TY - JOUR
T1 - The histamine H3R and dopamine D2R/D3R antagonist ST-713 ameliorates autism-like behavioral features in BTBR T+tf/J mice by multiple actions
AU - Venkatachalam, Karthikkumar
AU - Eissa, Nermin
AU - Awad, Mohamed Al
AU - Jayaprakash, Petrilla
AU - Zhong, Sicheng
AU - Stölting, Frauke
AU - Stark, Holger
AU - Sadek, Bassem
N1 - Funding Information:
The Office of Graduate Studies and Research of UAE University as well as Zayed-Center for Health Sciences are thanked for the support provided to BS with funds ( 31R233 and 31R244 ). The authors also acknowledge the partial support of DFG INST 208/664-1 FUGG and COST Actions CA15135 , CA18133 , and CA18240 , which were kindly provided to HS.
Funding Information:
The Office of Graduate Studies and Research of UAE University as well as Zayed-Center for Health Sciences are thanked for the support provided to BS with funds (31R233 and 31R244). The authors also acknowledge the partial support of DFG INST 208/664-1 FUGG and COST Actions CA15135, CA18133, and CA18240, which were kindly provided to HS.
Publisher Copyright:
© 2021 The Authors
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
KW - Autistic spectrum disorder
KW - BTBR mice
KW - Dopamine D2/D3R antagonist
KW - Histamine H3 receptor antagonist
KW - Neuroinflammation
KW - Stereotyped repetitive behavior
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U2 - 10.1016/j.biopha.2021.111517
DO - 10.1016/j.biopha.2021.111517
M3 - Article
C2 - 33773463
AN - SCOPUS:85103112591
SN - 0753-3322
VL - 138
JO - Biomedicine and Pharmacotherapy
JF - Biomedicine and Pharmacotherapy
M1 - 111517
ER -