{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T21:26:28Z","timestamp":1776374788564,"version":"3.51.2"},"reference-count":188,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T00:00:00Z","timestamp":1605830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG046619"],"award-info":[{"award-number":["R01AG046619"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG059088"],"award-info":[{"award-number":["RF1AG059088"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21NS093368"],"award-info":[{"award-number":["R21NS093368"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21ES029657"],"award-info":[{"award-number":["R21ES029657"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AG065928"],"award-info":[{"award-number":["R21AG065928"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>This review highlights the pre-clinical and clinical work performed to use intranasal delivery of various compounds from growth factors to stem cells to reduce neuroimmune interactions. We introduce the concept of intranasal (IN) delivery and the variations of this delivery method based on the model used (i.e., rodents, non-human primates, and humans). We summarize the literature available on IN delivery of growth factors, vitamins and metabolites, cytokines, immunosuppressants, exosomes, and lastly stem cells. We focus on the improvement of neuroimmune interactions, such as the activation of resident central nervous system (CNS) immune cells, expression or release of cytokines, and detrimental effects of signaling processes. We highlight common diseases that are linked to dysregulations in neuroimmune interactions, such as Alzheimer\u2019s disease, Parkinson\u2019s disease, stroke, multiple sclerosis, and traumatic brain injury.<\/jats:p>","DOI":"10.3390\/pharmaceutics12111120","type":"journal-article","created":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T09:46:18Z","timestamp":1605865578000},"page":"1120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Intranasal Delivery: Effects on the Neuroimmune Axes and Treatment of Neuroinflammation"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8118-120X","authenticated-orcid":false,"given":"Elizabeth M.","family":"Rhea","sequence":"first","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aric F.","family":"Logsdon","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William A.","family":"Banks","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-1594","authenticated-orcid":false,"given":"Michelle E.","family":"Erickson","sequence":"additional","affiliation":[{"name":"Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/138032a0","article-title":"A syndrome produced by diverse nocuous agents","volume":"138","author":"Selye","year":"1936","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1146\/annurev.ps.44.020193.000413","article-title":"Psychoneuroimmunology\u2014Conditioning and stress","volume":"44","author":"Ader","year":"1993","journal-title":"Annu. Rev. Psychol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.bbi.2010.10.015","article-title":"Immune modulation of learning, memory, neural plasticity and neurogenesis","volume":"25","author":"Yirmiya","year":"2011","journal-title":"Brain Behav. Immun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1006\/brbi.1997.0508","article-title":"Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo: A potential role for leukocyte trafficking","volume":"11","author":"Dhabhar","year":"1997","journal-title":"Brain Behav. Immun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.bbi.2006.09.006","article-title":"Twenty years of research on cytokine-induced sickness behavior","volume":"21","author":"Dantzer","year":"2007","journal-title":"Brain Behav. Immun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.bbi.2015.03.016","article-title":"Altered fecal microbiota composition in patients with major depressive disorder","volume":"48","author":"Jiang","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1124\/pr.117.014647","article-title":"Neuroimmune Axes of the Blood-Brain Barriers and Blood-Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions","volume":"70","author":"Erickson","year":"2018","journal-title":"Pharm. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Banks, W.A. (2016). From blood-brain barrier to blood-brain interface: New opportunities for CNS drug delivery. Nat. Rev. Drug Discov.","DOI":"10.1038\/nrd.2015.21"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1208\/s12248-015-9719-7","article-title":"Intranasal Delivery of Proteins and Peptides in the Treatment of Neurodegenerative Diseases","volume":"17","author":"Meredith","year":"2015","journal-title":"AAPS J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/0006-8993(95)00637-6","article-title":"Quantitative analysis of the olfactory pathway for drug delivery to the brain","volume":"692","author":"Thorne","year":"1995","journal-title":"Brain Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/BF00237470","article-title":"Transneuronal transport of peroxidase-conjugated wheat germ agglutinin (WGA-HRP) from the olfactory epithelium to the brain of the adult rat","volume":"63","author":"Baker","year":"1986","journal-title":"Exp. Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1002\/cne.902510209","article-title":"Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey","volume":"251","author":"Balin","year":"1986","journal-title":"J. Comp. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0022-510X(01)00532-9","article-title":"Intranasal administration of insulin-like growth factor-I bypasses the blood-brain barrier and protects against focal cerebral ischemic damage","volume":"187","author":"Liu","year":"2001","journal-title":"J. Neurol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ullah, I., Chung, K., Beloor, J., Lee, S.K., and Kumar, P. (2019). A Positioning Device for the Placement of Mice During Intranasal siRNA Delivery to the Central Nervous System. J. Vis. Exp.","DOI":"10.3791\/59201-v"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hanson, L.R., Fine, J.M., Svitak, A.L., and Faltesek, K.A. (2013). Intranasal administration of CNS therapeutics to awake mice. J. Vis. Exp.","DOI":"10.3791\/4440"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1124\/jpet.103.063222","article-title":"Brain uptake of the glucagon-like peptide-1 antagonist exendin(9-39) after intranasal administration","volume":"309","author":"Banks","year":"2004","journal-title":"J. Pharm. Exp."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.ejps.2005.01.009","article-title":"Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents","volume":"24","author":"Westin","year":"2005","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s11095-020-02786-z","article-title":"Pre-Clinical Assessment of the Nose-to-Brain Delivery of Zonisamide After Intranasal Administration","volume":"37","author":"Goncalves","year":"2020","journal-title":"Pharm. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.neuroscience.2008.01.013","article-title":"Delivery of interferon-beta to the monkey nervous system following intranasal administration","volume":"152","author":"Thorne","year":"2008","journal-title":"Neuroscience"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/s11095-019-2613-8","article-title":"Direct Drug Delivery of Low-Permeable Compounds to the Central Nervous System Via Intranasal Administration in Rats and Monkeys","volume":"36","author":"Iwasaki","year":"2019","journal-title":"Pharm. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"14239","DOI":"10.1523\/JNEUROSCI.3878-07.2007","article-title":"Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates","volume":"27","author":"Deadwyler","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/mp.2017.27","article-title":"Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: Determination using a novel oxytocin assay","volume":"23","author":"Lee","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.neuroimage.2019.03.050","article-title":"Modulation of midbrain neurocircuitry by intranasal insulin","volume":"194","author":"Iglesias","year":"2019","journal-title":"NeuroImage"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Craft, S., Raman, R., Chow, T.W., Rafii, M.S., Sun, C.K., Rissman, R.A., Donohue, M.C., Brewer, J.B., Jenkins, C., and Harless, K. (2020). Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol.","DOI":"10.1001\/jamaneurol.2020.1840"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.addr.2011.11.002","article-title":"Intranasal delivery of biologics to the central nervous system","volume":"64","author":"Lochhead","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.peptides.2012.05.021","article-title":"Intranasal administration of PACAP: Uptake by brain and regional brain targeting with cyclodextrins","volume":"36","author":"Nonaka","year":"2012","journal-title":"Peptides"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1124\/jpet.107.132381","article-title":"Delivery of galanin-like peptide to the brain: Targeting with intranasal delivery and cyclodextrins","volume":"325","author":"Nonaka","year":"2008","journal-title":"J. Pharm. Exp."},{"key":"ref_28","first-page":"387","article-title":"P174: Intranasal administration of insulin-like growth factor-1 (IGF-1): A non-invasive CNS drug delivery strategy for bypassing the blood-brain barrier","volume":"9","author":"Thorne","year":"1999","journal-title":"Igf \u201899 Abstr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1007\/s12975-015-0409-7","article-title":"Intranasal Insulin and Insulin-Like Growth Factor 1 as Neuroprotectants in Acute Ischemic Stroke","volume":"6","author":"Lioutas","year":"2015","journal-title":"Transl. Stroke Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s11357-019-00065-3","article-title":"Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice","volume":"41","author":"Mao","year":"2019","journal-title":"Geroscience"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1159\/000477898","article-title":"Neuroprotective Effects of Intranasal IGF-1 against Neonatal Lipopolysaccharide-Induced Neurobehavioral Deficits and Neuronal Inflammation in the Substantia Nigra and Locus Coeruleus of Juvenile Rats","volume":"39","author":"Tien","year":"2017","journal-title":"Dev. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.neuroscience.2011.08.003","article-title":"Intranasal administration of insulin-like growth factor-1 protects against lipopolysaccharide-induced injury in the developing rat brain","volume":"194","author":"Cai","year":"2011","journal-title":"Neuroscience"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1203\/PDR.0b013e3181dc240f","article-title":"IGF-1 can either protect against or increase LPS-induced damage in the developing rat brain","volume":"67","author":"Pang","year":"2010","journal-title":"Pediatr. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.neulet.2007.08.031","article-title":"IGF-1 exacerbates the neurotoxicity of the mitochondrial inhibitor 3NP in rats","volume":"425","author":"Escartin","year":"2007","journal-title":"Neurosci. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.expneurol.2018.11.007","article-title":"Routes for the delivery of insulin to the central nervous system: A comparative review","volume":"313","author":"Rhea","year":"2019","journal-title":"Exp. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4084","DOI":"10.1210\/en.2004-0592","article-title":"Insulin attenuates the systemic inflammatory response in endotoxemic rats","volume":"145","author":"Jeschke","year":"2004","journal-title":"Endocrinology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s12974-015-0282-z","article-title":"Insulin improves memory and reduces chronic neuroinflammation in the hippocampus of young but not aged brains","volume":"12","author":"Adzovic","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"170175","DOI":"10.1016\/j.peptides.2019.170175","article-title":"Intranasal insulin treatment modulates the neurotropic, inflammatory, and oxidant mechanisms in the cortex and hippocampus in a low-grade inflammation model","volume":"123","author":"Simon","year":"2020","journal-title":"Peptides"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.3233\/JAD-190707","article-title":"Molecular Mechanisms of Intranasal Insulin in SAMP8 Mice","volume":"71","author":"Rhea","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"45971","DOI":"10.1038\/srep45971","article-title":"Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer\u2019s rat model","volume":"7","author":"Guo","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6507","DOI":"10.1007\/s12035-016-0169-8","article-title":"Intranasal Insulin Administration Ameliorates Streptozotocin (ICV)-Induced Insulin Receptor Dysfunction, Neuroinflammation, Amyloidogenesis, and Memory Impairment in Rats","volume":"54","author":"Rajasekar","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"715","DOI":"10.3233\/JAD-150307","article-title":"Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition","volume":"47","author":"Salameh","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.bbadis.2011.01.005","article-title":"Biliverdin reductase--a protein levels and activity in the brains of subjects with Alzheimer disease and mild cognitive impairment","volume":"1812","author":"Barone","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jneuroim.2018.04.018","article-title":"Thymoquinone increases the expression of neuroprotective proteins while decreasing the expression of pro-inflammatory cytokines and the gene expression NFkappaB pathway signaling targets in LPS\/IFNgamma -activated BV-2 microglia cells","volume":"320","author":"Taka","year":"2018","journal-title":"J. Neuroimmunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s12974-018-1155-z","article-title":"Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS\/NO pathway","volume":"15","author":"Zhang","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2922","DOI":"10.1007\/s12035-018-1231-5","article-title":"Biliverdin Reductase-A Mediates the Beneficial Effects of Intranasal Insulin in Alzheimer Disease","volume":"56","author":"Barone","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3203","DOI":"10.1177\/0271678X16685106","article-title":"Intranasal insulin treatment of an experimental model of moderate traumatic brain injury","volume":"37","author":"Brabazon","year":"2017","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"241","DOI":"10.3233\/JAD-161095","article-title":"Intranasal Insulin Transport is Preserved in Aged SAMP8 Mice and is Altered by Albumin and Insulin Receptor Inhibition","volume":"57","author":"Rhea","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1046\/j.1474-9728.2003.00046.x","article-title":"Neurogenesis and aging: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice","volume":"2","author":"Jin","year":"2003","journal-title":"Aging Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.ijpharm.2011.12.008","article-title":"Enhancement of nose-to-brain delivery of basic fibroblast growth factor for improving rat memory impairments induced by co-injection of beta-amyloid and ibotenic acid into the bilateral hippocampus","volume":"423","author":"Feng","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1007\/s11481-013-9501-5","article-title":"Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration","volume":"9","author":"Woodbury","year":"2014","journal-title":"J. Neuroimmune Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.intimp.2018.01.048","article-title":"Improving hyperglycemic effect of FGF-21 is associated with alleviating inflammatory state in diabetes","volume":"56","author":"Wang","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3389\/fphar.2020.00154","article-title":"FGF21 Attenuated LPS-Induced Depressive-Like Behavior via Inhibiting the Inflammatory Pathway","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Pharm."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1007\/s12640-019-00151-6","article-title":"FGF21 Protects Dopaminergic Neurons in Parkinson\u2019s Disease Models Via Repression of Neuroinflammation","volume":"37","author":"Fang","year":"2020","journal-title":"Neurotox. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"351","DOI":"10.2165\/00003088-200746040-00007","article-title":"Tolerability, safety and pharmacokinetics of the FGLL peptide, a novel mimetic of neural cell adhesion molecule, following intranasal administration in healthy volunteers","volume":"46","author":"Anand","year":"2007","journal-title":"Clin. Pharm."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1111\/j.1460-9568.2005.04345.x","article-title":"A synthetic NCAM-derived peptide, FGL, protects hippocampal neurons from ischemic insult both in vitro and in vivo","volume":"22","author":"Skibo","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0306-4522(03)00597-9","article-title":"Post-training administration of a synthetic peptide ligand of the neural cell adhesion molecule, C3d, attenuates long-term expression of contextual fear conditioning","volume":"122","author":"Cambon","year":"2003","journal-title":"Neuroscience"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1016\/j.neuroscience.2006.04.059","article-title":"A neural cell adhesion molecule-derived fibroblast growth factor receptor agonist, the FGL-peptide, promotes early postnatal sensorimotor development and enhances social memory retention","volume":"141","author":"Secher","year":"2006","journal-title":"Neuroscience"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.neuroscience.2006.11.060","article-title":"A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25-35","volume":"145","author":"Klementiev","year":"2007","journal-title":"Neuroscience"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.jconrel.2019.06.021","article-title":"Nose-to-brain delivery of hyaluronate\u2014FG loop peptide conjugate for non-invasive hypoxic-ischemic encephalopathy therapy","volume":"307","author":"Kim","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.lfs.2018.01.030","article-title":"The role of hippocampal brain-derived neurotrophic factor in age-related differences in neuropathic pain behavior in rats","volume":"197","author":"Tateiwa","year":"2018","journal-title":"Life Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.neurobiolaging.2010.04.003","article-title":"Object recognition memory and BDNF expression are reduced in young TgCRND8 mice","volume":"33","author":"Francis","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"637","DOI":"10.2147\/NDT.S227598","article-title":"A Study of Antidepressant Effect and Mechanism on Intranasal Delivery of BDNF-HA2TAT\/AAV to Rats with Post-Stroke Depression","volume":"16","author":"Chen","year":"2020","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"22404","DOI":"10.1038\/srep22404","article-title":"Intranasal Delivery of Recombinant AAV Containing BDNF Fused with HA2TAT: A Potential Promising Therapy Strategy for Major Depressive Disorder","volume":"6","author":"Ma","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.parkreldis.2016.05.023","article-title":"Low BDNF is associated with cognitive impairments in patients with Parkinson\u2019s disease","volume":"29","author":"Wang","year":"2016","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/0896-6273(91)90273-3","article-title":"BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer\u2019s disease","volume":"7","author":"Phillips","year":"1991","journal-title":"Neuron"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1016\/S0028-3908(98)00141-5","article-title":"Transport of brain-derived neurotrophic factor across the blood-brain barrier","volume":"37","author":"Pan","year":"1998","journal-title":"Neuropharmacology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"19402","DOI":"10.1038\/s41598-019-55294-5","article-title":"Focused ultrasound enhanced intranasal delivery of brain derived neurotrophic factor produces neurorestorative effects in a Parkinson\u2019s disease mouse model","volume":"9","author":"Ji","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"112488","DOI":"10.1016\/j.bbr.2020.112488","article-title":"Exercise effects on brain and behavior in healthy mice, Alzheimer\u2019s disease and Parkinson\u2019s disease model-A systematic review and meta-analysis","volume":"383","year":"2020","journal-title":"Behav. Brain Res."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Szymura, J., Kubica, J., Wiecek, M., and Pera, J. (2020). The Immunomodulary Effects of Systematic Exercise in Older Adults and People with Parkinson\u2019s Disease. J. Clin. Med., 9.","DOI":"10.3390\/jcm9010184"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.jneuroim.2018.12.005","article-title":"Effects of moderate- versus high- intensity swimming training on inflammatory and CD4(+) T cell subset profiles in experimental autoimmune encephalomyelitis mice","volume":"328","author":"Xie","year":"2019","journal-title":"J. Neuroimmunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s11011-018-0343-y","article-title":"Neuroprotective effects of exercise in rodent models of memory deficit and Alzheimer\u2019s","volume":"34","author":"Jahangiri","year":"2019","journal-title":"Metab. Brain Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"316","DOI":"10.2174\/1567205016666190228125429","article-title":"Distinctive Effects of Aerobic and Resistance Exercise Modes on Neurocognitive and Biochemical Changes in Individuals with Mild Cognitive Impairment","volume":"16","author":"Tsai","year":"2019","journal-title":"Curr. Alzheimer Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.brainres.2013.10.047","article-title":"Alteration in BDNF and its receptors, full-length and truncated TrkB and p75(NTR) following penetrating traumatic brain injury","volume":"1542","author":"Rostami","year":"2014","journal-title":"Brain Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"13646","DOI":"10.1038\/s41598-019-49428-y","article-title":"Pioglitazone treatment prior to transplantation improves the efficacy of human mesenchymal stem cells after traumatic brain injury in rats","volume":"9","author":"Das","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1089\/neu.2015.3949","article-title":"Circulating Brain-Derived Neurotrophic Factor Has Diagnostic and Prognostic Value in Traumatic Brain Injury","volume":"33","author":"Korley","year":"2016","journal-title":"J. Neurotrauma"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1002\/jnr.24510","article-title":"Brain-derived neurotrophic factor and post-stroke depression","volume":"98","author":"Zhang","year":"2020","journal-title":"J. Neurosci. Res."},{"key":"ref_78","unstructured":"Han, Z., Wang, Y., Qi, L., Wang, J., Wong, J., Chen, J., Luo, X., and Wang, Q.M. (2020). Differential association of serum BDNF with post-stroke depression and post-stroke anxiety. Arch. Phys. Med. Rehabil."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.neuroscience.2010.10.054","article-title":"Intranasal brain-derived neurotrophic factor protects brain from ischemic insult via modulating local inflammation in rats","volume":"172","author":"Jiang","year":"2011","journal-title":"Neuroscience"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3109\/08977194.2013.804073","article-title":"Nerve growth factor: Basic studies and possible therapeutic applications","volume":"31","author":"Manni","year":"2013","journal-title":"Growth Factors"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3109\/10717549709051878","article-title":"Delivery of 125I-NGF to the Brain via the Olfactory Route","volume":"4","author":"Frey","year":"1997","journal-title":"Drug Deliv."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.brainres.2012.11.028","article-title":"Intranasal delivery of nerve growth factor attenuates aquaporins-4-induced edema following traumatic brain injury in rats","volume":"1493","author":"Lv","year":"2013","journal-title":"Brain Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1007\/s00381-020-04590-x","article-title":"Intranasal nerve growth factor administration improves neurological outcome after GBS meningitis","volume":"36","author":"Chiaretti","year":"2020","journal-title":"Childs Nerv. Syst."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Herold, R., Schroten, H., and Schwerk, C. (2019). Virulence Factors of Meningitis-Causing Bacteria: Enabling Brain Entry across the Blood-Brain Barrier. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215393"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"245","DOI":"10.3345\/kjp.2018.61.8.245","article-title":"Patterns of ischemic injury on brain images in neonatal group B Streptococcal meningitis","volume":"61","author":"Choi","year":"2018","journal-title":"Korean J. Pediatr."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1080\/02699052.2017.1376760","article-title":"Intranasal Nerve Growth Factor administration improves cerebral functions in a child with severe traumatic brain injury: A case report","volume":"31","author":"Chiaretti","year":"2017","journal-title":"Brain Inj."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1111\/j.1749-6632.1996.tb17489.x","article-title":"Transport of pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier and the prevention of ischemia-induced death of hippocampal neurons","volume":"805","author":"Banks","year":"1996","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.1096\/fj.10-180133","article-title":"Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer\u2019s disease-like pathology in amyloid precursor protein-transgenic mice","volume":"25","author":"Rat","year":"2011","journal-title":"FASEB J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"370ra181","DOI":"10.1126\/scitranslmed.aaf9526","article-title":"Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy","volume":"8","author":"Polanco","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"8263","DOI":"10.1007\/s12035-018-0972-5","article-title":"Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Enhances Hippocampal Synaptic Plasticity and Improves Memory Performance in Huntington\u2019s Disease","volume":"55","author":"Masana","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_91","first-page":"e005","article-title":"Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARs)","volume":"7","author":"Germain","year":"2009","journal-title":"Nucl. Recept. Signal."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1146\/annurev-immunol-041015-055427","article-title":"Retinoic Acid and Retinoic Acid Receptors as Pleiotropic Modulators of the Immune System","volume":"34","author":"Larange","year":"2016","journal-title":"Annu. Rev. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1159\/000442076","article-title":"A Vitamin on the Mind: New Discoveries on Control of the Brain by Vitamin A","volume":"115","author":"Stoney","year":"2016","journal-title":"World Rev. Nutr. Diet."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1152\/physrev.2000.80.3.1021","article-title":"Retinoids in embryonal development","volume":"80","author":"Ross","year":"2000","journal-title":"Physiol. Rev."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/nrn2212","article-title":"Retinoic acid in the development, regeneration and maintenance of the nervous system","volume":"8","author":"Maden","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3067126","DOI":"10.1155\/2018\/3067126","article-title":"Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases","volume":"2018","author":"Oliveira","year":"2018","journal-title":"Mediat. Inflamm."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/imm.12040","article-title":"All-trans-retinoic acid ameliorates experimental allergic encephalomyelitis by affecting dendritic cell and monocyte development","volume":"138","author":"Zhan","year":"2013","journal-title":"Immunology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1186\/s12974-019-1557-6","article-title":"All trans-retinoic acid protects against acute ischemic stroke by modulating neutrophil functions through STAT1 signaling","volume":"16","author":"Cai","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1369\/0022155416679638","article-title":"All- Trans-Retinoic Acid Augments the Histopathological Outcome of Neuroinflammation and Neurodegeneration in Lupus-Prone MRL\/lpr Mice","volume":"65","author":"Theus","year":"2017","journal-title":"J. Histochem. Cytochem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1001\/archderm.1987.01660340137036","article-title":"Side effects and long-term toxicity of synthetic retinoids","volume":"123","author":"Yob","year":"1987","journal-title":"Arch. Derm."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/355359a0","article-title":"9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha","volume":"355","author":"Levin","year":"1992","journal-title":"Nature"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1073\/pnas.90.1.30","article-title":"Retinoic acid receptors and retinoid X receptors: Interactions with endogenous retinoic acids","volume":"90","author":"Allenby","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.neulet.2004.07.086","article-title":"Midkine and retinoic acid reduce cerebral infarction induced by middle cerebral artery ligation in rats","volume":"369","author":"Harvey","year":"2004","journal-title":"Neurosci. Lett."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"4512","DOI":"10.1038\/s41598-017-04048-2","article-title":"9-cis retinoic acid induces neurorepair in stroke brain","volume":"7","author":"Yu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Yin, L.H., Shen, H., Diaz-Ruiz, O., Backman, C.M., Bae, E., Yu, S.J., and Wang, Y. (2012). Early post-treatment with 9-cis retinoic acid reduces neurodegeneration of dopaminergic neurons in a rat model of Parkinson\u2019s disease. BMC Neurosci., 13.","DOI":"10.1186\/1471-2202-13-120"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"5469","DOI":"10.18632\/aging.102970","article-title":"Intranasal delivery of 9-cis retinoic acid reduces beta-amyloid deposition via inhibiting astrocyte-mediated inflammation","volume":"12","author":"Zhao","year":"2020","journal-title":"Aging (Albany Ny)"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"112738","DOI":"10.1016\/j.ejmech.2020.112738","article-title":"Vitamin D and its analogs as anticancer and anti-inflammatory agents","volume":"207","author":"Chen","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_108","first-page":"69","article-title":"Vitamin D and inflammatory diseases","volume":"7","author":"Yin","year":"2014","journal-title":"J. Inflamm. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.1177\/0271678X16671147","article-title":"Intranasal administration of vitamin D attenuates blood-brain barrier disruption through endogenous upregulation of osteopontin and activation of CD44\/P-gp glycosylation signaling after subarachnoid hemorrhage in rats","volume":"37","author":"Enkhjargal","year":"2017","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S1471-4914(01)01963-3","article-title":"A crucial role for CD44 in inflammation","volume":"7","author":"Pure","year":"2001","journal-title":"Trends Mol. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1186\/s12967-020-02488-5","article-title":"The importance of vitamin d metabolism as a potential prophylactic, immunoregulatory and neuroprotective treatment for COVID-19","volume":"18","author":"Xu","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Ambrogini, P., Betti, M., Galati, C., Di Palma, M., Lattanzi, D., Savelli, D., Galli, F., Cuppini, R., and Minelli, A. (2016). alpha-Tocopherol and Hippocampal Neural Plasticity in Physiological and Pathological Conditions. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122107"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"148","DOI":"10.3389\/fneur.2019.00148","article-title":"Dietary Vitamin E as a Protective Factor for Parkinson\u2019s Disease: Clinical and Experimental Evidence","volume":"10","author":"Schirinzi","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2382563","DOI":"10.1155\/2019\/2382563","article-title":"Vitamin E Loaded Naringenin Nanoemulsion via Intranasal Delivery for the Management of Oxidative Stress in a 6-OHDA Parkinson\u2019s Disease Model","volume":"2019","author":"Gaba","year":"2019","journal-title":"Biomed. Res. Int."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"5012341","DOI":"10.1155\/2016\/5012341","article-title":"A Review of Recent Advances in Neuroprotective Potential of 3-N-Butylphthalide and Its Derivatives","volume":"2016","author":"Abdoulaye","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.neuint.2017.03.017","article-title":"DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice","volume":"111","author":"Zhao","year":"2017","journal-title":"Neurochem. Int."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.nbd.2017.11.009","article-title":"Axl activation attenuates neuroinflammation by inhibiting the TLR\/TRAF\/NF-kappaB pathway after MCAO in rats","volume":"110","author":"Wu","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"139","DOI":"10.4049\/jimmunol.1303284","article-title":"Astrocytic TGF-beta signaling limits inflammation and reduces neuronal damage during central nervous system Toxoplasma infection","volume":"193","author":"Cekanaviciute","year":"2014","journal-title":"J. Immunol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1096\/fj.08-124545","article-title":"Increased IkappaB alpha expression is essential for the tolerogenic property of TGF-beta-exposed APCs","volume":"23","author":"Ghafoori","year":"2009","journal-title":"FASEB J."},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Ma, M., Ma, Y., Yi, X., Guo, R., Zhu, W., Fan, X., Xu, G., Frey, W.H., and Liu, X. (2008). Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone. BMC Neurosci, 9.","DOI":"10.1186\/1471-2202-9-117"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1002\/iub.361","article-title":"The multifaceted effects of granulocyte colony-stimulating factor in immunomodulation and potential roles in intestinal immune homeostasis","volume":"62","author":"Martins","year":"2010","journal-title":"IUBMB Life"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/1742-2094-8-74","article-title":"Granulocyte colony stimulating factor attenuates inflammation in a mouse model of amyotrophic lateral sclerosis","volume":"8","author":"Pollari","year":"2011","journal-title":"J. Neuroinflamm."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.bbi.2015.10.002","article-title":"Assessing blood granulocyte colony-stimulating factor as a potential biomarker of acute traumatic brain injury in mice and humans","volume":"52","author":"Banks","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1007\/s12035-014-8984-2","article-title":"Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats","volume":"53","author":"Sun","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1172\/JCI29834","article-title":"A mighty mouse: Building a better model of multiple sclerosis","volume":"116","author":"Ransohoff","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1016\/S0140-6736(08)61620-7","article-title":"Multiple sclerosis","volume":"372","author":"Compston","year":"2008","journal-title":"Lancet"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.2165\/00003495-200161120-00001","article-title":"Interferon-beta therapy in multiple sclerosis: Evidence for a clinically relevant dose response","volume":"61","author":"Goodin","year":"2001","journal-title":"Drugs"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jneuroim.2004.02.011","article-title":"Intranasal administration of interferon beta bypasses the blood-brain barrier to target the central nervous system and cervical lymph nodes: A non-invasive treatment strategy for multiple sclerosis","volume":"151","author":"Ross","year":"2004","journal-title":"J. Neuroimmunol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.immuni.2008.04.006","article-title":"Type 1 interferons cool the inflamed brain","volume":"28","author":"Axtell","year":"2008","journal-title":"Immunity"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0091-6749(98)70080-6","article-title":"The role of IL-13 and its receptor in allergy and inflammatory responses","volume":"102","year":"1998","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"799","DOI":"10.4049\/jimmunol.154.2.799","article-title":"IL-13 selectively induces vascular cell adhesion molecule-1 expression in human endothelial cells","volume":"154","author":"Bochner","year":"1995","journal-title":"J. Immunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.cell.2017.08.006","article-title":"Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch","volume":"171","author":"Oetjen","year":"2017","journal-title":"Cell"},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Ghezzi, L., Cantoni, C., Cignarella, F., Bollman, B., Cross, A.H., Salter, A., Galimberti, D., Cella, M., and Piccio, L. (2019). T cells producing GM-CSF and IL-13 are enriched in the cerebrospinal fluid of relapsing MS patients. Mult. Scler.","DOI":"10.1177\/1352458519852092"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.autrev.2019.03.012","article-title":"The role of interleukin-13 in chronic inflammatory intestinal disorders","volume":"18","author":"Giuffrida","year":"2019","journal-title":"Autoimmun. Rev."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1165\/rcmb.2015-0015OC","article-title":"Brain-Derived Neurotrophic Factor Expression in Asthma. Association with Severity and Type 2 Inflammatory Processes","volume":"53","author":"Watanabe","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.4049\/jimmunol.1900909","article-title":"IL-13 Ameliorates Neuroinflammation and Promotes Functional Recovery after Traumatic Brain Injury","volume":"204","author":"Miao","year":"2020","journal-title":"J. Immunol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"2597","DOI":"10.1038\/s41386-018-0154-1","article-title":"Resolution of inflammation-induced depression requires T lymphocytes and endogenous brain interleukin-10 signaling","volume":"43","author":"Laumet","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.neuroscience.2015.06.038","article-title":"TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects","volume":"302","author":"Probert","year":"2015","journal-title":"Neuroscience"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"49","DOI":"10.3389\/fnins.2019.00049","article-title":"Targeting TNFR2 as a Novel Therapeutic Strategy for Alzheimer\u2019s Disease","volume":"13","author":"Wu","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/1742-2094-5-45","article-title":"TNF signaling inhibition in the CNS: Implications for normal brain function and neurodegenerative disease","volume":"5","author":"McCoy","year":"2008","journal-title":"J. Neuroinflamm."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"S38","DOI":"10.5664\/JCSM.1360","article-title":"Biochemical regulation of sleep and sleep biomarkers","volume":"7","author":"Clinton","year":"2011","journal-title":"J. Clin. Sleep Med."},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Kunchok, A., Aksamit, A.J., Davis, J.M., Kantarci, O.H., Keegan, B.M., Pittock, S.J., Weinshenker, B.G., and McKeon, A. (2020). Association Between Tumor Necrosis Factor Inhibitor Exposure and Inflammatory Central Nervous System Events. JAMA Neurol.","DOI":"10.1001\/jamaneurol.2020.1162"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jbiotec.2010.01.011","article-title":"Selective targeting of a TNFR decoy receptor pharmaceutical to the primate brain as a receptor-specific IgG fusion protein","volume":"146","author":"Boado","year":"2010","journal-title":"J. Biotechnol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1159\/000097202","article-title":"Passage of cytokines across the blood-brain barrier","volume":"2","author":"Banks","year":"1995","journal-title":"Neuroimmunomodulation"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1212\/WNL.0b013e3181b6bb95","article-title":"Systemic inflammation and disease progression in Alzheimer disease","volume":"73","author":"Holmes","year":"2009","journal-title":"Neurology"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1212\/WNL.0000000000001617","article-title":"Etanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial","volume":"84","author":"Butchart","year":"2015","journal-title":"Neurology"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1179573517709278","DOI":"10.1177\/1179573517709278","article-title":"Tumor necrosis factor alpha Inhibition for Alzheimer\u2019s Disease","volume":"9","author":"Chang","year":"2017","journal-title":"J. Cent. Nerv. Syst. Dis."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1080\/13543784.2020.1709822","article-title":"Phase I\/II parallel double-blind randomized controlled clinical trial of perispinal etanercept for chronic stroke: Improved mobility and pain alleviation","volume":"29","author":"Ralph","year":"2020","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1002\/1529-0131(200109)44:9<1977::AID-ART345>3.0.CO;2-6","article-title":"Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism: By what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis?","volume":"44","author":"Robinson","year":"2001","journal-title":"Arthritis Rheum"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1136\/gut.30.8.1154","article-title":"Leukaemoid reaction and ulcerative colitis","volume":"30","author":"Merrin","year":"1989","journal-title":"Gut"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"101162","DOI":"10.1016\/j.redox.2019.101162","article-title":"Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome","volume":"23","author":"Tramutola","year":"2019","journal-title":"Redox Biol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s40035-018-0133-9","article-title":"Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome","volume":"7","author":"Tramutola","year":"2018","journal-title":"Transl. Neurodegener."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"170276","DOI":"10.1155\/2012\/170276","article-title":"Neuroinflammation in the aging down syndrome brain; lessons from Alzheimer\u2019s disease","volume":"2012","author":"Wilcock","year":"2012","journal-title":"Curr. Gerontol. Geriatr. Res."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1159\/000441419","article-title":"Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down\u2019s Syndrome","volume":"16","author":"Tramutola","year":"2016","journal-title":"Neurodegener. Dis."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1177\/0271678X16656201","article-title":"Sestrin2, as a negative feedback regulator of mTOR, provides neuroprotection by activation AMPK phosphorylation in neonatal hypoxic-ischemic encephalopathy in rat pups","volume":"37","author":"Shi","year":"2017","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1124\/jpet.118.254672","article-title":"CNS Delivery and Anti-Inflammatory Effects of Intranasally Administered Cyclosporine-A in Cationic Nanoformulations","volume":"370","author":"Yadav","year":"2019","journal-title":"J. Pharm. Exp."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"248","DOI":"10.2133\/dmpk.DMPK-10-RG-108","article-title":"Nasal delivery of P-gp substrates to the brain through the nose-brain pathway","volume":"26","author":"Shingaki","year":"2011","journal-title":"Drug Metab. Pharm."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/nri855","article-title":"Exosomes: Composition, biogenesis and function","volume":"2","author":"Thery","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.biomaterials.2017.07.011","article-title":"Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain","volume":"142","author":"Yuan","year":"2017","journal-title":"Biomaterials"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"6206","DOI":"10.2174\/1381612823666170913164738","article-title":"The Transport Mechanism of Extracellular Vesicles at the Blood-Brain Barrier","volume":"23","author":"Matsumoto","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Banks, W.A., Sharma, P., Bullock, K.M., Hansen, K.M., Ludwig, N., and Whiteside, T.L. (2020). Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124407"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1038\/mt.2011.164","article-title":"Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain","volume":"19","author":"Zhuang","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jconrel.2015.03.033","article-title":"Exosomes as drug delivery vehicles for Parkinson\u2019s disease therapy","volume":"207","author":"Haney","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1007\/s00401-014-1314-y","article-title":"Plasma exosomal alpha-synuclein is likely CNS-derived and increased in Parkinson\u2019s disease","volume":"128","author":"Shi","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/j.jalz.2016.04.003","article-title":"CNS tau efflux via exosomes is likely increased in Parkinson\u2019s disease but not in Alzheimer\u2019s disease","volume":"12","author":"Shi","year":"2016","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1080\/17425247.2018.1378642","article-title":"Intranasal delivery of stem cell-based therapies for the treatment of brain malignancies","volume":"15","author":"Li","year":"2018","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1517\/17425247.2011.566267","article-title":"Intranasal delivery of stem cells to the brain","volume":"8","author":"Jiang","year":"2011","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"3152","DOI":"10.1007\/s12035-017-0566-7","article-title":"Neural Stem Cell-Based Regenerative Approaches for the Treatment of Multiple Sclerosis","volume":"55","author":"Xiao","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1089\/neu.2008.0818","article-title":"Therapeutic effects of human mesenchymal stem cells on traumatic brain injury in rats: Secretion of neurotrophic factors and inhibition of apoptosis","volume":"27","author":"Kim","year":"2010","journal-title":"J. Neurotrauma"},{"key":"ref_170","doi-asserted-by":"crossref","unstructured":"Chau, M.J., Deveau, T.C., Gu, X., Kim, Y.S., Xu, Y., Yu, S.P., and Wei, L. (2018). Delayed and repeated intranasal delivery of bone marrow stromal cells increases regeneration and functional recovery after ischemic stroke in mice. BMC Neurosci., 19.","DOI":"10.1186\/s12868-018-0418-z"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1089\/rej.2010.1130","article-title":"Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease","volume":"14","author":"Danielyan","year":"2011","journal-title":"Rejuvenation Res."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.biomaterials.2016.05.025","article-title":"Non-virally engineered human adipose mesenchymal stem cells produce BMP4, target brain tumors, and extend survival","volume":"100","author":"Mangraviti","year":"2016","journal-title":"Biomaterials"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/nature03128","article-title":"Identification of human brain tumour initiating cells","volume":"432","author":"Singh","year":"2004","journal-title":"Nature"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/ana.20912","article-title":"The neurobiology of neurooncology","volume":"60","author":"Read","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"2276","DOI":"10.1093\/brain\/awx154","article-title":"Cell-based therapeutic strategies for multiple sclerosis","volume":"140","author":"Scolding","year":"2017","journal-title":"Brain"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"e55","DOI":"10.1002\/cpsc.55","article-title":"A Method for Isolating and Characterizing Mesenchymal Stromal Cell-derived Extracellular Vesicles","volume":"46","author":"Reverberi","year":"2018","journal-title":"Curr. Protoc. Stem Cell Biol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1002\/sctm.16-0363","article-title":"Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Anti-Inflammatory Effects: Endorsement of Macrophage Polarization","volume":"6","author":"Reverberi","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1111\/cns.12759","article-title":"Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: Clinical, ophthalmological and radiological assessments of safety and efficacy","volume":"23","author":"Dahbour","year":"2017","journal-title":"CNS Neurosci. Ther."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.biochi.2018.07.026","article-title":"Exploiting the impact of the secretome of MSCs isolated from different tissue sources on neuronal differentiation and axonal growth","volume":"155","author":"Patricio","year":"2018","journal-title":"Biochimie"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/s41598-017-18867-w","article-title":"Human Mesenchymal Stromal Cell-Derived Extracellular Vesicles Modify Microglial Response and Improve Clinical Outcomes in Experimental Spinal Cord Injury","volume":"8","author":"Ruppert","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Losurdo, M., Pedrazzoli, M., D\u2019Agostino, C., Elia, C.A., Massenzio, F., Lonati, E., Mauri, M., Rizzi, L., Molteni, L., and Bresciani, E. (2020). Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer\u2019s disease. Stem Cells Transl. Med.","DOI":"10.1002\/sctm.19-0327"},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Kodali, M., Castro, O.W., Kim, D.K., Thomas, A., Shuai, B., Attaluri, S., Upadhya, R., Gitai, D., Madhu, L.N., and Prockop, D.J. (2019). Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010181"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.expneurol.2015.03.011","article-title":"Intranasal delivery of hypoxia-preconditioned bone marrow-derived mesenchymal stem cells enhanced regenerative effects after intracerebral hemorrhagic stroke in mice","volume":"272","author":"Sun","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"249","DOI":"10.2147\/NDT.S238646","article-title":"Intranasal Delivery of Bone Marrow Stromal Cells Preconditioned with Fasudil to Treat a Mouse Model of Parkinson\u2019s Disease","volume":"16","author":"Tang","year":"2020","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"909657","DOI":"10.1155\/2014\/909657","article-title":"Human umbilical cord mesenchymal stem cells infected with adenovirus expressing HGF promote regeneration of damaged neuron cells in a Parkinson\u2019s disease model","volume":"2014","author":"Liu","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"101792","DOI":"10.1016\/j.jchemneu.2020.101792","article-title":"Intranasal administration of conditioned medium derived from mesenchymal stem cells-differentiated oligodendrocytes ameliorates experimental autoimmune encephalomyelitis","volume":"106","author":"Mohamadi","year":"2020","journal-title":"J. Chem. Neuroanat."},{"key":"ref_187","doi-asserted-by":"crossref","unstructured":"Erickson, M.A., and Banks, W.A. (2019). Age-Associated Changes in the Immune System and Blood(-)Brain Barrier Functions. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20071632"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s12987-020-00187-3","article-title":"In vitro modeling of blood-brain barrier and interface functions in neuroimmune communication","volume":"17","author":"Erickson","year":"2020","journal-title":"Fluids Barriers CNS"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/11\/1120\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:35:04Z","timestamp":1760178904000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/11\/1120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,20]]},"references-count":188,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["pharmaceutics12111120"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics12111120","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,20]]}}}