Simultaneous Blockade of Histamine H<sub>3</sub> Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of Autism
Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder defined by persistent deficits in social interaction and the presence of patterns of repetitive and restricted behaviors. The central neurotransmitters histamine (HA) and acetylcholine (ACh) play pleiotropic roles in physio...
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| Format: | Article |
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MDPI AG
2020-08-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/9/1251 |
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| author | Nermin Eissa Petrilla Jayaprakash Holger Stark Dorota Łażewska Katarzyna Kieć-Kononowicz Bassem Sadek |
| author_facet | Nermin Eissa Petrilla Jayaprakash Holger Stark Dorota Łażewska Katarzyna Kieć-Kononowicz Bassem Sadek |
| author_sort | Nermin Eissa |
| collection | DOAJ |
| description | Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder defined by persistent deficits in social interaction and the presence of patterns of repetitive and restricted behaviors. The central neurotransmitters histamine (HA) and acetylcholine (ACh) play pleiotropic roles in physiological brain functions that include the maintenance of wakefulness, depression, schizophrenia, epilepsy, anxiety and narcolepsy, all of which are found to be comorbid with ASD. Therefore, the palliative effects of subchronic systemic treatment using the multiple-active test compound E100 with high H<sub>3</sub>R antagonist affinity and AChE inhibitory effect on ASD-like behaviors in male BTBR T+tf/J (BTBR) mice as an idiopathic ASD model were assessed. E100 (5, 10 and 15 mg/kg, i.p.) dose-dependently palliated social deficits of BTBR mice and significantly alleviated the repetitive/compulsive behaviors of tested animals. Moreover, E100 modulated disturbed anxiety levels, but failed to modulate hyperactivity parameters, whereas the reference AChE inhibitor donepezil (DOZ, one milligram per kilogram) significantly obliterated the increased hyperactivity measures of tested mice. Furthermore, E100 mitigated the increased levels of AChE activity in BTBR mice with observed effects comparable to that of DOZ and significantly reduced the number of activated microglial cells compared to the saline-treated BTBR mice. In addition, the E100-provided effects on ASD-like parameters, AChE activity, and activated microglial cells were entirely reversed by co-administration of the H<sub>3</sub>R agonist (<i>R</i>)-α-methylhistamine (RAM). These initial overall results observed in an idiopathic ASD mice model show that E100 (5 mg/kg) alleviated the assessed behavioral deficits and demonstrate that simultaneous targeting of brain histaminergic and cholinergic neurotransmissions is crucial for palliation of ASD-like features, albeit further in vivo assessments on its effects on brain levels of ACh as well as HA are still needed. |
| first_indexed | 2024-03-10T16:45:06Z |
| format | Article |
| id | doaj.art-a440167b3f204f0da88eb8efcf418c3d |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T16:45:06Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-a440167b3f204f0da88eb8efcf418c3d2023-11-20T11:42:32ZengMDPI AGBiomolecules2218-273X2020-08-01109125110.3390/biom10091251Simultaneous Blockade of Histamine H<sub>3</sub> Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of AutismNermin Eissa0Petrilla Jayaprakash1Holger Stark2Dorota Łażewska3Katarzyna Kieć-Kononowicz4Bassem Sadek5Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, UAEDepartment of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, UAEInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, GermanyDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University-Medical College, Medyczna 9 St., 30-688 Kraków, PolandDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University-Medical College, Medyczna 9 St., 30-688 Kraków, PolandDepartment of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, UAEAutism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder defined by persistent deficits in social interaction and the presence of patterns of repetitive and restricted behaviors. The central neurotransmitters histamine (HA) and acetylcholine (ACh) play pleiotropic roles in physiological brain functions that include the maintenance of wakefulness, depression, schizophrenia, epilepsy, anxiety and narcolepsy, all of which are found to be comorbid with ASD. Therefore, the palliative effects of subchronic systemic treatment using the multiple-active test compound E100 with high H<sub>3</sub>R antagonist affinity and AChE inhibitory effect on ASD-like behaviors in male BTBR T+tf/J (BTBR) mice as an idiopathic ASD model were assessed. E100 (5, 10 and 15 mg/kg, i.p.) dose-dependently palliated social deficits of BTBR mice and significantly alleviated the repetitive/compulsive behaviors of tested animals. Moreover, E100 modulated disturbed anxiety levels, but failed to modulate hyperactivity parameters, whereas the reference AChE inhibitor donepezil (DOZ, one milligram per kilogram) significantly obliterated the increased hyperactivity measures of tested mice. Furthermore, E100 mitigated the increased levels of AChE activity in BTBR mice with observed effects comparable to that of DOZ and significantly reduced the number of activated microglial cells compared to the saline-treated BTBR mice. In addition, the E100-provided effects on ASD-like parameters, AChE activity, and activated microglial cells were entirely reversed by co-administration of the H<sub>3</sub>R agonist (<i>R</i>)-α-methylhistamine (RAM). These initial overall results observed in an idiopathic ASD mice model show that E100 (5 mg/kg) alleviated the assessed behavioral deficits and demonstrate that simultaneous targeting of brain histaminergic and cholinergic neurotransmissions is crucial for palliation of ASD-like features, albeit further in vivo assessments on its effects on brain levels of ACh as well as HA are still needed.https://www.mdpi.com/2218-273X/10/9/1251autism spectrum disorderBTBR micehistaminehistamine H<sub>3</sub> receptor antagonistacetylcholineacetylcholine esterase inhibitor |
| spellingShingle | Nermin Eissa Petrilla Jayaprakash Holger Stark Dorota Łażewska Katarzyna Kieć-Kononowicz Bassem Sadek Simultaneous Blockade of Histamine H<sub>3</sub> Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of Autism Biomolecules autism spectrum disorder BTBR mice histamine histamine H<sub>3</sub> receptor antagonist acetylcholine acetylcholine esterase inhibitor |
| title | Simultaneous Blockade of Histamine H<sub>3</sub> Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of Autism |
| title_full | Simultaneous Blockade of Histamine H<sub>3</sub> Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of Autism |
| title_fullStr | Simultaneous Blockade of Histamine H<sub>3</sub> Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of Autism |
| title_full_unstemmed | Simultaneous Blockade of Histamine H<sub>3</sub> Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of Autism |
| title_short | Simultaneous Blockade of Histamine H<sub>3</sub> Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of Autism |
| title_sort | simultaneous blockade of histamine h sub 3 sub receptors and inhibition of acetylcholine esterase alleviate autistic like behaviors in btbr t tf j mouse model of autism |
| topic | autism spectrum disorder BTBR mice histamine histamine H<sub>3</sub> receptor antagonist acetylcholine acetylcholine esterase inhibitor |
| url | https://www.mdpi.com/2218-273X/10/9/1251 |
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