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Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism

Altered regulation of neurotransmitters may lead to many pathophysiological changes in brain disorders including autism spectrum disorder (ASD). Given the fact that there are no FDA-approved effective treatments for the social deficits in ASD, the present study determined the effects of chronic syst...

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Autores principales: Eissa, Nermin, Venkatachalam, Karthikkumar, Jayaprakash, Petrilla, Yuvaraju, Priya, Falkenstein, Markus, Stark, Holger, Sadek, Bassem
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9414676/
https://www.ncbi.nlm.nih.gov/pubmed/36015079
http://dx.doi.org/10.3390/ph15080929
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author Eissa, Nermin
Venkatachalam, Karthikkumar
Jayaprakash, Petrilla
Yuvaraju, Priya
Falkenstein, Markus
Stark, Holger
Sadek, Bassem
author_facet Eissa, Nermin
Venkatachalam, Karthikkumar
Jayaprakash, Petrilla
Yuvaraju, Priya
Falkenstein, Markus
Stark, Holger
Sadek, Bassem
author_sort Eissa, Nermin
collection PubMed
description Altered regulation of neurotransmitters may lead to many pathophysiological changes in brain disorders including autism spectrum disorder (ASD). Given the fact that there are no FDA-approved effective treatments for the social deficits in ASD, the present study determined the effects of chronic systemic treatment of the novel multiple-active H(3)R/D(2)R/D(3)R receptor antagonist ST-2223 on ASD-related social deficits in a male Black and Tan Brachyury (BTBR) mice. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly and dose-dependently mitigated social deficits and disturbed anxiety levels of BTBR mice (p < 0.05) in comparison to the effects of aripiprazole (1 mg/kg, i.p.). Moreover, levels of monoaminergic neurotransmitters quantified by LC-MS/MS in four brain regions including the prefrontal cortex, cerebellum, striatum, and hippocampus unveiled significant elevation of histamine (HA) in the cerebellum and striatum; dopamine (DA) in the prefrontal cortex and striatum; as well as acetylcholine (ACh) in the prefrontal cortex, striatum, and hippocampus following ST-2223 (5 mg/kg) administration (all p < 0.05). These in vivo findings demonstrate the mitigating effects of a multiple-active H(3)R/D(2)R/D(3)R antagonist on social deficits of assessed BTBR mice, signifying its pharmacological potential to rescue core ASD-related behaviors and altered monoaminergic neurotransmitters. Further studies on neurochemical alterations in ASD are crucial to elucidate the early neurodevelopmental variations behind the core symptoms and heterogeneity of ASD, leading to new approaches for the future therapeutic management of ASD.
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spelling pubmed-94146762022-08-27 Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism Eissa, Nermin Venkatachalam, Karthikkumar Jayaprakash, Petrilla Yuvaraju, Priya Falkenstein, Markus Stark, Holger Sadek, Bassem Pharmaceuticals (Basel) Article Altered regulation of neurotransmitters may lead to many pathophysiological changes in brain disorders including autism spectrum disorder (ASD). Given the fact that there are no FDA-approved effective treatments for the social deficits in ASD, the present study determined the effects of chronic systemic treatment of the novel multiple-active H(3)R/D(2)R/D(3)R receptor antagonist ST-2223 on ASD-related social deficits in a male Black and Tan Brachyury (BTBR) mice. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly and dose-dependently mitigated social deficits and disturbed anxiety levels of BTBR mice (p < 0.05) in comparison to the effects of aripiprazole (1 mg/kg, i.p.). Moreover, levels of monoaminergic neurotransmitters quantified by LC-MS/MS in four brain regions including the prefrontal cortex, cerebellum, striatum, and hippocampus unveiled significant elevation of histamine (HA) in the cerebellum and striatum; dopamine (DA) in the prefrontal cortex and striatum; as well as acetylcholine (ACh) in the prefrontal cortex, striatum, and hippocampus following ST-2223 (5 mg/kg) administration (all p < 0.05). These in vivo findings demonstrate the mitigating effects of a multiple-active H(3)R/D(2)R/D(3)R antagonist on social deficits of assessed BTBR mice, signifying its pharmacological potential to rescue core ASD-related behaviors and altered monoaminergic neurotransmitters. Further studies on neurochemical alterations in ASD are crucial to elucidate the early neurodevelopmental variations behind the core symptoms and heterogeneity of ASD, leading to new approaches for the future therapeutic management of ASD. MDPI 2022-07-27 /pmc/articles/PMC9414676/ /pubmed/36015079 http://dx.doi.org/10.3390/ph15080929 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Eissa, Nermin
Venkatachalam, Karthikkumar
Jayaprakash, Petrilla
Yuvaraju, Priya
Falkenstein, Markus
Stark, Holger
Sadek, Bassem
Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism
title Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism
title_full Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism
title_fullStr Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism
title_full_unstemmed Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism
title_short Experimental Studies Indicate That ST-2223, the Antagonist of Histamine H3 and Dopamine D2/D3 Receptors, Restores Social Deficits and Neurotransmission Dysregulation in Mouse Model of Autism
title_sort experimental studies indicate that st-2223, the antagonist of histamine h3 and dopamine d2/d3 receptors, restores social deficits and neurotransmission dysregulation in mouse model of autism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9414676/
https://www.ncbi.nlm.nih.gov/pubmed/36015079
http://dx.doi.org/10.3390/ph15080929
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