{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T02:35:46Z","timestamp":1785465346911,"version":"3.56.0"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Behav. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory deficits. Mounting evidence highlights the role of cholinergic and histaminergic neurotransmissions in the pathophysiology of AD. Hence, developing agents that target multiple neurotransmitter systems may provide improved therapeutic benefits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study investigated the effects of acute systemic administration of E100, a dual-active cholinesterase inhibitor (ChEI) and histamine H3 receptor (H3R) antagonist, on scopolamine (SCO)-induced memory impairment in male C57BL\/6 mice. Behavioral assessments, including the Novel Object Recognition Test (NORT), Y-Maze test (YMT), Three-Chamber Test (TCT), Fear Conditioning test (FCT), and Elevated Plus Maze (EPM), were conducted to assess cognitive performance while biochemical analyses assessed apoptotic markers, oxidative stress, neuroinflammation and acetylcholinesterase activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Systemic administration of E100 (10 mg\/kg, i.p.) significantly improved memory function in SCO-induced amnesia, as evidenced by enhanced short-term memory (STM) (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001) and long-term memory (LTM) (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.01) performance in the NORT, as well as improved spatial memory in YMT (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001) and FCT (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001; for cued fear memory) and (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001; for contextual fear memory). Additionally, E100 treatment in the TCT, improved social memory (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001) and alleviated SCO-induced anxiety-related deficits in the EPM (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001). Moreover, treatment with E100 (10 mg\/kg, i.p.) attenuated SCO-induced neuroinflammation by reducing TNF-\u03b1 and IL-1\u03b2 levels and mitigated oxidative stress by increasing GSH and SOD while decreasing MDA levels in the hippocampus and cerebellum (\n                      <jats:italic>p<\/jats:italic>\n                      \u2019s &amp;lt; 0.001). E100 also reduced caspase-1 activity (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.001), suggesting its anti-apoptotic effect. Furthermore, E100 attenuated the elevated AChE activity observed in SCO-induced amnesic mice (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.01), providing effects comparable to those of the reference drug Donepezil.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These findings provide extensive\n                      <jats:italic>in vivo<\/jats:italic>\n                      evidence of the neuroprotective effects of E100, demonstrating its ability to ameliorate memory deficits, mitigate neuroinflammation and restore oxidative as well as AChE activity balance. By targeting both cholinergic and histaminergic dysfunction in the brain, E100 offers a promising therapeutic strategy for AD and related neurodegenerative disorders. This study highlights the potential role of dual-active ChEIs and H3R antagonists in memory impairment, and addressing multiple neuropathological mechanisms underlying AD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnbeh.2026.1722019","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T06:41:42Z","timestamp":1769668902000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Simultaneous inhibition of cholinesterase and antagonism of histamine H3 receptors alleviates cognitive deficits and mitigates apoptosis in scopolamine-induced amnesia in mice"],"prefix":"10.3389","volume":"20","author":[{"given":"Wajd","family":"Ebdah","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University","place":["Al Ain, United Arab Emirates"]},{"name":"Zayed Center for Health Sciences, United Arab Emirates University","place":["Al Ain, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilu Deepa","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University","place":["Al Ain, United Arab Emirates"]},{"name":"Zayed Center for Health Sciences, United Arab Emirates University","place":["Al Ain, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nermin","family":"Eissa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University","place":["Abu Dhabi, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petrilla","family":"Jayaprakash","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University","place":["Al Ain, United Arab Emirates"]},{"name":"Zayed Center for Health Sciences, United Arab Emirates University","place":["Al Ain, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"\u0141a\u017cewska","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University-Medical College","place":["Krak\u00f3w, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Kie\u0107-Kononowicz","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University-Medical College","place":["Krak\u00f3w, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassem","family":"Sadek","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University","place":["Al Ain, United Arab Emirates"]},{"name":"Zayed Center for Health Sciences, United Arab Emirates University","place":["Al Ain, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"12719","DOI":"10.3390\/ijms241612719","article-title":"The potent and selective histamine H3 receptor antagonist E169 counteracts cognitive deficits and mitigates disturbances in the PI3K\/AKT\/GSK-3\u03b2 signaling pathway in MK801-induced amnesia in mice.","volume":"24","author":"Abdalla","year":"2023","journal-title":"Int. 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