{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T06:24:29Z","timestamp":1777962269795,"version":"3.51.4"},"reference-count":91,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre, Poland","award":["2018\/29\/N\/NZ4\/00616"],"award-info":[{"award-number":["2018\/29\/N\/NZ4\/00616"]}]},{"name":"MMRI statutory budget theme No. 7"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Type 2 diabetes mellitus (T2DM) is a rapidly expanding worldwide health issue associated with impairments in memory and executive functions. The bioactive sphingolipid sphingosine-1-phosphate (S1P) regulates cell death\/survival and the inflammatory response by acting on S1P receptors (S1PRs). Unfortunately, the role of S1PRs signaling in the T2DM brain remains elusive. Methods: The effect of fingolimod (FTY720, S1PRs modulator) on the behavior and expression profile of genes encoding S1PRs, sphingosine kinases (SPHK1 and 2), glucose transporters, proteins engaged in insulin signaling, sirtuin 1 (SIRT1), and proinflammatory cytokines in the brain cortex and hippocampus of diabetic mice was examined. Results: We observed a significant reduction in S1pr1, Sirt1, and insulin-like growth factor-1 (Igf1) gene expression that was accompanied by elevation of Sphk2, S1pr3, Il6, and Tnf in T2DM mice. Moreover, animals showed anxiety-like behavior and memory deficits. Fingolimod administration recovered downregulated S1pr1, Sirt1, and Igf1 expression and upregulated Slc2a4 (GLUT-4) and Ide (insulin-degrading enzyme). Furthermore, FTY720 reduced the elevated expression of Il6 and Tnf. Fingolimod also exerted an anxiolytic effect in T2DM. Conclusions: Results indicate an important role of S1PR modulation in T2DM. Moreover, fingolimod affected mRNA levels of proteins engaged in glucose metabolism\/insulin signaling and improved the behavior of diabetic mice.<\/jats:p>","DOI":"10.3390\/biom15111485","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T08:41:08Z","timestamp":1761122468000},"page":"1485","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Fingolimod Improves Anxiety-like Behavior and Modulates Sphingosine-1-Phosphate Receptors Gene Expression in a Diabetic Mouse Model"],"prefix":"10.3390","volume":"15","author":[{"given":"Przemys\u0142aw Leonard","family":"Wencel","sequence":"first","affiliation":[{"name":"Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0990-3017","authenticated-orcid":false,"given":"Kamilla","family":"Blecharz-Klin","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, 1B Banacha St., 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0335-3288","authenticated-orcid":false,"given":"Agnieszka","family":"Piechal","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, 1B Banacha St., 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0776-8077","authenticated-orcid":false,"given":"Justyna","family":"Pyrzanowska","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, 1B Banacha St., 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6294-3256","authenticated-orcid":false,"given":"Dagmara","family":"Mirowska-Guzel","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, 1B Banacha St., 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert Piotr","family":"Strosznajder","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Research and Environmental Agents, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"112152","DOI":"10.1016\/j.diabres.2025.112152","article-title":"IDF global clinical practice recommendations for managing type 2 diabetes-2025","volume":"222","author":"Ceriello","year":"2025","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1210\/clinem\/dgad595","article-title":"Plasma Sphingolipid Profile of Healthy Black and White Adults Differs Based on Their Parental History of Type 2 Diabetes","volume":"109","author":"Mandal","year":"2024","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eadr1725","DOI":"10.1126\/sciadv.adr1725","article-title":"Reduced circulating sphingolipids and CERS2 activity are linked to T2D risk and impaired insulin secretion","volume":"11","author":"Khan","year":"2025","journal-title":"Sci. Adv."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1186\/s12933-024-02505-7","article-title":"Sphingolipid profiling as a biomarker of type 2 diabetes risk: Evidence from the MIDUS and PREDIMED studies","volume":"23","author":"Berkowitz","year":"2024","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Asuzu, P., Aliye, N., Stentz, F., Wan, J., Mandal, N., and Dagogo-Jack, S. (2025). Plasma Sphingolipids in Relation to Glycemia and Glucose Tolerance in People Without Diabetes. J. Clin. Endocrinol. Metab., dgaf378.","DOI":"10.1210\/clinem\/dgaf378"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hammad, S.M., and Lopes-Virella, M.F. (2023). Circulating Sphingolipids in Insulin Resistance, Diabetes and Associated Complications. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202308.1042.v1"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Grassi, S., Mauri, L., Prioni, S., Cabitta, L., Sonnino, S., Prinetti, A., and Giussani, P. (2019). Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00807"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1194\/jlr.R046300","article-title":"An update on the biology of sphingosine 1-phosphate receptors","volume":"55","author":"Blaho","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Guitton, J., Bandet, C.L., Mariko, M.L., Tan-Chen, S., Bourron, O., Benomar, Y., Hajduch, E., and Le Stunff, H. (2020). Sphingosine-1-Phosphate Metabolism in the Regulation of Obesity\/Type 2 Diabetes. Cells, 9.","DOI":"10.3390\/cells9071682"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"103526","DOI":"10.1016\/j.mcn.2020.103526","article-title":"Pharmacological inhibition of sphingosine-1-phosphate lyase partially reverses spatial memory impairment in streptozotocin-diabetic rats","volume":"107","author":"Baranowska","year":"2020","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.neuroscience.2015.06.063","article-title":"Chronic maternal hyperglycemia induced during mid-pregnancy in rats increases RAGE expression, augments hippocampal excitability, and alters behavior of the offspring","volume":"303","author":"Chandna","year":"2015","journal-title":"Neuroscience"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.2174\/0118715303275039231228065050","article-title":"The Antidiabetic Drug Metformin Attenuated Depressive and Anxiety-like Behaviors and Oxidative Stress in the Brain in a Rodent Model of Inflammation Induced by Lipopolysaccharide in Male Rats","volume":"24","author":"Kakhki","year":"2024","journal-title":"Endocr. Metab. Immune. Disord. Drug Targets"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Marathe, C.K., Thorat, V.G., Kokate, I.P., Pawar, A.T., and Bhatt, S. (2025). Antidepressant- and anxiolytic-like effects of linezolid in streptozotocin-induced diabetic mice via modulation of brain serotonin and plasma corticosterone activity. Biochem. Biophys. Res. Commun., 765.","DOI":"10.1016\/j.bbrc.2025.151843"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jns.2013.02.011","article-title":"Fingolimod: Direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy","volume":"328","author":"Groves","year":"2013","journal-title":"J. Neurol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Pournajaf, S., Dargahi, L., Javan, M., and Pourgholami, M.H. (2022). Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.807639"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1111\/j.1476-5381.2009.00451.x","article-title":"FTY720 (fingolimod) in Multiple Sclerosis: Therapeutic effects in the immune and the central nervous system","volume":"158","author":"Brinkmann","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s40268-020-00316-1","article-title":"Fingolimod as a Treatment in Neurologic Disorders Beyond Multiple Sclerosis","volume":"20","author":"Bascunana","year":"2020","journal-title":"Drugs R. D."},{"key":"ref_18","first-page":"6018","article-title":"The association between fingolimod and mental health outcomes in a cohort of Multiple Sclerosis patients with stress","volume":"27","author":"Gammoh","year":"2023","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1037\/h0071444","article-title":"Emotional behavior in the rat. I. Defecation and urination as measures of individual differences in emotionality","volume":"18","author":"Hall","year":"1934","journal-title":"J. Comp. Psychol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.bbr.2009.12.036","article-title":"One-trial object recognition in rats and mice: Methodological and theoretical issues","volume":"215","author":"Ennaceur","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.bbr.2012.03.022","article-title":"Object recognition testing: Methodological considerations on exploration and discrimination measures","volume":"232","author":"Akkerman","year":"2012","journal-title":"Behav. Brain Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s10339-011-0430-z","article-title":"The novel object recognition memory: Neurobiology, test procedure, and its modifications","volume":"13","author":"Antunes","year":"2012","journal-title":"Cogn. Process."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1038\/nprot.2013.155","article-title":"Object recognition test in mice","volume":"8","author":"Leger","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_24","first-page":"55718","article-title":"Novel Object Recognition Test for the Investigation of Learning and Memory in Mice","volume":"126","author":"Lueptow","year":"2017","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.pbb.2018.03.004","article-title":"Early paracetamol exposure decreases brain-derived neurotrophic factor (BDNF) in striatum and affects social behaviour and exploration in rats","volume":"168","author":"Wawer","year":"2018","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Krzysztoforska, K., Piechal, A., Wojnar, E., Blecharz-Klin, K., Pyrzanowska, J., Joniec-Maciejak, I., Krzysztoforski, J., and Widy-Tyszkiewicz, E. (2023). Protocatechuic Acid Prevents Some of the Memory-Related Behavioural and Neurotransmitter Changes in a Pyrithiamine-Induced Thiamine Deficiency Model of Wernicke-Korsakoff Syndrome in Rats. Nutrients, 15.","DOI":"10.3390\/nu15030625"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.nlm.2005.07.002","article-title":"Integrated memory for objects, places, and temporal order: Evidence for episodic-like memory in mice","volume":"84","author":"Dere","year":"2005","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1101\/lm.1625310","article-title":"Post-training reversible inactivation of the hippocampus enhances novel object recognition memory","volume":"17","author":"Oliveira","year":"2010","journal-title":"Learn. Mem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF00504983","article-title":"Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of \u2018fear\u2019-motivated behaviour","volume":"327","author":"Handley","year":"1984","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Holscher, C. (2019). Insulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer\u2019s Disease. Front. Aging Neurosci., 11.","DOI":"10.3389\/fnagi.2019.00088"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/jdi.12235","article-title":"Modeling type 2 diabetes in rats using high fat diet and streptozotocin","volume":"5","author":"Skovso","year":"2014","journal-title":"J. Diabetes Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.tem.2017.03.005","article-title":"Sphingolipids and Lipoproteins in Health and Metabolic Disorders","volume":"28","author":"Iqbal","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Christoffersen, C. (2021). Apolipoprotein M-A Marker or an Active Player in Type II Diabetes?. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.665393"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13457","DOI":"10.1074\/jbc.M111.268185","article-title":"Sphingosine 1-phosphate (S1P) regulates glucose-stimulated insulin secretion in pancreatic beta cells","volume":"287","author":"Morris","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Di Pietro, P., Izzo, C., Abate, A.C., Iesu, P., Rusciano, M.R., Venturini, E., Visco, V., Sommella, E., Ciccarelli, M., and Carrizzo, A. (2023). The Dark Side of Sphingolipids: Searching for Potential Cardiovascular Biomarkers. Biomolecules, 13.","DOI":"10.3390\/biom13010168"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"27493","DOI":"10.1074\/jbc.M701641200","article-title":"Protein kinase D-mediated phosphorylation and nuclear export of sphingosine kinase 2","volume":"282","author":"Ding","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3636","DOI":"10.1096\/fj.201801496R","article-title":"Sphingosine kinase 2 promotes lipotoxicity in pancreatic beta-cells and the progression of diabetes","volume":"33","author":"Song","year":"2019","journal-title":"FASEB J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.bbadis.2018.12.012","article-title":"Sphk2(-\/-) mice are protected from obesity and insulin resistance","volume":"1865","author":"Ravichandran","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"eaar5551","DOI":"10.1126\/science.aar5551","article-title":"Sphingosine 1-phosphate: Lipid signaling in pathology and therapy","volume":"366","author":"Cartier","year":"2019","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1007\/s40263-022-00927-z","article-title":"The Two Sides of Siponimod: Evidence for Brain and Immune Mechanisms in Multiple Sclerosis","volume":"36","author":"Cohan","year":"2022","journal-title":"CNS Drugs"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1007\/s13311-023-01403-2","article-title":"Fingolimod Modulates the Gene Expression of Proteins Engaged in Inflammation and Amyloid-Beta Metabolism and Improves Exploratory and Anxiety-Like Behavior in Obese Mice","volume":"20","author":"Wencel","year":"2023","journal-title":"Neurotherapeutics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1167\/iovs.15-18658","article-title":"FTY720 Attenuates Retinal Inflammation and Protects Blood-Retinal Barrier in Diabetic Rats","volume":"57","author":"Fan","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4859","DOI":"10.1038\/ncomms5859","article-title":"Hypothalamic S1P\/S1PR1 axis controls energy homeostasis","volume":"5","author":"Silva","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1007\/s11064-023-04033-4","article-title":"Density of Sphingosine-1-Phosphate Receptors Is Altered in Cortical Nerve-Terminals of Insulin-Resistant Goto-Kakizaki Rats and Diet-Induced Obese Mice","volume":"49","author":"Skoug","year":"2024","journal-title":"Neurochem. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.3892\/ijmm.2015.2100","article-title":"Role of sphingosine-1-phosphate receptor 1 and sphingosine-1-phosphate receptor 2 in hyperglycemia-induced endothelial cell dysfunction","volume":"35","author":"Chen","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"795","DOI":"10.4239\/wjd.v14.i6.795","article-title":"Diabetes and cognitive decline: Challenges and future direction","volume":"14","author":"Omar","year":"2023","journal-title":"World J. Diabetes"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.neuroscience.2016.03.056","article-title":"The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity","volume":"325","author":"Dyer","year":"2016","journal-title":"Neuroscience"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/bs.vh.2021.11.009","article-title":"Chapter Fourteen-A role for insulin-like growth factor-1 in hippocampal plasticity following traumatic brain injury","volume":"Volume 118","author":"Litwack","year":"2022","journal-title":"Vitamins and Hormones"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e1259709","DOI":"10.1080\/23262133.2016.1259709","article-title":"Therapeutic potential of IGF-I on hippocampal neurogenesis and function during aging","volume":"4","author":"Morel","year":"2017","journal-title":"Neurogenesis"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"S217","DOI":"10.3233\/JAD-2012-111728","article-title":"Dysfunctional pro-ceramide, ER stress, and insulin\/IGF signaling networks with progression of Alzheimer\u2019s disease","volume":"30","author":"Re","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"FSO25","DOI":"10.4155\/fso.15.23","article-title":"Brain signaling systems in the Type 2 diabetes and metabolic syndrome: Promising target to treat and prevent these diseases","volume":"1","author":"Shpakov","year":"2015","journal-title":"Future Sci. OA."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.brainres.2009.09.063","article-title":"Insulin and IGF-I prevent brain atrophy and DNA loss in diabetes","volume":"1303","author":"Serbedzija","year":"2009","journal-title":"Brain Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"S601","DOI":"10.4103\/2230-8210.105578","article-title":"Insulin and insulin-like growth factor prevent brain atrophy and cognitive impairment in diabetic rats","volume":"16","author":"Serbedzija","year":"2012","journal-title":"Indian J. Endocrinol. Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1002\/jnr.10791","article-title":"Systemic insulin-like growth factor-I administration prevents cognitive impairment in diabetic rats, and brain IGF regulates learning\/memory in normal adult rats","volume":"74","author":"Lupien","year":"2003","journal-title":"J. Neurosci. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/2044-5040-2-15","article-title":"Sphingosine kinase\/sphingosine 1-phosphate axis: A new player for insulin-like growth factor-1-induced myoblast differentiation","volume":"2","author":"Bernacchioni","year":"2012","journal-title":"Skelet. Muscle."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.bbr.2017.09.033","article-title":"Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4","volume":"338","author":"Jahagirdar","year":"2018","journal-title":"Behav. Brain Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"11851","DOI":"10.1523\/JNEUROSCI.1700-16.2016","article-title":"Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory","volume":"36","author":"McNay","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Corraliza-Gomez, M., Lillo, C., Cozar-Castellano, I., Arranz, E., Sanchez, D., and Ganfornina, M.D. (2022). Evolutionary Origin of Insulin-Degrading Enzyme and Its Subcellular Localization and Secretion Mechanism: A Study in Microglial Cells. Cells, 11.","DOI":"10.3390\/cells11020227"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Abdul-Hay, S.O., Kang, D., McBride, M., Li, L., Zhao, J., and Leissring, M.A. (2011). Deletion of insulin-degrading enzyme elicits antipodal, age-dependent effects on glucose and insulin tolerance. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020818"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"101999","DOI":"10.1016\/j.arr.2023.101999","article-title":"Insulin-degrading enzyme: Roles and pathways in ameliorating cognitive impairment associated with Alzheimer\u2019s disease and diabetes","volume":"90","author":"Tian","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.tem.2015.11.003","article-title":"Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus","volume":"27","author":"Tang","year":"2016","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Juszczak, F., Arnould, T., and Decleves, A.E. (2024). The Role of Mitochondrial Sirtuins (SIRT3, SIRT4 and SIRT5) in Renal Cell Metabolism: Implication for Kidney Diseases. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25136936"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1007\/s11064-016-2110-y","article-title":"Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders","volume":"42","author":"Jesko","year":"2017","journal-title":"Neurochem. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"934","DOI":"10.7150\/ijbs.7529","article-title":"SIRT1 deacetylates FOXA2 and is critical for Pdx1 transcription and beta-cell formation","volume":"9","author":"Wang","year":"2013","journal-title":"Int. J. Biol. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1093\/cvr\/cvae100","article-title":"Inhibition of de novo ceramide synthesis by sirtuin-1 improves beta-cell function and glucose metabolism in type 2 diabetes","volume":"120","author":"Velagapudi","year":"2024","journal-title":"Cardiovasc. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1007\/s11011-025-01662-2","article-title":"Mechanisms of SIRT1\/SIRT3-mediated reduction of mitochondrial regeneration and inflammatory response in diabetic cerebral ischemia-reperfusion injury","volume":"40","author":"Xin","year":"2025","journal-title":"Metab. Brain Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.4103\/1673-5374.313051","article-title":"Hippocampal insulin resistance and the Sirtuin 1 signaling pathway in diabetes-induced cognitive dysfunction","volume":"16","author":"Yang","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Chamgordani, M.K., Bardestani, A., Ebrahimpour, S., and Esmaeili, A. (2023). In diabetic male Wistar rats, quercetin-conjugated superparamagnetic iron oxide nanoparticles have an effect on the SIRT1\/p66Shc-mediated pathway related to cognitive impairment. BMC Pharmacol. Toxicol., 24.","DOI":"10.1186\/s40360-023-00725-3"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41392-022-01257-8","article-title":"The sirtuin family in health and disease","volume":"7","author":"Wu","year":"2022","journal-title":"Signal. Transduct. Target Ther."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Kitada, M., Ogura, Y., Monno, I., and Koya, D. (2019). Sirtuins and Type 2 Diabetes: Role in Inflammation, Oxidative Stress, and Mitochondrial Function. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00187"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.biocel.2016.02.018","article-title":"SIRT1 mediates Sphk1\/S1P-induced proliferation and migration of endothelial cells","volume":"74","author":"Gao","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1002\/ehf2.14707","article-title":"Chlorogenic acid attenuates cardiac hypertrophy via up-regulating Sphingosine-1-phosphate receptor1 to inhibit endoplasmic reticulum stress","volume":"11","author":"Ping","year":"2024","journal-title":"ESC Heart Fail."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"6271","DOI":"10.1007\/s11033-013-2739-4","article-title":"Association of IL-6, TNF-alpha and IL-10 gene polymorphisms with type 2 diabetes mellitus","volume":"40","author":"Saxena","year":"2013","journal-title":"Mol. Biol. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1007\/s10528-021-10047-w","article-title":"Association of NFkappabeta, TNFalpha, IL-6, IL-1beta, and LPL Polymorphisms with Type 2 Diabetes Mellitus and Biochemical Parameters in a Mexican Population","volume":"59","author":"Rubio","year":"2021","journal-title":"Biochem. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Piatkowska-Chmiel, I., Herbet, M., Gawronska-Grzywacz, M., Ostrowska-Lesko, M., and Dudka, J. (2021). The Role of Molecular and Inflammatory Indicators in the Assessment of Cognitive Dysfunction in a Mouse Model of Diabetes. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083878"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.bbi.2024.12.154","article-title":"Cognitive decline and neuroinflammation in a mouse model of obesity: An accelerating role of ageing","volume":"125","author":"Rajput","year":"2025","journal-title":"Brain Behav. Immun."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Xie, Y., Chu, A., Feng, Y., Chen, L., Shao, Y., Luo, Q., Deng, X., Wu, M., Shi, X., and Chen, Y. (2018). MicroRNA-146a: A Comprehensive Indicator of Inflammation and Oxidative Stress Status Induced in the Brain of Chronic T2DM Rats. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00478"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s12035-022-03120-x","article-title":"Fingolimod Alleviates Cognitive Deficit in Type 2 Diabetes by Promoting Microglial M2 Polarization via the pSTAT3-jmjd3 Axis","volume":"60","author":"Sood","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1007\/s12035-018-1195-5","article-title":"Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models","volume":"56","author":"Rom","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.bbr.2017.01.004","article-title":"Liraglutide prevents cognitive decline in a rat model of streptozotocin-induced diabetes independently from its peripheral metabolic effects","volume":"321","author":"Palleria","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1007\/s00221-022-06446-z","article-title":"CaMKIV\/CREB\/BDNF signaling pathway expression in prefrontal cortex, amygdala, hippocampus and hypothalamus in streptozotocin-induced diabetic mice with anxious-like behavior","volume":"240","author":"Espasandin","year":"2022","journal-title":"Exp. Brain Res."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Dunacka, J., Swiatek, G., and Wrona, D. (2024). High Behavioral Reactivity to Novelty as a Susceptibility Factor for Memory and Anxiety Disorders in Streptozotocin-Induced Neuroinflammation as a Rat Model of Alzheimer\u2019s Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252111562"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e00135","DOI":"10.1002\/prp2.135","article-title":"Antidepressant activity of fingolimod in mice","volume":"3","author":"Orlando","year":"2015","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.physbeh.2014.02.036","article-title":"Antidepressant effects of insulin in streptozotocin induced diabetic mice: Modulation of brain serotonin system","volume":"129","author":"Gupta","year":"2014","journal-title":"Physiol. Behav."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1111\/jnc.16073","article-title":"The sphingosine 1-phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus","volume":"168","author":"Magalhaes","year":"2024","journal-title":"J. Neurochem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1159\/000534669","article-title":"Chronic Stress Exacerbates Hyperglycemia-Induced Affective Symptoms in Male Mice","volume":"30","author":"McCready","year":"2023","journal-title":"Neuroimmunomodulation"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.neuroscience.2020.03.041","article-title":"Beneficial Effects of Fingolimod on Social Interaction, CNS and Peripheral Immune Response in the BTBR Mouse Model of Autism","volume":"435","author":"Butera","year":"2020","journal-title":"Neuroscience"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.ejphar.2015.11.033","article-title":"Favorable effects of vildagliptin on metabolic and cognitive dysfunctions in streptozotocin-induced diabetic rats","volume":"769","author":"Shafik","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"115493","DOI":"10.1016\/j.bbr.2025.115493","article-title":"Sigma-1 receptor agonist PRE-084 increases BDNF by activating the ERK\/CREB pathway to rescue learning and memory impairment caused by type II diabetes","volume":"484","author":"Shi","year":"2025","journal-title":"Behav. Brain Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/nn.3728","article-title":"Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory","volume":"17","author":"Hait","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.bbr.2018.09.008","article-title":"Posttraumatic stress disorder-type behaviors in streptozotocin-induced diabetic rats can be prevented by prolonged treatment with vitamin E","volume":"359","author":"Gambeta","year":"2019","journal-title":"Behav. Brain Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1485\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T04:20:25Z","timestamp":1761279625000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/11\/1485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,22]]},"references-count":91,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["biom15111485"],"URL":"https:\/\/doi.org\/10.3390\/biom15111485","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,22]]}}}