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Autophagic deficiency also contributes to social behavior deficits in ASD. Histamine H3 receptor (H3R) antagonism is a potential treatment strategy for brain disorders with features overlapping ASD, such as schizophrenia and Alzheimer\u2019s disease. Methods: This study investigated the effects of sub-chronic systemic treatment with the H3R antagonist E159 on social deficits, repetitive behaviors, neuroinflammation, and autophagic disruption in male BTBR mice. Results: E159 (2.5, 5, and 10 mg\/kg, i.p.) improved stereotypic repetitive behavior by reducing self-grooming time and enhancing spontaneous alternation in addition to attenuating social deficits. It also decreased pro-inflammatory cytokines in the cerebellum and hippocampus of treated BTBR mice. In BTBR mice, reduced expression of autophagy-related proteins LC3A\/B and Beclin 1 was observed, which was elevated following treatment with E159, attenuating the disruption in autophagy. The co-administration with the H3R agonist MHA (10 mg\/kg, i.p.) reversed these effects, highlighting the role of histaminergic neurotransmission in observed behavioral improvements. Conclusions: These preliminary findings suggest the therapeutic potential of H3R antagonists in targeting neuroinflammation and autophagic disruption to improve ASD-like behaviors.<\/jats:p>","DOI":"10.3390\/ph17101293","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T03:12:28Z","timestamp":1727665948000},"page":"1293","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Alleviation of Autophagic Deficits and Neuroinflammation by Histamine H3 Receptor Antagonist E159 Ameliorates Autism-Related Behaviors in BTBR Mice"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0778-8833","authenticated-orcid":false,"given":"Shilu Deepa","family":"Thomas","sequence":"first","affiliation":[{"name":"Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates"},{"name":"Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petrilla","family":"Jayaprakash","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates"},{"name":"Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nurfirzana Z. H. J.","family":"Marwan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates"},{"name":"Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezzatul A. B. A.","family":"Aziz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates"},{"name":"Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3077-5539","authenticated-orcid":false,"given":"Kamil","family":"Kuder","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8454-4440","authenticated-orcid":false,"given":"Dorota","family":"\u0141a\u017cewska","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6752-7443","authenticated-orcid":false,"given":"Katarzyna","family":"Kie\u0107-Kononowicz","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna Str. 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0320-1487","authenticated-orcid":false,"given":"Bassem","family":"Sadek","sequence":"additional","affiliation":[{"name":"Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 17666, United Arab Emirates"},{"name":"Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Thomas, S.D., Jha, N.K., Ojha, S., and Sadek, B. (2023). mTOR Signaling Disruption and Its Association with the Development of Autism Spectrum Disorder. Molecules, 28.","DOI":"10.3390\/molecules28041889"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s11689-019-9268-y","article-title":"Impaired Neurodevelopmental Pathways in Autism Spectrum Disorder: A Review of Signaling Mechanisms and Crosstalk","volume":"11","author":"Kumar","year":"2019","journal-title":"J. Neurodev. 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