{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T20:29:51Z","timestamp":1788640191658,"version":"build-2803163510"},"reference-count":78,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":71,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Misr University for Science & Technology"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurobiol"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Neuroinflammation is a critical aspect implicated in cognitive dysfunctions and neurodegenerative ailments such as Alzheimer\u2019s disease (AD). \u03b2-amyloid (A\u03b2) peptide deposits and alterations in behavior and memory are important contributors to neuro-inflammatory pathways. The renin-angiotensin system (RAS) and endocannabinoid system (ECS) play a vital role in the pathophysiology of AD. The aim of this study is to illuminate the ameliorative effect of the antihypertensive drug valsartan (VAL) against lipopolysaccharide (LPS)-induced AD and study the cross-talk between ECS and RAS. Thirty two male Swiss mice were randomly divided into 4 groups as follows: Normal control group; LPS group (250 \u00b5g\/kg; ip); valsartan groups (20 and 40 mg\/kg; po). All treatments continued daily with LPS for seven consecutive days. Neuroprotective effects exerted by VAL are emphasized by improving motor functions and enhancing animal performance via the activity cage and Y-maze behavioral tests respectively. VAL inhibited toll-like receptor 4 (TLR4), which in turn deactivated the tumor necrosis factor-\u03b1 (TNF-\u03b1)\/nuclear factor kappa-B (NF-\u03baB) inflammatory pathway together with a reduction of angiotensin-1 receptor (AT1R1) levels as compared to LPS-injected animals. Additionally, VAL improved neuronal and cognitive dysfunction by reducing acetylcholine esterase activity (AChE) by 73% and amyloid beta (A\u03b2 1\u201342) by 53%, along with an elevation in the expression of cannabinoid 1 receptor (CB1R). Moreover, VAL enhanced the expression of protein kinase B (AKT) and heme oxygenase-1 (HO-1) gene levels and consequently restored the antioxidant cellular defense mechanism. VAL ultimately combats against microglial activation, mitigates cognitive dysfunction, and halts the neurodegenerative perturbations of LPS via inhibiting A\u03b2 deposition, neuroinflammation, and RAS with stimulation of ECS.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s12035-026-05728-9","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T01:19:12Z","timestamp":1773364752000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Valsartan Mitigates LPS-Induced Neuroinflammation and Cognitive Deficits via Modulation of RAS\u2013ECS Crosstalk in Mice"],"prefix":"10.1007","volume":"63","author":[{"given":"Abeer","family":"Salama","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rania","family":"Elgohary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wessam H.","family":"Elesawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"5728_CR1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.796867","volume":"12","author":"J Xie","year":"2022","unstructured":"Xie J, Van Hoecke L, Vandenbroucke RE (2022) The impact of systemic inflammation on Alzheimer\u2019s disease pathology. Front Immunol 12:796867","journal-title":"Front Immunol"},{"issue":"1","key":"5728_CR2","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1515\/bmc-2016-0029","volume":"8","author":"M Bol\u00f3s","year":"2017","unstructured":"Bol\u00f3s M, Perea JR, Avila J (2017) Alzheimer\u2019s disease as an inflammatory disease. Biomol Concepts 8(1):37\u201343","journal-title":"Biomol Concepts"},{"issue":"1","key":"5728_CR3","doi-asserted-by":"publisher","DOI":"10.1186\/s13195-023-01337-z","volume":"15","author":"Q Ji","year":"2023","unstructured":"Ji Q, Yang Y, Xiong Y, Zhang YJ, Jiang J, Zhou LP et al (2023) Blockade of adenosine A2A receptors reverses early spatial memory defects in the APP\/PS1 mouse model of Alzheimer\u2019s disease by promoting synaptic plasticity of adult-born granule cells. Alzheimers Res Ther 15(1):187","journal-title":"Alzheimers Res Ther"},{"issue":"2","key":"5728_CR4","doi-asserted-by":"publisher","first-page":"53","DOI":"10.5535\/arm.22027","volume":"46","author":"JH Shin","year":"2022","unstructured":"Shin JH (2022) Dementia epidemiology fact sheet 2022. Ann Rehabil Med 46(2):53\u201359","journal-title":"Ann Rehabil Med"},{"issue":"10284","key":"5728_CR5","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","volume":"397","author":"P Scheltens","year":"2021","unstructured":"Scheltens P, De Strooper B, Kivipelto M, Holstege H, Ch\u00e9telat G, Teunissen CE et al (2021) Alzheimer\u2019s disease. Lancet 397(10284):1577\u20131590","journal-title":"Lancet"},{"key":"5728_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13024-020-00391-7","volume":"15","author":"T Guo","year":"2020","unstructured":"Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y (2020) Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer\u2019s disease. Mol neurodegener 15:1\u201337","journal-title":"Mol neurodegener"},{"key":"5728_CR7","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.clinbiochem.2019.04.001","volume":"72","author":"T Ozben","year":"2019","unstructured":"Ozben T, Ozben S (2019) Neuro-inflammation and anti-inflammatory treatment options for Alzheimer\u2019s disease. Clin Biochem 72:87\u201389","journal-title":"Clin Biochem"},{"issue":"729","key":"5728_CR8","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abg8744","volume":"15","author":"X Liu","year":"2022","unstructured":"Liu X, Wei L, Xu F, Zhao F, Huang Y, Fan Z et al (2022) SARS-CoV-2 spike protein\u2013induced cell fusion activates the cGAS-STING pathway and the interferon response. Sci Signal 15(729):eabg8744","journal-title":"Sci Signal"},{"key":"5728_CR9","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.ejphar.2016.11.051","volume":"795","author":"M Zarezadeh","year":"2017","unstructured":"Zarezadeh M, Baluchnejadmojarad T, Kiasalari Z, Afshin-Majd S, Roghani M (2017) Garlic active constituent s-allyl cysteine protects against lipopolysaccharide-induced cognitive deficits in the rat: possible involved mechanisms. Eur J Pharmacol 795:13\u201321","journal-title":"Eur J Pharmacol"},{"issue":"3","key":"5728_CR10","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1111\/jnc.13411","volume":"136","author":"MR Minter","year":"2016","unstructured":"Minter MR, Taylor JM, Crack PJ (2016) The contribution of neuroinflammation to amyloid toxicity in Alzheimer\u2019s disease. J Neurochem 136(3):457\u2013474","journal-title":"J Neurochem"},{"key":"5728_CR11","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.bbi.2021.06.014","volume":"97","author":"E Dom\u00ednguez-Rivas","year":"2021","unstructured":"Dom\u00ednguez-Rivas E, \u00c1vila-Mu\u00f1oz E, Schwarzacher SW, Zepeda A (2021) Adult hippocampal neurogenesis in the context of lipopolysaccharide-induced neuroinflammation: a molecular, cellular and behavioral review. Brain Behav Immun 97:286\u2013302","journal-title":"Brain Behav Immun"},{"issue":"9","key":"5728_CR12","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20092293","volume":"20","author":"CRA Batista","year":"2019","unstructured":"Batista CRA, Gomes GF, Candelario-Jalil E, Fiebich BL, de Oliveira ACP (2019) Lipopolysaccharide-induced neuroinflammation as a bridge to understand neurodegeneration. Int J Mol Sci 20(9):2293","journal-title":"Int J Mol Sci"},{"key":"5728_CR13","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1007\/s11064-016-2171-y","volume":"42","author":"Y Jin","year":"2017","unstructured":"Jin Y, Peng J, Wang X, Zhang D, Wang T (2017) Ameliorative effect of ginsenoside Rg1 on lipopolysaccharide-induced cognitive impairment: role of cholinergic system. Neurochem Res 42:1299\u20131307","journal-title":"Neurochem Res"},{"issue":"9","key":"5728_CR14","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1038\/hr.2013.51","volume":"36","author":"S Yagi","year":"2013","unstructured":"Yagi S, Akaike M, Ise T, Ueda Y, Iwase T, Sata M (2013) Renin\u2013angiotensin\u2013aldosterone system has a pivotal role in cognitive impairment. Hypertens Res 36(9):753\u2013758","journal-title":"Hypertens Res"},{"key":"5728_CR15","doi-asserted-by":"publisher","first-page":"2253","DOI":"10.2741\/2839","volume":"13","author":"S Takeda","year":"2008","unstructured":"Takeda S, Sato N, Ogihara T, Morishita R (2008) The renin-angiotensin system, hypertension and cognitive dysfunction in Alzheimer\u2019s disease: new therapeutic potential. Front Biosci 13:2253\u20132265","journal-title":"Front Biosci"},{"issue":"3","key":"5728_CR16","doi-asserted-by":"publisher","first-page":"943","DOI":"10.3233\/JAD-215231","volume":"85","author":"S Tran","year":"2022","unstructured":"Tran S, Kuruppu S, Rajapakse NW (2022) Chronic renin-angiotensin system activation induced neuroinflammation: common mechanisms underlying hypertension and dementia? J Alzheimers Dis 85(3):943\u2013955","journal-title":"J Alzheimers Dis"},{"issue":"4","key":"5728_CR17","doi-asserted-by":"publisher","first-page":"531","DOI":"10.15171\/apb.2016.067","volume":"6","author":"YA Abbassi","year":"2016","unstructured":"Abbassi YA, Mohammadi MT, Foroshani MS, Sarshoori JR (2016) Captopril and valsartan may improve cognitive function through potentiation of the brain antioxidant defense system and attenuation of oxidative\/nitrosative damage in STZ-induced dementia in rat. Adv Pharm Bull 6(4):531\u2013539","journal-title":"Adv Pharm Bull"},{"issue":"4","key":"5728_CR18","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1093\/gerona\/glab376","volume":"77","author":"C Cosarderelioglu","year":"2022","unstructured":"Cosarderelioglu C, Nidadavolu LS, George CJ, Marx-Rattner R, Powell L, Xue QL et al (2022) Higher angiotensin II type 1 receptor levels and activity in the postmortem brains of older persons with Alzheimer\u2019s dementia. J Gerontol A Biol Sci Med Sci 77(4):664\u2013672","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"7","key":"5728_CR19","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1177\/1753944718773690","volume":"12","author":"VM Mart\u00edn Gim\u00e9nez","year":"2018","unstructured":"Mart\u00edn Gim\u00e9nez VM, Noriega SE, Kassuha DE, Fuentes LB, Manucha W (2018) Anandamide and endocannabinoid system: an attractive therapeutic approach for cardiovascular disease. Ther Adv Cardiovasc Dis 12(7):177\u2013190","journal-title":"Ther Adv Cardiovasc Dis"},{"issue":"23","key":"5728_CR20","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242316728","volume":"24","author":"B Bietar","year":"2023","unstructured":"Bietar B, Tanner S, Lehmann C (2023) Neuroprotection and beyond: the central role of CB1 and CB2 receptors in stroke recovery. Int J Mol Sci 24(23):16728","journal-title":"Int J Mol Sci"},{"issue":"3","key":"5728_CR21","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1074\/jbc.M109.069294","volume":"285","author":"E Kozela","year":"2010","unstructured":"Kozela E, Pietr M, Juknat A, Rimmerman N, Levy R, Vogel Z (2010) Cannabinoids \u03949-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-\u03baB and interferon-\u03b2\/STAT proinflammatory pathways in BV-2 microglial cells. J Biol Chem 285(3):1616\u20131626","journal-title":"J Biol Chem"},{"issue":"5","key":"5728_CR22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0155823","volume":"11","author":"N Torika","year":"2016","unstructured":"Torika N, Asraf K, Danon A, Apte RN, Fleisher-Berkovich S (2016) Telmisartan modulates glial activation: in vitro and in vivo studies. PLoS One 11(5):e0155823","journal-title":"PLoS One"},{"key":"5728_CR23","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00037","volume":"5","author":"E Aso","year":"2014","unstructured":"Aso E, Ferrer I (2014) Cannabinoids for treatment of Alzheimer\u2019s disease: moving toward the clinic. Front Pharmacol 5:37","journal-title":"Front Pharmacol"},{"key":"5728_CR24","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.neuropharm.2017.01.025","volume":"117","author":"YE Kim","year":"2017","unstructured":"Kim YE, Hwang CJ, Lee HP, Kim CS, Son DJ, Ham YW et al (2017) Inhibitory effect of punicalagin on lipopolysaccharide-induced neuroinflammation, oxidative stress and memory impairment via inhibition of nuclear factor-kappaB. Neuropharmacology 117:21\u201332","journal-title":"Neuropharmacology"},{"issue":"11","key":"5728_CR25","doi-asserted-by":"publisher","first-page":"3393","DOI":"10.1172\/JCI31547","volume":"117","author":"J Wang","year":"2007","unstructured":"Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X et al (2007) Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J Clin Invest 117(11):3393\u20133402","journal-title":"J Clin Invest"},{"issue":"3","key":"5728_CR26","doi-asserted-by":"publisher","DOI":"10.3390\/molecules28031354","volume":"28","author":"E-S Khafagy","year":"2023","unstructured":"Khafagy E-S, Soliman GA, Shahba A-W et al (2023) Brain targeting by intranasal drug delivery: effect of different formulations of the biflavone \u201ccupressuflavone\u201d from Juniperus sabina L. on the motor activity of rats. Molecules 28(3):1354","journal-title":"Molecules"},{"key":"5728_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.107867","volume":"101","author":"A Salama","year":"2021","unstructured":"Salama A, Elgohary R (2021) L-carnitine and Co Q10 ameliorate potassium dichromate -induced acute brain injury in rats targeting AMPK\/AKT\/NF-\u03ba\u03b2. Int Immunopharmacol 101:107867","journal-title":"Int Immunopharmacol"},{"issue":"4","key":"5728_CR28","first-page":"269","volume":"65","author":"N Hidaka","year":"2011","unstructured":"Hidaka N, Suemaru K, Takechi K, Li B, Araki H (2011) Inhibitory effects of valproate on impairment of Y-maze alternation behavior induced by repeated electroconvulsive seizures and c-Fos protein levels in rat brains. Acta Med Okayama 65(4):269\u2013277","journal-title":"Acta Med Okayama"},{"key":"5728_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1742-2094-8-153","volume":"8","author":"M Miwa","year":"2011","unstructured":"Miwa M, Tsuboi M, Noguchi Y, Enokishima A, Nabeshima T, Hiramatsu M (2011) Effects of betaine on lipopolysaccharide-induced memory impairment in mice and the involvement of GABA transporter 2. J Neuroinflammation 8:1\u201313","journal-title":"J Neuroinflammation"},{"issue":"2","key":"5728_CR30","doi-asserted-by":"publisher","first-page":"153","DOI":"10.4103\/1735-5362.335174","volume":"17","author":"AAA Salama","year":"2022","unstructured":"Salama AAA, Mostafa RE, Elgohary R (2022) Effect of L-carnitine on potassium dichromate-induced nephrotoxicity in rats: modulation of PI3K\/AKT signaling pathway. Res Pharm Sci 17(2):153\u2013163","journal-title":"Res Pharm Sci"},{"issue":"4","key":"5728_CR31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0283779","volume":"18","author":"FK El-Baz","year":"2023","unstructured":"El-Baz FK, Ali SI, Elgohary R, Salama A (2023) Natural \u03b2-carotene prevents acute lung injury induced by cyclophosphamide in mice. PLoS One 18(4):e0283779","journal-title":"PLoS One"},{"issue":"6","key":"5728_CR32","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2021.e07207","volume":"7","author":"A Salama","year":"2021","unstructured":"Salama A, Fayed HM, Elgohary R (2021) L-carnitine alleviated acute lung injuries induced by potassium dichromate in rats: involvement of Nrf2\/HO-1 signaling pathway. Heliyon 7(6):e07207","journal-title":"Heliyon"},{"issue":"9","key":"5728_CR33","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15092290","volume":"15","author":"DC Ababei","year":"2023","unstructured":"Ababei DC, Bild V, Macadan I, Vasincu A, Rusu RN, Blaj M et al (2023) Therapeutic implications of renin\u2013angiotensin system modulators in Alzheimer\u2019s dementia. Pharmaceutics 15(9):2290","journal-title":"Pharmaceutics"},{"key":"5728_CR34","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.bbi.2022.12.013","volume":"108","author":"EB Engler-Chiurazzi","year":"2023","unstructured":"Engler-Chiurazzi EB, Russell AE, Povroznik JM, McDonald KO, Porter KN, Wang DS et al (2023) Intermittent systemic exposure to lipopolysaccharide-induced inflammation disrupts hippocampal long-term potentiation and impairs cognition in aging male mice. Brain Behav Immun 108:279\u2013291","journal-title":"Brain Behav Immun"},{"key":"5728_CR35","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2023.115411","volume":"209","author":"X Wang","year":"2023","unstructured":"Wang X, Li Z, Li X, Liu X, YingMao CF, Zhu X, Zhang J (2023) Integrated metabolomics and transcriptomics reveal the neuroprotective effect of nervonic acid on LPS-induced AD model mice. Biochem Pharmacol 209:115411","journal-title":"Biochem Pharmacol"},{"key":"5728_CR36","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/978-1-4939-8994-2_10","volume":"1916","author":"AK Kraeuter","year":"2019","unstructured":"Kraeuter AK, Guest PC, Sarnyai Z (2019) The Y-maze for assessment of spatial working and reference memory in mice. Methods Mol Biol 1916:105\u2013111","journal-title":"Methods Mol Biol"},{"issue":"1","key":"5728_CR37","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/4183670","volume":"2018","author":"B Lee","year":"2018","unstructured":"Lee B, Shim I, Lee H (2018) Gypenosides attenuate lipopolysaccharide-induced neuroinflammation and memory impairment in rats. Evid Based Complement Alternat Med 2018(1):4183670","journal-title":"Evid Based Complement Alternat Med"},{"issue":"10","key":"5728_CR38","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1517\/13543784.2013.812631","volume":"22","author":"EL Ashby","year":"2013","unstructured":"Ashby EL, Kehoe PG (2013) Current status of renin\u2013aldosterone angiotensin system-targeting anti-hypertensive drugs as therapeutic options for Alzheimer\u2019s disease. Expert Opin Investig Drugs 22(10):1229\u20131242","journal-title":"Expert Opin Investig Drugs"},{"issue":"2","key":"5728_CR39","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1177\/1470320312459977","volume":"14","author":"B Singh","year":"2013","unstructured":"Singh B, Sharma B, Jaggi AS, Singh N (2013) Attenuating effect of lisinopril and telmisartan in intracerebroventricular streptozotocin induced experimental dementia of Alzheimer\u2019s disease type: possible involvement of PPAR-gamma agonistic property. J Renin Angiotensin Aldosterone Syst 14(2):124\u2013136","journal-title":"J Renin Angiotensin Aldosterone Syst"},{"issue":"1","key":"5728_CR40","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.jneuroim.2008.08.015","volume":"205","author":"E Tyagi","year":"2008","unstructured":"Tyagi E, Agrawal R, Nath C, Shukla R (2008) Influence of LPS-induced neuroinflammation on acetylcholinesterase activity in rat brain. J Neuroimmunol 205(1):51\u201356","journal-title":"J Neuroimmunol"},{"issue":"11","key":"5728_CR41","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1038\/s41401-018-0206-4","volume":"40","author":"X Cui","year":"2019","unstructured":"Cui X, Guo Y-E, Fang J-H, Shi C-J, Suo N, Zhang R, Xie X (2019) Donepezil, a drug for Alzheimer\u2019s disease, promotes oligodendrocyte generation and remyelination. Acta Pharmacol Sin 40(11):1386\u20131393","journal-title":"Acta Pharmacol Sin"},{"key":"5728_CR42","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.ejphar.2016.06.053","volume":"789","author":"M Arikawa","year":"2016","unstructured":"Arikawa M, Kakinuma Y, Noguchi T, Todaka H, Sato T (2016) Donepezil, an acetylcholinesterase inhibitor, attenuates LPS-induced inflammatory response in murine macrophage cell line RAW 264.7 through inhibition of nuclear factor kappa B translocation. Eur J Pharmacol 789:17\u201326","journal-title":"Eur J Pharmacol"},{"issue":"11","key":"5728_CR43","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1016\/j.apmr.2010.05.017","volume":"91","author":"DK Menon","year":"2010","unstructured":"Menon DK, Schwab K, Wright DW et al (2010) Position statement: definition of traumatic brain injury. Arch Phys Med Rehabil 91(11):1637\u20131640","journal-title":"Arch Phys Med Rehabil"},{"issue":"2","key":"5728_CR44","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.molimm.2014.06.037","volume":"63","author":"A Broggi","year":"2015","unstructured":"Broggi A, Granucci F (2015) Microbe- and danger-induced inflammation. Mol Immunol 63(2):127\u2013133","journal-title":"Mol Immunol"},{"key":"5728_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2023.175809","volume":"953","author":"D Gao","year":"2023","unstructured":"Gao D, Hao J, Li B, Zheng C, Miao B, Zhang L et al (2023) Tetrahydroxy stilbene glycoside ameliorates neuroinflammation for Alzheimer\u2019s disease via cGAS-STING. Eur J Pharmacol 953:175809","journal-title":"Eur J Pharmacol"},{"key":"5728_CR46","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111579","volume":"139","author":"A Saviano","year":"2021","unstructured":"Saviano A, Casillo GM, Raucci F, Pernice A, Santarcangelo C, Piccolo M, Ferraro MG, Ciccone M, et al. (2021) Supplementation with ribonucleotide-based ingredient (Ribodiet\u00ae) lessens oxidative stress, brain inflammation, and amyloid pathology in a murine model of Alzheimer. Biomed Pharmacother 139:111579","journal-title":"Biomed Pharmacother"},{"issue":"04","key":"5728_CR47","first-page":"125","volume":"14","author":"NS Mahmoud","year":"2024","unstructured":"Mahmoud NS, Elbaset MA, Mohawed OA, Ahmed HH (2024) Trimetazidine attenuates neuroinflammation via TLR4\/NF-KB pathway inhibition in lipopolysaccharides-induced dementia in rats. J Appl Pharm Sci 14(04):125\u2013142","journal-title":"J Appl Pharm Sci"},{"issue":"9","key":"5728_CR48","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1038\/nrd3505","volume":"10","author":"E Karran","year":"2011","unstructured":"Karran E, Mercken M, Strooper BD (2011) The amyloid cascade hypothesis for Alzheimer\u2019s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698\u2013712","journal-title":"Nat Rev Drug Discov"},{"issue":"4","key":"5728_CR49","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.3233\/JAD-171160","volume":"63","author":"J Miron","year":"2018","unstructured":"Miron J, Picard C, Frappier J, Dea D, Th\u00e9roux L, Poirier J (2018) TLR4 gene expression and pro-inflammatory cytokines in Alzheimer\u2019s disease and in response to hippocampal deafferentation in rodents. J Alzheimers Dis 63(4):1547\u20131556","journal-title":"J Alzheimers Dis"},{"issue":"8","key":"5728_CR50","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2619-5","volume":"11","author":"IJ Yeo","year":"2020","unstructured":"Yeo IJ, Yun J, Son DJ, Han SB, Hong JT (2020) Antifungal drug miconazole ameliorated memory deficits in a mouse model of LPS-induced memory loss through targeting iNOS. Cell Death Dis 11(8):623","journal-title":"Cell Death Dis"},{"key":"5728_CR51","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2021.105221","volume":"152","author":"M Cai","year":"2022","unstructured":"Cai M, Zhuang W, Lv E, Liu Z, Wang Y, Zhang W et al (2022) Kaemperfol alleviates pyroptosis and microglia-mediated neuroinflammation in Parkinson\u2019s disease via inhibiting p38MAPK\/NF-\u03baB signaling pathway. Neurochem Int 152:105221","journal-title":"Neurochem Int"},{"issue":"2","key":"5728_CR52","doi-asserted-by":"publisher","first-page":"H853","DOI":"10.1152\/ajpheart.00737.2007","volume":"294","author":"J Varagic","year":"2008","unstructured":"Varagic J, Frohlich ED, Susic D, Ahn J, Matavelli L, L\u00f3pez B, D\u00edez J (2008) AT1 receptor antagonism attenuates target organ effects of salt excess in SHRs without affecting pressure. Am J Physiol Heart Circ Physiol 294(2):H853\u2013H858","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"2","key":"5728_CR53","doi-asserted-by":"publisher","first-page":"1360","DOI":"10.3892\/mmr.2017.6706","volume":"16","author":"Y Lu","year":"2017","unstructured":"Lu Y, Guo H, Sun Y, Pan X, Dong J, Gao D, Chen W, Xu Y, et al. (2017) Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents. Mol Med Rep 16(2):1360\u20131368","journal-title":"Mol Med Rep"},{"issue":"1","key":"5728_CR54","doi-asserted-by":"publisher","first-page":"28","DOI":"10.4161\/adip.21837","volume":"2","author":"M Iwashita","year":"2013","unstructured":"Iwashita M, Nakatsu Y, Sakoda H, Fujishiro M, Kushiyama A, Fukushima T, Kumamoto S, Shinjo T, et al. (2013) Valsartan restores inflammatory response by macrophages in adipose and hepatic tissues of LPS-infused mice. Adipocyte 2(1):28\u201332","journal-title":"Adipocyte"},{"issue":"3","key":"5728_CR55","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1080\/08923973.2018.1431924","volume":"40","author":"H Mojiri-Forushani","year":"2018","unstructured":"Mojiri-Forushani H, Hemmati AA, Khodadadi A, Rashno M (2018) Valsartan attenuates bleomycin-induced pulmonary fibrosis by inhibition of NF-\u03baB expression and regulation of Th1\/Th2 cytokines. Immunopharmacol Immunotoxicol 40(3):225\u2013231","journal-title":"Immunopharmacol Immunotoxicol"},{"key":"5728_CR56","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.727838","volume":"12","author":"W Liang","year":"2021","unstructured":"Liang W, Xie BK, Ding PW, Wang M, Yuan J, Cheng X, Liao YH, Yu M (2021) Sacubitril\/valsartan alleviates experimental autoimmune myocarditis by inhibiting Th17 cell differentiation independently of the NLRP3 inflammasome pathway. Front Pharmacol 12:727838","journal-title":"Front Pharmacol"},{"issue":"1","key":"5728_CR57","doi-asserted-by":"publisher","first-page":"5","DOI":"10.18097\/pbmc20135901005","volume":"59","author":"E Kugaevskaya","year":"2013","unstructured":"Kugaevskaya E (2013) Angiotensin converting enzyme and Alzheimer\u2019s disease. Biomed Khim 59(1):5\u201324","journal-title":"Biomed Khim"},{"issue":"3","key":"5728_CR58","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1016\/j.sjbs.2020.01.026","volume":"27","author":"OA Abiodun","year":"2020","unstructured":"Abiodun OA, Ola MS (2020) Role of brain renin angiotensin system in neurodegeneration: an update. Saudi J Biol Sci 27(3):905\u2013912","journal-title":"Saudi J Biol Sci"},{"key":"5728_CR59","doi-asserted-by":"publisher","DOI":"10.1177\/03946320231161469","volume":"37","author":"AS El-Din Hussein","year":"2023","unstructured":"El-Din Hussein AS, Abou-El Nour RKE, Khorshid OA, Osman AS (2023) Study of the possible effect of sacubitril\/valsartan combination versus valsartan on the cognitive function in Alzheimer\u2019s disease model in rats. Int J Immunopathol Pharmacol 37:3946320231161469","journal-title":"Int J Immunopathol Pharmacol"},{"issue":"3","key":"5728_CR60","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/j.bbrc.2008.08.032","volume":"375","author":"M Mogi","year":"2008","unstructured":"Mogi M, Li JM, Tsukuda K, Iwanami J, Min LJ, Sakata A et al (2008) Telmisartan prevented cognitive decline partly due to PPAR-\u03b3 activation. Biochem Biophys Res Commun 375(3):446\u2013449","journal-title":"Biochem Biophys Res Commun"},{"issue":"3","key":"5728_CR61","doi-asserted-by":"publisher","first-page":"495","DOI":"10.3233\/JAD-2008-15315","volume":"15","author":"J Koppel","year":"2008","unstructured":"Koppel J, Davies P (2008) Targeting the endocannabinoid system in Alzheimer\u2019s disease. J Alzheimers Dis 15(3):495\u2013504","journal-title":"J Alzheimers Dis"},{"issue":"3","key":"5728_CR62","doi-asserted-by":"publisher","first-page":"715","DOI":"10.2174\/1570159X20666220201091006","volume":"21","author":"S Li","year":"2023","unstructured":"Li S, Huang Y, Yu L, Ji X, Wu J (2023) Impact of the cannabinoid system in Alzheimer\u2019s disease. Curr Neuropharmacol 21(3):715\u2013726","journal-title":"Curr Neuropharmacol"},{"issue":"1","key":"5728_CR63","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41582-019-0284-z","volume":"16","author":"L Cristino","year":"2020","unstructured":"Cristino L, Bisogno T, Di Marzo V (2020) Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol 16(1):9\u201329","journal-title":"Nat Rev Neurol"},{"issue":"8","key":"5728_CR64","doi-asserted-by":"publisher","first-page":"2987","DOI":"10.1523\/JNEUROSCI.19-08-02987.1999","volume":"19","author":"T Nagayama","year":"1999","unstructured":"Nagayama T, Sinor AD, Simon RP, Chen J, Graham SH, Jin K et al (1999) Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci 19(8):2987\u20132995","journal-title":"J Neurosci"},{"issue":"6855","key":"5728_CR65","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/35097089","volume":"413","author":"D Panikashvili","year":"2001","unstructured":"Panikashvili D, Simeonidou C, Ben-Shabat S, Hanu\u0161 L, Breuer A, Mechoulam R et al (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413(6855):527\u2013531","journal-title":"Nature"},{"issue":"17","key":"5728_CR66","doi-asserted-by":"publisher","first-page":"6475","DOI":"10.1523\/JNEUROSCI.21-17-06475.2001","volume":"21","author":"M Van der Stelt","year":"2001","unstructured":"Van der Stelt M, Veldhuis W, B\u00e4r P, Veldink G, Vliegenthart J, Nicolay K (2001) Neuroprotection by \u03949-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. J Neurosci 21(17):6475\u20136479","journal-title":"J Neurosci"},{"issue":"1","key":"5728_CR67","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1007\/s12035-021-02611-7","volume":"59","author":"M Kumar","year":"2022","unstructured":"Kumar M, Bansal N (2022) Implications of phosphoinositide 3-kinase-akt (PI3K-Akt) pathway in the pathogenesis of Alzheimer\u2019s disease. Mol Neurobiol 59(1):354\u2013385","journal-title":"Mol Neurobiol"},{"issue":"1","key":"5728_CR68","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/9364364","volume":"2018","author":"M Tanaka","year":"2018","unstructured":"Tanaka M, Kishimoto Y, Sasaki M, Sato A, Kamiya T, Iida K, Kondo K (2018) Terminalia bellirica (Gaertn.) Roxb. extract and gallic acid attenuate LPS-induced inflammation and oxidative stress via MAPK\/NF-kappaB and Akt\/AMPK\/Nrf2 pathways. Oxid Med Cell Longev 2018(1):9364364","journal-title":"Oxid Med Cell Longev"},{"key":"5728_CR69","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.111471","volume":"128","author":"F Gouveia","year":"2024","unstructured":"Gouveia F, Fonseca C, Silva A, Camins A, Cruz MT, Ettcheto M, Fortuna A (2024) Intranasal irbesartan reverts cognitive decline and activates the PI3K\/AKT pathway in an LPS-induced neuroinflammation mice model. Int Immunopharmacol 128:111471","journal-title":"Int Immunopharmacol"},{"issue":"1","key":"5728_CR70","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1021\/acsomega.0c03655","volume":"6","author":"Q Dong","year":"2020","unstructured":"Dong Q, Li Y, Chen J, Wang N (2020) Azilsartan suppressed LPS-induced inflammation in U937 macrophages through suppressing oxidative stress and inhibiting the TLR2\/MyD88 signal pathway. ACS Omega 6(1):113\u2013118","journal-title":"ACS Omega"},{"key":"5728_CR71","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.109166","volume":"117","author":"WB Zhang","year":"2019","unstructured":"Zhang WB, Yang F, Wang Y, Jiao FZ, Zhang HY, Wang LW, Gong ZJ (2019) Inhibition of HDAC6 attenuates LPS induced inflammation in macrophages by regulating oxidative stress and suppressing the TLR4-MAPK\/NF-kappaB pathways. Biomed Pharmacother 117:109166","journal-title":"Biomed Pharmacother"},{"key":"5728_CR72","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.ijbiomac.2022.12.071","volume":"227","author":"L Bai","year":"2023","unstructured":"Bai L, Tan C, Ren J, Liu J, Zou W, Liu G, Sheng Y (2023) Cordyceps militaris acidic polysaccharides improve learning and memory impairment in mice with exercise fatigue through the PI3K\/NRF2\/HO-1 signalling pathway. Int J Biol Macromol 227:158\u2013172","journal-title":"Int J Biol Macromol"},{"issue":"8","key":"5728_CR73","doi-asserted-by":"publisher","first-page":"1904","DOI":"10.1523\/JNEUROSCI.4540-04.2005","volume":"25","author":"BG Ram\u00edrez","year":"2005","unstructured":"Ram\u00edrez BG, Bl\u00e1zquez C, Del Pulgar TG, Guzm\u00e1n M, de Ceballos ML (2005) Prevention of Alzheimer\u2019s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 25(8):1904\u20131913","journal-title":"J Neurosci"},{"issue":"3","key":"5728_CR74","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10030440","volume":"10","author":"OY Kwon","year":"2021","unstructured":"Kwon OY, Lee SH (2021) Ishige okamurae suppresses trimethyltin-induced neurodegeneration and glutamate-mediated excitotoxicity by regulating MAPKs\/Nrf2\/HO-1 antioxidant pathways. Antioxidants 10(3):440","journal-title":"Antioxidants"},{"key":"5728_CR75","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.108335","volume":"101","author":"S Jin","year":"2021","unstructured":"Jin S, Wang X, Xiang X, Wu Y, Hu J, Li Y, Dong YL, Tan Y, et al. (2021) Inhibition of GPR17 with cangrelor improves cognitive impairment and synaptic deficits induced by A\u03b21\u201342 through Nrf2\/HO-1 and NF-\u03baB signaling pathway in mice. Int Immunopharmacol 101:108335","journal-title":"Int Immunopharmacol"},{"issue":"3","key":"5728_CR76","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0089715","volume":"9","author":"M Yang","year":"2014","unstructured":"Yang M, Jiang L, Huang H, Zeng S, Qiu F, Yu M, Li X, Wei S (2014) Dietary exposure to aluminium and health risk assessment in the residents of Shenzhen, China. PLoS One 9(3):e89715","journal-title":"PLoS One"},{"issue":"7","key":"5728_CR77","doi-asserted-by":"publisher","first-page":"6608","DOI":"10.1039\/D0FO01030H","volume":"11","author":"E Amraie","year":"2020","unstructured":"Amraie E, Pouraboli I, Rajaei Z (2020) Neuroprotective effects of Levisticum officinale on LPS-induced spatial learning and memory impairments through neurotrophic, anti-inflammatory, and antioxidant properties. Food Funct 11(7):6608\u20136621","journal-title":"Food Funct"},{"issue":"1-3","key":"5728_CR78","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.ejphar.2010.02.029","volume":"634","author":"A Zarifkar","year":"2010","unstructured":"Zarifkar A, Choopani S, Ghasemi R, Naghdi N, Maghsoudi AH, Maghsoudi N et al (2010) Agmatine prevents LPS-induced spatial memory impairment and hippocampal apoptosis. Eur J Pharmacol 634(1\u20133):84\u20138","journal-title":"Eur J Pharmacol"}],"container-title":["Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-026-05728-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12035-026-05728-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-026-05728-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T14:03:29Z","timestamp":1773410609000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12035-026-05728-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":78,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["5728"],"URL":"https:\/\/doi.org\/10.1007\/s12035-026-05728-9","relation":{},"ISSN":["0893-7648","1559-1182"],"issn-type":[{"value":"0893-7648","type":"print"},{"value":"1559-1182","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"1 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The animal experiments were carried out in accordance with the guidelines for the Care and Use of Laboratory Animals provided by the Ethical Committee of MUST, Egypt (approval no. PTREC.28).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"All authors have participated in the manuscript.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"All authors have consented for publication of the manuscript in the Journal of Molecular Neurobiology.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"496"}}