{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:52:42Z","timestamp":1786981962472,"version":"build-2736575974"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG061447"],"award-info":[{"award-number":["R01AG061447"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroimmune Pharmacol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) is a devastating neurodegenerative disease (AD) and has no treatment that can cure or halt the disease progression. This study explored the therapeutic potential of lithium salt dissolved in Ryanodex formulation vehicle (RFV) and delivered to the brain by intranasal application. We first compared lithium concentrations in the brain and blood of wild-type mice following intranasal or oral administration of lithium chloride (LiCl) dissolved in either RFV or water. The beneficial and side effects of intranasal versus oral LiCl in RFV in these mice were assessed and potential mechanisms underlying the efficacy of anti-inflammation and anti-pyroptosis in the brains were also investigated in both wild-type and 5XFAD Alzheimer\u2019s Disease (AD) mice brains.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      For the study of brain versus blood lithium concentrations, wild-type (WT) B6SJLF1\/J mice at 2\u00a0months of age were treated with intranasal or oral LiCl (3\u00a0mmol\/kg) dissolved in RFV or in water. Brain and blood lithium concentrations were measured at various times after drugs administration. Brain\/blood lithium concentration ratios were then determined. For studying therapeutic efficacy versus side effects and their underlying mechanisms, 5XFAD and WT B6SJLF1\/J mice were treated with intranasal LiCl (3\u00a0mmol\/kg) daily, Monday to Friday each week, in RFV beginning at 2 or 9\u00a0months of age with a 12-week treatment duration. Animal behaviors were assessed for depression (tail suspension), cognition (fear conditioning and Y maze), olfaction (buried food test), and motor functions (rotarod) at the age of 5 and 12\u00a0months. Blood and brain tissue were harvested from these mice at 13\u00a0months. Blood biomarkers for the functions of thyroid (thyroid stimulating hormone, TSH) and kidney (creatinine) were measured using ELISA. Changes in protein expression levels of the endoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release channels type 1 InsP\n                      <jats:sub>3<\/jats:sub>\n                      receptors (InsP\n                      <jats:sub>3<\/jats:sub>\n                      R-1), malondialdehyde (MDA)-modified proteins and 4-hydroxy-2-nonenal (4-HNE), pyroptosis regulatory proteins (NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, N-terminal of Gasdermin D (GSDMD)), cytotoxic (IL-1\u03b2, IL-18, IL-6, TNF-\u03b1) and cytoprotective (IL-10) cytokines and synapse proteins (PSD-95, synapsin-1) were determined using immunoblotting. Mouse body weights were monitored regularly.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared to oral LiCl in RFV nanoparticles, intranasal treatment of WT mice with LiCl in RFV markedly decreased blood concentrations at the time range of 30\u2013120\u00a0min. The ratio of brain\/blood lithium concentration after intranasal lithium chloride in RFV significantly increased, in comparison to those after oral administration lithium chloride in RFV or intranasal administration of lithium chloride in water. Intranasal lithium chloride in RFV inhibited both memory loss and depressive behavior in adult and aged 5XFAD mice. Additionally intranasal treatment of aged 5XFAD mice with LiCl in RFV effectively suppressed the increases in InsP\n                      <jats:sub>3<\/jats:sub>\n                      R-1, intracellular oxidative stress markers (4-HNE-bound and MDA-modified proteins), pyroptosis activation proteins (NLRP3, cleaved caspase-1, N-terminal GSDMD) and cytotoxic cytokines (IL-1\u03b2, IL-6, TNF-\u03b1), but reversed the down-regulation of cytoprotective cytokine IL-10. Intranasal LiCl in RFV also alleviated the loss of the postsynaptic synapse proteins PSD-95, but not synapsin-1, in aged 5XFAD mice. Blood level of the kidney function marker creatinine was significantly increased in 5XFAD than in WT mice in an age-dependent manner and this elevation was abolished by intranasal delivery of LiCl in RFV. Intranasal LiCl in RFV for 12\u00a0weeks in both WT or 5XFAD mice did not affect blood biomarkers for thyroid function, nor did it affect smell or muscle function or body weight.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Intranasal administration of LiCl in RFV significantly decreased lithium blood concentrations and increased brain\/blood lithium concentration ratio, in comparison to its oral administration. Intranasal administration of LiCl in RFV robustly protected against both memory loss and depressive-like behavior, while had no side effects concerning thyroid and kidney toxicity in 5XFAD mice. These lithium-induced beneficial effects were strongly associated with lithium\u2019s suppression of InsP\n                      <jats:sub>3<\/jats:sub>\n                      R-1 Ca\n                      <jats:sup>2+<\/jats:sup>\n                      channel receptor increase, pathological neuroinflammation and activation of the pyroptosis pathway, as well as the loss of the synaptic protein PSD-95. Intranasal delivery of lithium salt in RFV could become an effective and potent inhibitor of pathological inflammation\/pyroptosis in the CNS and serve as a new treatment for both AD-associated dementia and depression with minimal unwanted side effects including peripheral organ toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                    <jats:p>Intranasal delivery of lithium salt in Ryanodex Formulation Vehicle (RFV) robustly protected against both cognitive dysfunction and depression-like behavior 5XFAD mice, with no side effects or organ toxicity on thyroid and kidney functions. These lithium-induced beneficial effects were strongly associated with lithium\u2019s suppression of pathological elevation type I InsP3 receptors (InsP3R-1) Ca2+ channel receptor proteins, oxidative stress, pathological neuroinflammation and activation of the pyroptosis pathway (Increased proteins of NLRP3, cleaved caspase-1, N-terminal GSDMD, IL-1\u03b2 and IL-18). Intranasal delivery of lithium salt in RFV could become an effective drug in treating AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11481-025-10185-7","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T04:20:38Z","timestamp":1742185238000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Intranasal Delivery of Lithium Salt Suppresses Inflammatory Pyroptosis in the Brain and Ameliorates Memory Loss and Depression-like Behavior in 5XFAD Mice"],"prefix":"10.1007","volume":"20","author":[{"given":"Piplu","family":"Bhuiyan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Vera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Chae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyulee","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren St.","family":"Louis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"De-Maw","family":"Chuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huafeng","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"key":"10185_CR1","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1002\/alz.12328","volume":"17","author":"Alzheimer's Association","year":"2021","unstructured":"Association Alzheimer\u2019s (2021) Alzheimer\u2019s disease facts and figures. Alzheimers Dement 17:327\u2013406","journal-title":"Alzheimers Dement"},{"key":"10185_CR2","doi-asserted-by":"publisher","first-page":"311","DOI":"10.2174\/156720501704200520094610","volume":"17","author":"H Wei","year":"2020","unstructured":"Wei H (2020) New Approaches to Develop Drug Treatment for Alzheimer\u2019s Disease: Targeting Calcium Dysregulation. Curr Alzheimer Res 17:311\u2013312","journal-title":"Curr Alzheimer Res"},{"key":"10185_CR3","first-page":"780","volume":"5","author":"J Fessel","year":"2019","unstructured":"Fessel J (2019) Prevention of Alzheimer\u2019s disease by treating mild cognitive impairment with combinations chosen from eight available drugs. Alzheimers Dement 5:780\u2013788","journal-title":"Alzheimers Dement"},{"issue":"5","key":"10185_CR4","doi-asserted-by":"publisher","first-page":"4367","DOI":"10.3390\/ijms24054367","volume":"24","author":"K Wojtunik-Kulesza","year":"2023","unstructured":"Wojtunik-Kulesza K, Rudkowska M, Orzel-Sajdlowska A (2023) Aducanumab-Hope or Disappointment for Alzheimer\u2019s Disease. Int J Mol Sci 24(5):4367","journal-title":"Int J Mol Sci"},{"key":"10185_CR5","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.jatmed.2024.04.002","volume":"3","author":"W Zhang","year":"2024","unstructured":"Zhang W, Zhao X, Bhuiyan P, Liu H, Wei H (2024) Neuroprotective effects of dantrolene in neurodegenerative disease: Role of inhibition of pathological inflammation. J Anesth Transl Med 3:27\u201335","journal-title":"J Anesth Transl Med"},{"key":"10185_CR6","doi-asserted-by":"publisher","first-page":"996646","DOI":"10.3389\/fnagi.2022.996646","volume":"14","author":"Y Huang","year":"2022","unstructured":"Huang Y, Li X, Luo G, Wang J, Li R, Zhou C, Wan T, Yang F (2022) Pyroptosis as a candidate therapeutic target for Alzheimer\u2019s disease. Front Aging Neurosci 14:996646","journal-title":"Front Aging Neurosci"},{"key":"10185_CR7","doi-asserted-by":"publisher","first-page":"108740","DOI":"10.1016\/j.neuropharm.2021.108740","volume":"199","author":"LL Moroz","year":"2021","unstructured":"Moroz LL, Nikitin MA, Policar PG, Kohn AB, Romanova DY (2021) Evolution of glutamatergic signaling and synapses. Neuropharmacology 199:108740","journal-title":"Neuropharmacology"},{"issue":"12","key":"10185_CR8","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.2174\/1381612826666200113162641","volume":"26","author":"O Binvignat","year":"2020","unstructured":"Binvignat O, Olloquequi J (2020) Excitotoxicity as a Target against Neurodegenerative Processes. Curr Pharm Des 26(12):1251\u201362","journal-title":"Curr Pharm Des"},{"key":"10185_CR9","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1016\/j.neuron.2008.04.015","volume":"58","author":"KH Cheung","year":"2008","unstructured":"Cheung KH, Shineman D, Muller M, Cardenas C, Mei LJ, Yang J, Tomita T, Iwatsubo T, Lee VMY, Foskett JK (2008) Mechanism of Ca2+ disruption in Alzheimer\u2019s disease by presenilin regulation of InsP(3) receptor channel gating. Neuron 58:871\u2013883","journal-title":"Neuron"},{"key":"10185_CR10","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1097\/ALN.0000000000003224","volume":"132","author":"Y Wang","year":"2020","unstructured":"Wang Y, Liang G, Liang S, Mund R, Shi Y, Wei H (2020a) Dantrolene Ameliorates Impaired Neurogenesis and Synaptogenesis in Induced Pluripotent Stem Cell Lines Derived from Patients with Alzheimer\u2019s Disease. Anesthesiology 132:1062\u20131079","journal-title":"Anesthesiology"},{"key":"10185_CR11","doi-asserted-by":"publisher","first-page":"2590","DOI":"10.1073\/pnas.89.7.2590","volume":"89","author":"A Frandsen","year":"1992","unstructured":"Frandsen A, Schousboe A (1992) Mobilization of dantrolene-sensitive intracellular calcium pools is involved in the cytotoxicity induced by quisqualate and N-methyl-D-aspartate but not by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate and kainate in cultured cerebral cortical neurons. Proc Natl Acad Sci U S A 89:2590\u20132594","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"Suppl 2","key":"10185_CR12","doi-asserted-by":"publisher","first-page":"S487","DOI":"10.3233\/JAD-2010-100306","volume":"20","author":"C Supnet","year":"2010","unstructured":"Supnet C, Bezprozvanny I (2010) Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer\u2019s disease. J Alzheimers Dis 20(Suppl 2):S487-498","journal-title":"J Alzheimers Dis"},{"key":"10185_CR13","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1089\/ars.2021.0177","volume":"36","author":"NG Rummel","year":"2022","unstructured":"Rummel NG, Butterfield DA (2022) Altered Metabolism in Alzheimer Disease Brain: Role of Oxidative Stress. Antioxid Redox Signal 36:1289\u20131305","journal-title":"Antioxid Redox Signal"},{"key":"10185_CR14","doi-asserted-by":"publisher","first-page":"129","DOI":"10.31083\/j.jin2205129","volume":"22","author":"Y Ju","year":"2023","unstructured":"Ju Y, Zhao L, Li S, Zhao Q (2023) The Role of Pyroptosis in Alzheimer\u2019s Disease. J Integr Neurosci 22:129","journal-title":"J Integr Neurosci"},{"key":"10185_CR15","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1007\/s00401-022-02528-y","volume":"145","author":"S Moonen","year":"2023","unstructured":"Moonen S, Koper MJ, Van Schoor E, Schaeverbeke JM, Vandenberghe R, von Arnim CAF, Tousseyn T, De Strooper B, Thal DR (2023) Pyroptosis in Alzheimer\u2019s disease: cell type-specific activation in microglia, astrocytes and neurons. Acta Neuropathol 145:175\u2013195","journal-title":"Acta Neuropathol"},{"key":"10185_CR16","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.12659\/MSM.893176","volume":"21","author":"P Galecki","year":"2015","unstructured":"Galecki P, Talarowska M, Anderson G, Berk M, Maes M (2015) Mechanisms underlying neurocognitive dysfunctions in recurrent major depression. Med Sci Monit 21:1535\u20131547","journal-title":"Med Sci Monit"},{"key":"10185_CR17","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.pharmthera.2010.07.006","volume":"128","author":"CT Chiu","year":"2010","unstructured":"Chiu CT, Chuang DM (2010) Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther 128:281\u2013304","journal-title":"Pharmacol Ther"},{"key":"10185_CR18","doi-asserted-by":"publisher","first-page":"1408462","DOI":"10.3389\/fphar.2024.1408462","volume":"15","author":"Y Shen","year":"2024","unstructured":"Shen Y, Zhao M, Zhao P, Meng L, Zhang Y, Zhang G, Taishi Y, Sun L (2024) Molecular mechanisms and therapeutic potential of lithium in Alzheimer\u2019s disease: repurposing an old class of drugs. Front Pharmacol 15:1408462","journal-title":"Front Pharmacol"},{"key":"10185_CR19","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/S0014-5793(03)00167-4","volume":"538","author":"R Hashimoto","year":"2003","unstructured":"Hashimoto R, Fujimaki K, Jeong MR, Christ L, Chuang DM (2003) Lithium-induced inhibition of Src tyrosine kinase in rat cerebral cortical neurons: a role in neuroprotection against N-methyl-D-aspartate receptor-mediated excitotoxicity. FEBS Lett 538:145\u2013148","journal-title":"FEBS Lett"},{"key":"10185_CR20","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1172\/JCI22466","volume":"116","author":"C Schlecker","year":"2006","unstructured":"Schlecker C, Boehmerle W, Jeromin A, DeGray B, Varshney A, Sharma Y, Szigeti-Buck K, Ehrlich BE (2006) Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium. J Clin Invest 116:1668\u20131674","journal-title":"J Clin Invest"},{"key":"10185_CR21","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1021\/cn5000309","volume":"5","author":"OV Forlenza","year":"2014","unstructured":"Forlenza OV, De-Paula VJ, Diniz BS (2014) Neuroprotective effects of lithium: implications for the treatment of Alzheimer\u2019s disease and related neurodegenerative disorders. ACS Chem Neurosci 5:443\u2013450","journal-title":"ACS Chem Neurosci"},{"key":"10185_CR22","doi-asserted-by":"publisher","first-page":"337","DOI":"10.2174\/0929867325666180904124733","volume":"27","author":"B Medic","year":"2020","unstructured":"Medic B, Stojanovic M, Stimec BV, Divac N, Vujovic KS, Stojanovic R, Colovic M, Krstic D, Prostran M (2020) Lithium - Pharmacological and Toxicological Aspects: The Current State of the Art. Curr Med Chem 27:337\u2013351","journal-title":"Curr Med Chem"},{"key":"10185_CR23","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s40345-016-0068-y","volume":"4","author":"M Gitlin","year":"2016","unstructured":"Gitlin M (2016) Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar Disord 4:27","journal-title":"Int J Bipolar Disord"},{"key":"10185_CR24","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.jconrel.2014.06.053","volume":"189","author":"L Kozlovskaya","year":"2014","unstructured":"Kozlovskaya L, Abou-Kaoud M, Stepensky D (2014) Quantitative analysis of drug delivery to the brain via nasal route. J Control Release 189:133\u2013140","journal-title":"J Control Release"},{"key":"10185_CR25","doi-asserted-by":"publisher","first-page":"11654","DOI":"10.3390\/ijms222111654","volume":"22","author":"RGR Pinheiro","year":"2021","unstructured":"Pinheiro RGR, Coutinho AJ, Pinheiro M, Neves AR (2021) Nanoparticles for Targeted Brain Drug Delivery: What Do We Know? Int J Mol Sci 22:11654","journal-title":"Int J Mol Sci"},{"key":"10185_CR26","doi-asserted-by":"publisher","first-page":"1941","DOI":"10.1515\/ntrev-2021-0115","volume":"10","author":"AAHAF Abdellatifm","year":"2021","unstructured":"Abdellatifm AAHAF, lsowinea (2021) Approved and marketed nanoparticles for disease targeting and applications in COVID-19. Nanotechnol Rev 10:1941\u20131977","journal-title":"Nanotechnol Rev"},{"key":"10185_CR27","doi-asserted-by":"publisher","first-page":"e0229156","DOI":"10.1371\/journal.pone.0229156","volume":"15","author":"J Wang","year":"2020","unstructured":"Wang J, Shi Y, Yu S, Wang Y, Meng Q, Liang G, Eckenhoff MF, Wei H (2020b) Intranasal administration of dantrolene increased brain concentration and duration. PLoS ONE 15:e0229156","journal-title":"PLoS ONE"},{"key":"10185_CR28","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.3233\/JAD-200227","volume":"76","author":"Y Shi","year":"2020","unstructured":"Shi Y, Zhang L, Gao X, Zhang J, Ben Abou M, Liang G, Meng Q, Hepner A, Eckenhoff MF, Wei H (2020) Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice. J Alzheimers Dis 76:1375\u20131389","journal-title":"J Alzheimers Dis"},{"key":"10185_CR29","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"},{"key":"10185_CR30","doi-asserted-by":"crossref","unstructured":"Can A, Dao DT, Terrillion CE, Piantadosi SC, Bhat S, Gould TD (2012) The tail suspension test. J Vis Exp e3769","DOI":"10.3791\/3769-v"},{"key":"10185_CR31","doi-asserted-by":"publisher","first-page":"6910","DOI":"10.1523\/JNEUROSCI.5441-13.2014","volume":"34","author":"D Shilling","year":"2014","unstructured":"Shilling D, Muller M, Takano H, Mak DO, Abel T, Coulter DA, Foskett JK (2014) Suppression of InsP3 receptor-mediated Ca2+ signaling alleviates mutant presenilin-linked familial Alzheimer\u2019s disease pathogenesis. J Neurosci 34:6910\u20136923","journal-title":"J Neurosci"},{"key":"10185_CR32","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.3390\/antiox13091138","volume":"13","author":"T Gogna","year":"2024","unstructured":"Gogna T, Housden BE, Houldsworth A (2024) Exploring the Role of Reactive Oxygen Species in the Pathogenesis and Pathophysiology of Alzheimer\u2019s and Parkinson\u2019s Disease and the Efficacy of Antioxidant Treatment. Antioxidants 13:1138","journal-title":"Antioxidants"},{"key":"10185_CR33","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.2174\/1567205015666180904154446","volume":"15","author":"EN Wilson","year":"2018","unstructured":"Wilson EN, Do Carmo S, Iulita MF, Hall H, Austin GL, Jia DT, Malcolm JC, Foret MK, Marks AR, Butterfield DA, Cuello AC (2018) Microdose Lithium NP03 Diminishes Pre-Plaque Oxidative Damage and Neuroinflammation in a Rat Model of Alzheimer\u2019s-like Amyloidosis. Curr Alzheimer Res 15:1220\u20131230","journal-title":"Curr Alzheimer Res"},{"key":"10185_CR34","doi-asserted-by":"publisher","first-page":"2467","DOI":"10.1007\/s10565-023-09820-x","volume":"39","author":"KJ Wu","year":"2023","unstructured":"Wu KJ, Wang WR, Cheng QH, Li H, Yan WZ, Zhou FR, Zhang RJ (2023) Pyroptosis in neurodegenerative diseases: from bench to bedside. Cell Biol Toxicol 39:2467\u20132499","journal-title":"Cell Biol Toxicol"},{"key":"10185_CR35","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.pneurobio.2016.01.001","volume":"144","author":"LM Osborn","year":"2016","unstructured":"Osborn LM, Kamphuis W, Wadman WJ, Hol EM (2016) Astrogliosis: An integral player in the pathogenesis of Alzheimer\u2019s disease. Prog Neurobiol 144:121\u2013141","journal-title":"Prog Neurobiol"},{"key":"10185_CR36","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1007\/s00401-014-1330-y","volume":"128","author":"N Cartier","year":"2014","unstructured":"Cartier N, Lewis CA, Zhang R, Rossi FM (2014) The role of microglia in human disease: therapeutic tool or target? Acta Neuropathol 128:363\u2013380","journal-title":"Acta Neuropathol"},{"key":"10185_CR37","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s12035-008-8018-z","volume":"37","author":"M Knobloch","year":"2008","unstructured":"Knobloch M, Mansuy IM (2008) Dendritic spine loss and synaptic alterations in Alzheimer\u2019s disease. Mol Neurobiol 37:73\u201382","journal-title":"Mol Neurobiol"},{"key":"10185_CR38","doi-asserted-by":"publisher","first-page":"120811","DOI":"10.1016\/j.lfs.2022.120811","volume":"306","author":"S Kakhki","year":"2022","unstructured":"Kakhki S, Ahmadi-Soleimani SM (2022) Experimental data on lithium salts: From neuroprotection to multi-organ complications. Life Sci 306:120811","journal-title":"Life Sci"},{"key":"10185_CR39","doi-asserted-by":"publisher","first-page":"102231","DOI":"10.1016\/j.arr.2024.102231","volume":"95","author":"MP Singulani","year":"2024","unstructured":"Singulani MP, Ferreira AFF, Figueroa PS, Cuyul-Vasquez I, Talib LL, Britto LR, Forlenza OV (2024) Lithium and disease modification: A systematic review and meta-analysis in Alzheimer\u2019s and Parkinson\u2019s disease. Ageing Res Rev 95:102231","journal-title":"Ageing Res Rev"},{"issue":"Suppl 3","key":"10185_CR40","doi-asserted-by":"publisher","first-page":"S5","DOI":"10.1186\/1471-2202-9-S3-S5","volume":"9","author":"LR Hanson","year":"2008","unstructured":"Hanson LR, Frey WH 2nd (2008) Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci 9(Suppl 3):S5","journal-title":"BMC Neurosci"},{"key":"10185_CR41","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1007\/s13346-021-00940-7","volume":"11","author":"LC Fonseca","year":"2021","unstructured":"Fonseca LC, Lopes JA, Vieira J, Viegas C, Oliveira CS, Hartmann RP, Fonte P (2021) Intranasal drug delivery for treatment of Alzheimer\u2019s disease. Drug Deliv Transl Res 11:411\u2013425","journal-title":"Drug Deliv Transl Res"},{"issue":"5","key":"10185_CR42","doi-asserted-by":"publisher","first-page":"639","DOI":"10.3390\/ph17050639","volume":"17","author":"AO Egunlusi","year":"2024","unstructured":"Egunlusi AO, Joubert J (2024) NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders. Pharmaceuticals 17(5):639","journal-title":"Pharmaceuticals"},{"key":"10185_CR43","doi-asserted-by":"publisher","first-page":"e2252387","DOI":"10.1001\/jamanetworkopen.2022.52387","volume":"6","author":"H Stocker","year":"2023","unstructured":"Stocker H, Beyer L, Trares K, Perna L, Rujescu D, Holleczek B, Beyreuther K, Gerwert K, Schottker B, Brenner H (2023) Association of Kidney Function With Development of Alzheimer Disease and Other Dementias and Dementia-Related Blood Biomarkers. JAMA Netw Open 6:e2252387","journal-title":"JAMA Netw Open"},{"key":"10185_CR44","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1097\/00002093-200207000-00009","volume":"16","author":"Z Arvanitakis","year":"2002","unstructured":"Arvanitakis Z, Lucas JA, Younkin LH, Younkin SG, Graff-Radford NR (2002) Serum creatinine levels correlate with plasma amyloid Beta protein. Alzheimer Dis Assoc Disord 16:187\u2013190","journal-title":"Alzheimer Dis Assoc Disord"},{"key":"10185_CR45","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.3233\/JAD-220609","volume":"90","author":"XR Wu","year":"2022","unstructured":"Wu XR, Wu KM, Deng YT, Huang SY, Yang L, Dong Q, Feng JF, Cheng W, Yu JT (2022) Association of Kidney Function with Risk of Incident Dementia: A Prospective Cohort Study of 275,167 UK Biobank Participants. J Alzheimers Dis 90:1249\u20131261","journal-title":"J Alzheimers Dis"},{"key":"10185_CR46","doi-asserted-by":"publisher","first-page":"F96","DOI":"10.1152\/ajprenal.00351.2019","volume":"318","author":"Y Li","year":"2020","unstructured":"Li Y, Xia W, Wu M, Yin J, Wang Q, Li S, Zhang A, Huang S, Zhang Y, Jia Z (2020) Activation of GSDMD contributes to acute kidney injury induced by cisplatin. Am J Physiol Renal Physiol 318:F96\u2013F106","journal-title":"Am J Physiol Renal Physiol"},{"key":"10185_CR47","doi-asserted-by":"publisher","first-page":"2088","DOI":"10.1002\/alz.12543","volume":"18","author":"J Yao","year":"2022","unstructured":"Yao J, Liu Y, Sun B, Zhan X, Estillore JP, Turner RW, Chen SRW (2022) Increased RyR2 open probability induces neuronal hyperactivity and memory loss with or without Alzheimer\u2019s disease-causing gene mutations. Alzheimers Dement 18:2088\u20132098","journal-title":"Alzheimers Dement"},{"key":"10185_CR48","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.neulet.2012.04.008","volume":"516","author":"J Peng","year":"2012","unstructured":"Peng J, Liang G, Inan S, Wu Z, Joseph DJ, Meng Q, Peng Y, Eckenhoff MF, Wei H (2012) Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. Neurosci Lett 516:274\u2013279","journal-title":"Neurosci Lett"},{"key":"10185_CR49","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1097\/WAD.0000000000000075","volume":"29","author":"Z Wu","year":"2015","unstructured":"Wu Z, Yang B, Liu C, Liang G, Eckenhoff MF, Liu W, Pickup S, Meng Q, Tian Y, Li S, Wei H (2015) Long-term dantrolene treatment reduced intraneuronal amyloid in aged Alzheimer triple transgenic mice. Alzheimer Dis Assoc Disord 29:184\u2013191","journal-title":"Alzheimer Dis Assoc Disord"},{"key":"10185_CR50","doi-asserted-by":"publisher","first-page":"1430989","DOI":"10.3389\/fneur.2024.1430989","volume":"15","author":"KJ Campbell","year":"2024","unstructured":"Campbell KJ, Jiang P, Olker C, Lin X, Kim SY, Lee CJ, Song EJ, Turek FW, Vitaterna MH (2024) The impacts of sex and the 5xFAD model of Alzheimer\u2019s disease on the sleep and spatial learning responses to feeding time. Front Neurol 15:1430989","journal-title":"Front Neurol"},{"key":"10185_CR51","doi-asserted-by":"publisher","first-page":"755","DOI":"10.3233\/JAD-210523","volume":"85","author":"A Sil","year":"2022","unstructured":"Sil A, Erfani A, Lamb N, Copland R, Riedel G, Platt B (2022) Sex Differences in Behavior and Molecular Pathology in the 5XFAD Model. J Alzheimers Dis 85:755\u2013778","journal-title":"J Alzheimers Dis"},{"key":"10185_CR52","doi-asserted-by":"publisher","first-page":"114970","DOI":"10.1016\/j.bbr.2024.114970","volume":"465","author":"TP O'Leary","year":"2024","unstructured":"O\u2019Leary TP, Brown RE (2024) Age-related changes in species-typical behaviours in the 5xFAD mouse model of Alzheimer\u2019s disease from 4 to 16 months of age. Behav Brain Res 465:114970","journal-title":"Behav Brain Res"},{"key":"10185_CR53","doi-asserted-by":"publisher","first-page":"6766","DOI":"10.3390\/ijms25126766","volume":"25","author":"MS Padua","year":"2024","unstructured":"Padua MS, Guil-Guerrero JL, Lopes PA (2024) Behaviour Hallmarks in Alzheimer\u2019s Disease 5xFAD Mouse Model. Int J Mol Sci 25:6766","journal-title":"Int J Mol Sci"}],"container-title":["Journal of Neuroimmune Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11481-025-10185-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11481-025-10185-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11481-025-10185-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T04:48:41Z","timestamp":1742186921000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11481-025-10185-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,17]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["10185"],"URL":"https:\/\/doi.org\/10.1007\/s11481-025-10185-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.09.18.613794","asserted-by":"object"}]},"ISSN":["1557-1904"],"issn-type":[{"value":"1557-1904","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,17]]},"assertion":[{"value":"25 February 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 March 2025","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 authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"26"}}