Cargando…

The Multi-Targeting Ligand ST-2223 with Histamine H(3) Receptor and Dopamine D(2)/D(3) Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the presen...

Descripción completa

Detalles Bibliográficos
Autores principales: Eissa, Nermin, Venkatachalam, Karthikkumar, Jayaprakash, Petrilla, Falkenstein, Markus, Dubiel, Mariam, Frank, Annika, Reiner-Link, David, Stark, Holger, Sadek, Bassem
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920280/
https://www.ncbi.nlm.nih.gov/pubmed/33669336
http://dx.doi.org/10.3390/ijms22041947
_version_ 1783658244674158592
author Eissa, Nermin
Venkatachalam, Karthikkumar
Jayaprakash, Petrilla
Falkenstein, Markus
Dubiel, Mariam
Frank, Annika
Reiner-Link, David
Stark, Holger
Sadek, Bassem
author_facet Eissa, Nermin
Venkatachalam, Karthikkumar
Jayaprakash, Petrilla
Falkenstein, Markus
Dubiel, Mariam
Frank, Annika
Reiner-Link, David
Stark, Holger
Sadek, Bassem
author_sort Eissa, Nermin
collection PubMed
description Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H(3) receptor (H(3)R) and dopamine D(2)/D(3) receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data.
format Online
Article
Text
id pubmed-7920280
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-79202802021-03-02 The Multi-Targeting Ligand ST-2223 with Histamine H(3) Receptor and Dopamine D(2)/D(3) Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice Eissa, Nermin Venkatachalam, Karthikkumar Jayaprakash, Petrilla Falkenstein, Markus Dubiel, Mariam Frank, Annika Reiner-Link, David Stark, Holger Sadek, Bassem Int J Mol Sci Article Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H(3) receptor (H(3)R) and dopamine D(2)/D(3) receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data. MDPI 2021-02-16 /pmc/articles/PMC7920280/ /pubmed/33669336 http://dx.doi.org/10.3390/ijms22041947 Text en © 2021 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Eissa, Nermin
Venkatachalam, Karthikkumar
Jayaprakash, Petrilla
Falkenstein, Markus
Dubiel, Mariam
Frank, Annika
Reiner-Link, David
Stark, Holger
Sadek, Bassem
The Multi-Targeting Ligand ST-2223 with Histamine H(3) Receptor and Dopamine D(2)/D(3) Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice
title The Multi-Targeting Ligand ST-2223 with Histamine H(3) Receptor and Dopamine D(2)/D(3) Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice
title_full The Multi-Targeting Ligand ST-2223 with Histamine H(3) Receptor and Dopamine D(2)/D(3) Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice
title_fullStr The Multi-Targeting Ligand ST-2223 with Histamine H(3) Receptor and Dopamine D(2)/D(3) Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice
title_full_unstemmed The Multi-Targeting Ligand ST-2223 with Histamine H(3) Receptor and Dopamine D(2)/D(3) Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice
title_short The Multi-Targeting Ligand ST-2223 with Histamine H(3) Receptor and Dopamine D(2)/D(3) Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice
title_sort multi-targeting ligand st-2223 with histamine h(3) receptor and dopamine d(2)/d(3) receptor antagonist properties mitigates autism-like repetitive behaviors and brain oxidative stress in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920280/
https://www.ncbi.nlm.nih.gov/pubmed/33669336
http://dx.doi.org/10.3390/ijms22041947
work_keys_str_mv AT eissanermin themultitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT venkatachalamkarthikkumar themultitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT jayaprakashpetrilla themultitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT falkensteinmarkus themultitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT dubielmariam themultitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT frankannika themultitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT reinerlinkdavid themultitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT starkholger themultitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT sadekbassem themultitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT eissanermin multitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT venkatachalamkarthikkumar multitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT jayaprakashpetrilla multitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT falkensteinmarkus multitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT dubielmariam multitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT frankannika multitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT reinerlinkdavid multitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT starkholger multitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice
AT sadekbassem multitargetingligandst2223withhistamineh3receptoranddopamined2d3receptorantagonistpropertiesmitigatesautismlikerepetitivebehaviorsandbrainoxidativestressinmice