{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T13:30:32Z","timestamp":1783517432093,"version":"3.55.0"},"reference-count":73,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T00:00:00Z","timestamp":1621814400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002809","name":"Generalitat de Catalunya","doi-asserted-by":"publisher","award":["2018FI\u2010B\u201000227"],"award-info":[{"award-number":["2018FI\u2010B\u201000227"]}],"id":[{"id":"10.13039\/501100002809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005774","name":"Universitat de Barcelona","doi-asserted-by":"publisher","award":["UB2018"],"award-info":[{"award-number":["UB2018"]}],"id":[{"id":"10.13039\/501100005774","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005774","name":"Universitat de Barcelona","doi-asserted-by":"publisher","award":["UB2016"],"award-info":[{"award-number":["UB2016"]}],"id":[{"id":"10.13039\/501100005774","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010434","name":"\u201cla Caixa\u201d Foundation","doi-asserted-by":"publisher","award":["CI18\u201000002"],"award-info":[{"award-number":["CI18\u201000002"]}],"id":[{"id":"10.13039\/100010434","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003030","name":"Ag\u00e8ncia de Gesti\u00f3 d'Ajuts Universitaris i de Recerca","doi-asserted-by":"publisher","award":["2017SGR106"],"award-info":[{"award-number":["2017SGR106"]}],"id":[{"id":"10.13039\/501100003030","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2019\u2010106285RB\u2010I00"],"award-info":[{"award-number":["PID2019\u2010106285RB\u2010I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2019\u2010107991RB\u2010I00"],"award-info":[{"award-number":["PID2019\u2010107991RB\u2010I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>The development of effective therapeutic strategies against Alzheimer's disease (AD) remains a challenge. I<jats:sub>2<\/jats:sub> imidazoline receptor ligands have a neuroprotective role in AD. Moreover, co\u2010treatment of AChE inhibitors with neuroprotective agents have shown better effects on the prevention of dementia. Here, we assessed the potential therapeutic effect of the I<jats:sub>2<\/jats:sub> ligand, donepezil and their combination in 5XFAD mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>5XFAD female mice were treated with low doses (1\u2009mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>) of LSL60101, donepezil and donepezil plus LSL60101, during 4\u2009weeks per os. Novel object recognition, Morris water maze, open field, elevated plus maze and three\u2010chamber tests were used to evaluate the cognitive and behavioural status after treatment. The effects on AD\u2010like pathology were assessed with immunohistochemistry, western blot, ELISA and qPCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Chronic low\u2010dose treatment with LSL60101 and donepezil reversed cognitive deficits and impaired social behaviour. LSL60101 treatment did not affect anxiety\u2010like behaviour in contrast to donepezil. In the 5XFAD brains, LSL60101 and donepezil\/LSL60101 treatments attenuated amyloid\u2010\u03b2 pathology by decreasing amyloid\u2010\u03b2<jats:sub>40<\/jats:sub> and amyloid\u2010\u03b2<jats:sub>42<\/jats:sub> levels, amyloid\u2010\u03b2 plaque number and tau hyperphosphorylation. These alterations were accompanied by reduced microglia marker Iba\u20101 levels and increased <jats:italic>Trem2<\/jats:italic> gene expression. LSL60101 and donepezil decreased glial fibrillary acidic protein (GFAP) astrocytic marker reactivity. However, only LSL60101 and donepezil\/LSL60101 treatments significantly increased the synaptic marker levels of post\u2010synaptic density protein 95 and synaptophysin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Chronic low\u2010dose treatment with selective I<jats:sub>2<\/jats:sub>\u2010 ligands can be an effective treatment for AD and provide insights into combination treatments for symptomatic and disease\u2010modifying drugs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15478","type":"journal-article","created":{"date-parts":[[2021,4,5]],"date-time":"2021-04-05T08:28:57Z","timestamp":1617611337000},"page":"3017-3033","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Disease\u2010modifying treatment with I<sub>2<\/sub> imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: a comparative study with donepezil"],"prefix":"10.1111","volume":"178","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3656-7714","authenticated-orcid":false,"given":"Foteini","family":"Vasilopoulou","sequence":"first","affiliation":[{"name":"Pharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neuroci\u00e8ncies University of Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7400-0220","authenticated-orcid":false,"given":"Sergio","family":"Rodr\u00edguez\u2010Ar\u00e9valo","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB) University of Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Bag\u00e1n","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB) University of Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9117-8239","authenticated-orcid":false,"given":"Carmen","family":"Escolano","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB) University of Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5424-9130","authenticated-orcid":false,"given":"Christian","family":"Gri\u00f1\u00e1n\u2010Ferr\u00e9","sequence":"additional","affiliation":[{"name":"Pharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neuroci\u00e8ncies University of Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3095-4254","authenticated-orcid":false,"given":"Merc\u00e8","family":"Pall\u00e0s","sequence":"additional","affiliation":[{"name":"Pharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neuroci\u00e8ncies University of Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,5,24]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.6b00426"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b02080"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(00)00124-X"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(95)00214-6"},{"issue":"1","key":"e_1_2_13_6_1","first-page":"S1","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: Introduction and other protein targets","volume":"176","author":"Alexander S. P. H.","year":"2019","journal-title":"British Journal of Pharmacology"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-3472(73)80065-X"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4886(03)00252-8"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.2165\/00002512-200421010-00004"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0702031"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.118.016311"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703485"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics12030284"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.12050"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14153"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0333-5"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/0197-4580(92)90104-6"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2009.09.097"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166-4328(88)90157-X"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-003-1392-3"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-020-00928-w"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-180595"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881112450785"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(98)00265-1"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2008.143"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007679709322"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2016.03.014"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00224"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-018-00681-5"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0011-393X(03)00059-6"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43440-020-00148-5"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2010.02.003"},{"key":"e_1_2_13_35_1","first-page":"2897","article-title":"Effect of donepezil hydrochloride & aerobic exercise training on learning and memory and its mechanism of action in an Alzheimer's disease rat model","volume":"31","author":"Jiangbo N.","year":"2018","journal-title":"Pakistan Journal of Pharmaceutical Sciences"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2020.108354"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuro.2013.10.004"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2020.172976"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.0c00430"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-9-33"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.02.002"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15178"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/728983"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1995.tb32439.x"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnint.2013.00059"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15312"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(11)70156-9"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1202-06.2006"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1994.tb14842.x"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165975"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.490340611"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1999.tb09389.x"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2009.06.012"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-014-1250-1"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(93)90925-B"},{"key":"e_1_2_13_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703294"},{"key":"e_1_2_13_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2013.05.003"},{"key":"e_1_2_13_59_1","doi-asserted-by":"publisher","DOI":"10.2165\/00023210-200418130-00001"},{"key":"e_1_2_13_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2008.02.016"},{"key":"e_1_2_13_61_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006189"},{"key":"e_1_2_13_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2018.01.032"},{"key":"e_1_2_13_63_1","first-page":"233","article-title":"Cholinesterase inhibitors in Alzheimer's disease: Efficacy in a non\u2010selected population","volume":"18","author":"Sinforiani E.","year":"2003","journal-title":"Functional Neurology"},{"key":"e_1_2_13_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-47462-4"},{"key":"e_1_2_13_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2011.11.005"},{"key":"e_1_2_13_66_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics12050475"},{"key":"e_1_2_13_67_1","first-page":"27","article-title":"I2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway","author":"Vasilopoulou F.","year":"2020","journal-title":"GeroScience"},{"key":"e_1_2_13_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.44"},{"key":"e_1_2_13_69_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929866043407174"},{"key":"e_1_2_13_70_1","first-page":"1","article-title":"A novel targeted and high\u2010efficiency nanosystem for combinational therapy for Alzheimer's disease","volume":"7","author":"Yang H.","year":"2020","journal-title":"Advancement of Science"},{"key":"e_1_2_13_71_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2010-100681"},{"key":"e_1_2_13_72_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay6931"},{"key":"e_1_2_13_73_1","doi-asserted-by":"publisher","DOI":"10.2147\/NDT.S75546"},{"key":"e_1_2_13_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.01.031"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.15478","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bph.15478","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.15478","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T17:23:52Z","timestamp":1693329832000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.15478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,24]]},"references-count":73,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1111\/bph.15478"],"URL":"https:\/\/doi.org\/10.1111\/bph.15478","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,24]]},"assertion":[{"value":"2020-12-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}