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In hyperammonemic rats, cognitive function is impaired by altered glutamatergic neurotransmission induced by neuroinflammation. The underlying mechanisms remain unclear. Enhanced sphingosine-1-phosphate receptor 2 (S1PR2) activation in the cerebellum of hyperammonemic rats contributes to neuroinflammation. in In hyperammonemic rats, we assessed if blocking S1PR2 reduced hippocampal neuroinflammation and reversed cognitive impairment and if the signaling pathways were involved. S1PR2 was blocked with intracerebral JTE-013, and cognitive function was evaluated. The signaling pathways inducing neuroinflammation and altered glutamate receptors were analyzed in hippocampal slices. JTE-013 improved cognitive function in the hyperammonemic rats, and hyperammonemia increased S1P. This increased IL-1\u03b2, which enhanced Src activity, increased CCL2, activated microglia and increased the membrane expression of the NMDA receptor subunit GLUN2B. This increased p38-MAPK activity, which altered the membrane expression of AMPA receptor subunits and increased BDNF, which activated the TrkB \u2192 PI3K \u2192 Akt \u2192 CREB pathway, inducing sustained neuroinflammation. This report unveils key pathways involved in the induction and maintenance of neuroinflammation in the hippocampus of hyperammonemic rats and supports S1PR2 as a therapeutic target for cognitive impairment.<\/jats:p>","DOI":"10.3390\/ijms242417251","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T05:47:30Z","timestamp":1702014450000},"page":"17251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Enhanced Activation of the S1PR2-IL-1\u03b2-Src-BDNF-TrkB Pathway Mediates Neuroinflammation in the Hippocampus and Cognitive Impairment in Hyperammonemic Rats"],"prefix":"10.3390","volume":"24","author":[{"given":"Mar\u00eda","family":"Sancho-Alonso","sequence":"first","affiliation":[{"name":"Laboratory of Neurobiology, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, 46012 Valencia, Spain"},{"name":"Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain"},{"name":"Systems Neuropharmacology Research Group, Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Biomedical Research Networking Center for Mental Health (CIBERSAM), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6769-5888","authenticated-orcid":false,"given":"Yaiza M.","family":"Arenas","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, 46012 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6557-0483","authenticated-orcid":false,"given":"Paula","family":"Izquierdo-Altarejos","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, 46012 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar","family":"Martinez-Garcia","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, 46012 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5565-5907","authenticated-orcid":false,"given":"Marta","family":"Llansola","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, 46012 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3145-9538","authenticated-orcid":false,"given":"Vicente","family":"Felipo","sequence":"additional","affiliation":[{"name":"Laboratory of Neurobiology, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, 46012 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jhep.2003.10.016","article-title":"Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis","volume":"40","author":"Shawcross","year":"2004","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.neuint.2009.01.021","article-title":"Mechanisms of cognitive alterations in hyperammonemia and hepatic encephalopathy: Therapeutical implications","volume":"55","author":"Monfort","year":"2009","journal-title":"Neurochem. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e13270","DOI":"10.1111\/apha.13270","article-title":"Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications","volume":"226","author":"Llansola","year":"2019","journal-title":"Acta Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s11011-005-7919-z","article-title":"Attention, Memory, and Cognitive Function in Hepatic Encephalopathy","volume":"20","author":"Weissenborn","year":"2005","journal-title":"Metab. Brain Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1023\/B:MEBR.0000043975.01841.de","article-title":"Characteristics of Minimal Hepatic Encephalopathy","volume":"19","author":"Amodio","year":"2004","journal-title":"Metab. Brain Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1159\/000375348","article-title":"The Clinical Relevance of Minimal Hepatic Encephalopathy\u2014A Critical Look","volume":"33","author":"Weissenborn","year":"2015","journal-title":"Dig. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1089\/cpb.2008.0242","article-title":"Impairment of Driving Ability and Neuropsychological Function in Patients with MHE Disease","volume":"12","author":"Kim","year":"2009","journal-title":"CyberPsychology Behav."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.dld.2021.12.015","article-title":"Risk factors for hepatic encephalopathy and mortality in cirrhosis: The role of cognitive impairment, muscle alterations and shunts","volume":"54","author":"Nardelli","year":"2022","journal-title":"Dig. Liver Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3008","DOI":"10.1016\/j.cgh.2020.03.033","article-title":"Minimal Hepatic Encephalopathy and Mild Cognitive Impairment Worsen Quality of Life in Elderly Patients with Cirrhosis","volume":"18","author":"Bajaj","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1007\/s11011-019-00457-6","article-title":"Hippocampal atrophy and functional connectivity disruption in cirrhotic patients with minimal hepatic encephalopathy","volume":"34","author":"Lin","year":"2019","journal-title":"Metab. Brain Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.2214\/AJR.17.17827","article-title":"Brain Microstructural Abnormalities in Patients with Cirrhosis without Overt Hepatic Encephalopathy: A Voxel-Based Diffusion Kurtosis Imaging Study","volume":"209","author":"Chen","year":"2017","journal-title":"Am. J. Roentgenol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9664","DOI":"10.1038\/s41598-018-27978-x","article-title":"Learning and Memory Impairments in Patients with Minimal Hepatic Encephalopathy are Associated with Structural and Functional Connectivity Alterations in Hippocampus","volume":"8","author":"Urios","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s11011-007-9067-0","article-title":"NMDA receptors in hyperammonemia and hepatic encephalopathy","volume":"22","author":"Llansola","year":"2007","journal-title":"Metab. Brain Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12974-016-0505-y","article-title":"Hyperammonemia induces glial activation, neuroinflammation and alters neurotransmitter receptors in hippocampus, impairing spatial learning. Reversal by sulforaphane","volume":"13","author":"Malaguarnera","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"106","DOI":"10.3389\/fnmol.2016.00106","article-title":"Reducing Peripheral Inflammation with Infliximab Reduces Neuroinflammation and Improves Cognition in Rats with Hepatic Encephalopathy","volume":"9","author":"Dadsetan","year":"2016","journal-title":"Front. Mol. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/j.jhep.2019.01.008","article-title":"Chronic hyperammonemia induces peripheral inflammation that leads to cognitive impairment in rats: Reversed by anti-TNF-\u03b1 treatment","volume":"73","author":"Balzano","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.neuro.2017.05.006","article-title":"Hyperammonemia compromises glutamate metabolism and reduces BDNF in the rat hippocampus","volume":"62","author":"Galland","year":"2017","journal-title":"NeuroToxicology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.bbi.2016.05.011","article-title":"In vivo administration of extracellular cGMP normalizes TNF-\u03b1 and membrane expression of AMPA receptors in hippocampus and spatial reference memory but not IL-1\u03b2, NMDA receptors in membrane and working memory in hyperammonemic rats","volume":"57","author":"Balzano","year":"2016","journal-title":"Brain. Behav. Immun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9913","DOI":"10.1096\/fj.201900230RR","article-title":"Differential role of interleukin-1\u03b2 in neuroinflammation-induced impairment of spatial and nonspatial memory in hyperammonemic rats","volume":"33","author":"Arenas","year":"2019","journal-title":"FASEB J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.jneuroim.2006.03.001","article-title":"Interleukin-1 beta modulates AMPA receptor expression and phosphorylation in hippocampal neurons","volume":"175","author":"Lai","year":"2006","journal-title":"J. Neuroimmunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"30212","DOI":"10.1074\/jbc.M602156200","article-title":"Interleukin-1\u03b2 Released by gp120 Drives Neural Death through Tyrosine Phosphorylation and Trafficking of NMDA Receptors","volume":"281","author":"Viviani","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1523\/JNEUROSCI.4486-04.2005","article-title":"Differential Regulation of AMPA Receptor and GABA Receptor Trafficking by Tumor Necrosis Factor-\u03b1","volume":"25","author":"Stellwagen","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11391","DOI":"10.1523\/JNEUROSCI.3708-08.2008","article-title":"Cell Death after Spinal Cord Injury Is Exacerbated by Rapid TNF\u03b1-Induced Trafficking of GluR2-Lacking AMPARs to the Plasma Membrane","volume":"28","author":"Ferguson","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5369","DOI":"10.1093\/cercor\/bhx221","article-title":"Pharmacological Modulation of AMPAR Rescues Intellectual Disability-Like Phenotype in Tm4sf2\u2212\/y Mice","volume":"27","author":"Murru","year":"2017","journal-title":"Cereb. Cortex"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"38771","DOI":"10.1038\/srep38771","article-title":"Changes in hippocampal AMPA receptors and cognitive impairments in chronic ketamine addiction models: Another understanding of ketamine CNS toxicity","volume":"6","author":"Ding","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/1742-2094-11-121","article-title":"Neuronal CCL2 is upregulated during hepatic encephalopathy and contributes to microglia activation and neurological decline","volume":"11","author":"McMillin","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3389\/fncel.2017.00191","article-title":"Bile Acid-Mediated Sphingosine-1-Phosphate Receptor 2 Signaling Promotes Neuroinflammation during Hepatic Encephalopathy in Mice","volume":"11","author":"McMillin","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"352","DOI":"10.14218\/JCTH.2019.00025","article-title":"The Direct Contribution of Astrocytes and Microglia to the Pathogenesis of Hepatic Encephalopathy","volume":"7","author":"Jaeger","year":"2019","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3658","DOI":"10.1096\/fj.201600275R","article-title":"Effects of bile acids on neurological function and disease","volume":"30","author":"McMillin","year":"2016","journal-title":"FASEB J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s12974-016-0674-8","article-title":"Fractalkine suppression during hepatic encephalopathy promotes neuroinflammation in mice","volume":"13","author":"McMillin","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Arenas, Y.M., Balzano, T., Ivaylova, G., Llansola, M., and Felipo, V. (2022). The S1PR2-CCL2-BDNF-TrkB pathway mediates neuroinflammation and motor incoordination in hyperammonaemia. Neuropathol. Appl. Neurobiol., 48.","DOI":"10.1111\/nan.12799"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"132","DOI":"10.3389\/fphar.2019.00132","article-title":"Bicuculline reduces neuroinflammation in hippocampus and improves spatial learning and anxiety in hyperammonemic rats. Role of glutamate receptors","volume":"10","author":"Malaguarnera","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11047","DOI":"10.1038\/s41598-020-68110-2","article-title":"Activation of GPR40 induces hypothalamic neurogenesis through p38- and BDNF-dependent mechanisms","volume":"10","author":"Engel","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12974-020-1704-0","article-title":"BDNF promotes activation of astrocytes and microglia contributing to neuroinflammation and mechanical allodynia in cyclophosphamide-induced cystitis","volume":"17","author":"Ding","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Jain, V., Baitharu, I., Prasad, D., and Ilavazhagan, G. (2013). Enriched Environment Prevents Hypobaric Hypoxia Induced Memory Impairment and Neurodegeneration: Role of BDNF\/PI3K\/GSK3 b Pathway Coupled with CREB Activation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062235"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Qiao, L.-Y., Yu, S.J., Kay, J.C., and Xia, C.-M. (2013). In Vivo Regulation of Brain-Derived Neurotrophic Factor in Dorsal Root Ganglia Is Mediated by Nerve Growth Factor-Triggered Akt Activation during Cystitis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0081547"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3408","DOI":"10.1007\/s12035-017-0578-3","article-title":"Glucose Can Epigenetically Alter the Gene Expression of Neurotrophic Factors in the Murine Brain Cells","volume":"55","author":"Hossain","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"118020","DOI":"10.1016\/j.lfs.2020.118020","article-title":"CREB and BDNF: Neurobiology and treatment of Alzheimer\u2019s disease","volume":"257","author":"Amidfar","year":"2020","journal-title":"Life Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1152\/jn.00541.2015","article-title":"Interleukin-1\u03b2 activates an Src family kinase to stimulate the plasma membrane Ca2+pump in hippocampal neurons","volume":"115","author":"Ghosh","year":"2016","journal-title":"J. Neurophysiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3256","DOI":"10.1093\/brain\/awn271","article-title":"A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1","volume":"131","author":"Balosso","year":"2008","journal-title":"Brain"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"18048","DOI":"10.1523\/JNEUROSCI.4067-11.2011","article-title":"Neuron-Specific Effects of Interleukin-1\u03b2 Are Mediated by a Novel Isoform of the IL-1 Receptor Accessory Protein","volume":"31","author":"Huang","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.brainres.2015.07.055","article-title":"GluN2B-containing NMDA receptors are upregulated in plasma membranes by the sphingosine-1-phosphate analog FTY720P","volume":"1624","author":"Essis","year":"2015","journal-title":"Brain Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"108291","DOI":"10.1016\/j.neuropharm.2020.108291","article-title":"Activation of voltage-gated sodium channels by BmK NT1 augments NMDA receptor function through Src family kinase signaling pathway in primary cerebellar granule cell cultures","volume":"180","author":"Zou","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Zhang, L., Tan, J., Jiang, X., Qian, W., Yang, T., Sun, X., Chen, Z., and Zhu, Q. (2017). Neuron-derived CCL2 contributes to microglia activation and neurological decline in hepatic encephalopathy. Biol. Res., 50.","DOI":"10.1186\/s40659-017-0130-y"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.bbr.2017.05.066","article-title":"Astrocyte-derived CCL2 participates in surgery-induced cognitive dysfunction and neuroinflammation via evoking microglia activation","volume":"332","author":"Xu","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1186\/s12974-018-1241-2","article-title":"Role of MCP-1 and CCR2 in ethanol-induced neuroinflammation and neurodegeneration in the developing brain","volume":"15","author":"Zhang","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_47","first-page":"e44667","article-title":"Astrocyte morphogenesis is dependent on BDNF signaling via astrocytic TrkB","volume":"8","author":"Holt","year":"2019","journal-title":"T1. e-Life"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.neuroscience.2009.06.011","article-title":"Activation of p38 mitogen-activated protein kinase is required for in vivo brain-derived neurotrophic factor production in the rat hippocampus","volume":"163","author":"Kaneko","year":"2009","journal-title":"Neuroscience"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1111\/bph.14882","article-title":"Neurotrophic interactions between neurons and astrocytes following AAV1-Rheb(S16H) transduction in the hippocampus in vivo","volume":"177","author":"Jeon","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/978-3-030-21735-8_15","article-title":"Roles of Ceramides and Other Sphingolipids in Immune Cell Function and Inflammation","volume":"1161","author":"Albeituni","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1007\/s10495-007-0721-0","article-title":"Sphingolipids and cell death","volume":"12","author":"Morales","year":"2007","journal-title":"Apoptosis"},{"key":"ref_52","first-page":"713","article-title":"Sphingolipids and cell signaling: Involvement in apoptosis and atherogenesis","volume":"71","author":"Ipatova","year":"2006","journal-title":"Biochemistry"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"515","DOI":"10.3389\/fneur.2019.00515","article-title":"The Role of BDNF in the Neuroimmune Axis Regulation of Mood Disorders","volume":"10","author":"Jin","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Palasz, E., Wysocka, A., Gasiorowska, A., Chalimoniuk, M., Niewiadomski, W., and Niewiadomska, G. (2020). BDNF as a Promising Therapeutic Agent in Parkinson\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21031170"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"28","DOI":"10.5483\/BMBRep.2020.53.1.278","article-title":"Sphingolipids in neuroinflammation: A potential target for diagnosis and therapy","volume":"53","author":"Lee","year":"2020","journal-title":"BMB Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"102290","DOI":"10.1016\/j.jaut.2019.06.001","article-title":"Myeloid sphingosine-1-phosphate receptor 1 is important for CNS autoimmunity and neuroinflammation","volume":"105","author":"Tsai","year":"2019","journal-title":"J. Autoimmun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1007\/s10072-021-05049-w","article-title":"Efficacy and acceptability of the S1P receptor in the treatment of multiple sclerosis: A meta-analysis","volume":"42","author":"Tong","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref_58","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_59","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3389\/fphar.2020.00077","article-title":"Sphingosine-1-Phosphate Receptors Modulators Decrease Signs of Neuroinflammation and Prevent Parkinson\u2019s Disease Symptoms in Tetrahydropyridine Mouse Model","volume":"11","author":"Jalinier","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_60","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":"Brackhan","year":"2020","journal-title":"Drugs R&D"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1093\/brain\/awaa425","article-title":"Gamma subunit of complement component 8 is a neuroinflammation inhibitor","volume":"144","author":"Kim","year":"2021","journal-title":"Brain"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3411","DOI":"10.1161\/STROKEAHA.108.514612","article-title":"Antagonism of Sphingosine 1-Phosphate Receptor-2 Enhances Migration of Neural Progenitor Cells toward an Area of Brain Infarction","volume":"39","author":"Kimura","year":"2008","journal-title":"Stroke"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17251\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:35:14Z","timestamp":1760132114000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17251"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,8]]},"references-count":62,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242417251"],"URL":"https:\/\/doi.org\/10.3390\/ijms242417251","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,8]]}}}