. |
• | Simultaneous targeting of H3Rs and D2/D3R is important for amelioration of autistic features. |
Keywords : Autistic spectrum disorder, BTBR mice, Histamine H3 receptor antagonist, Dopamine D2/D3R antagonist, Stereotyped repetitive behavior, Neuroinflammation
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Vol 138
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