{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:45:43Z","timestamp":1791902743998,"version":"4.3.4"},"reference-count":159,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    The study investigates the neuroprotective potential of paeoniflorin (PNN) in mitigating the multifaceted pathology of multiple sclerosis (MS) in an ethidium bromide-induced (EBRO) rat model. A comprehensive approach utilizing\n                    <jats:italic>in silico<\/jats:italic>\n                    ,\n                    <jats:italic>in-vitro<\/jats:italic>\n                    , and\n                    <jats:italic>in-vivo<\/jats:italic>\n                    methodologies reveals that PNN targets key molecular pathways implicated in MS, including the GDNF\/GFRA1\/RET\/AKT\/ERK1\/2\/GSK3-Beta signaling cascade. PNN (50\u00a0mg\/kg, 100\u00a0mg\/kg,\n                    <jats:italic>p.o<\/jats:italic>\n                    .) administration, both as monotherapy and in combination with VB-12 (30\u00a0mg\/kg,\n                    <jats:italic>p.o<\/jats:italic>\n                    .), demonstrated significant efficacy in reducing EBRO-induced neurodegeneration, demyelination, synaptic dysfunction, and neuroinflammation. Behavioral assessments such as the rotarod, beam crossing, and Morris water maze tests highlighted PNN capacity to restore motor coordination, spatial memory, and cognitive function. Combination therapy with VB12 (30) further enhanced these outcomes, demonstrating synergistic therapeutic benefits. Histological and molecular analyses revealed that PNN100 alleviates demyelination, reduces inflammatory cytokines TNF-\u03b1, IL-1\u03b2, and restores anti-inflammatory markers (IL-10) in brain homogenates, CSF, and blood plasma. Moreover, PNN normalized neurotransmitter imbalances, including elevated glutamate and reduced GABA, dopamine, serotonin, and acetylcholine levels, highlighting its role in restoring excitatory-inhibitory balance. ELISA studies confirmed PNN ability to modulate apoptotic markers Bax, Bcl-2, and Caspase-3 and upregulate neurotrophic factors GDNF, and GFRA1 while downregulating hyperactivated pathways like AKT, ERK1\/2, and GSK3-Beta. Additionally, hematological parameters disrupted by EBRO were significantly restored by PNN, indicating its systemic anti-inflammatory and hematoprotective effects. This research provides the first evidence of PNN\u2019s role in modulating the GDNF\/GFRA1\/RET\/AKT\/ERK1\/2\/GSK3\u03b2 pathway in MS. Its synergistic action with VB12 underscores its potential as a combinatorial therapeutic strategy. The findings pave the way for innovative treatment approaches to improve outcomes for MS patients by addressing neurodegeneration, inflammation, and systemic immune dysregulation.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1792674","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:00:58Z","timestamp":1775800858000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Enhanced therapeutic potential of paeoniflorin and vitamin B12 in intracerebropeduncle ethidium bromide-induced multiple sclerosis-like pathology"],"prefix":"10.3389","volume":"17","author":[{"given":"MD Nasiruddin","family":"Khan","sequence":"first","affiliation":[{"name":"Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India (Affiliated to IK Gujral Punjab Technical University)","place":["Jalandhar, Punjab, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidharth","family":"Mehan","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India (Affiliated to IK Gujral Punjab Technical University)","place":["Jalandhar, Punjab, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Choudhary","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India (Affiliated to IK Gujral Punjab Technical University)","place":["Jalandhar, Punjab, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Rana","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India (Affiliated to IK Gujral Punjab Technical University)","place":["Jalandhar, Punjab, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghanshyam","family":"Das Gupta","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India (Affiliated to IK Gujral Punjab Technical University)","place":["Jalandhar, Punjab, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Acharan S.","family":"Narula","sequence":"additional","affiliation":[{"name":"Narula Research, LLC","place":["Chapel Hill, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1209477","DOI":"10.3389\/fneur.2023.1209477","article-title":"Impact of reflex locomotion and the bobath concept on clinical and biomolecular parameters in people with multiple sclerosis: study protocol for a randomized controlled trial","volume":"14","author":"Abreu-Corrales","year":"2023","journal-title":"Front. Neurology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e075972","DOI":"10.1002\/alz.075972","article-title":"Association of mild cognitive impairment, dementia and vitamin B12 levels in older adults","volume":"19","author":"Aguilar\u2010Navarro","year":"2023","journal-title":"Alzheimer\u2019s and Dementia"},{"key":"B3","doi-asserted-by":"publisher","first-page":"17018","DOI":"10.1038\/nrdp.2017.18","article-title":"Traumatic spinal cord injury","volume":"3","author":"Ahuja","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B4","doi-asserted-by":"publisher","first-page":"151","DOI":"10.4103\/2230-8229.189126","article-title":"Serum vitamin B12 and thyroid hormone levels in Saudi patients with multiple sclerosis","volume":"23","author":"Al-Khamis","year":"2016","journal-title":"J. Fam. Community Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2866","DOI":"10.3390\/biomedicines10112866","article-title":"Beta-boswellic acid reverses 3-Nitropropionic acid-induced molecular, mitochondrial, and histopathological defects in experimental rat model of huntington\u2019s disease","volume":"10","author":"Albekairi","year":"2022","journal-title":"Biomedicines"},{"key":"B420","first-page":"7951","article-title":"Effect of natural adenylcyclase\/cAMP\/CREB signalling activator forskolin against intra-striatal 6-OHDA-Lesioned parkinson\u2019s rats: preventing mitochondrial, motor and histopathological defects. Basel, Switzerland:","volume-title":"Molecules","author":"Alharbi","year":"2022"},{"key":"B6","doi-asserted-by":"publisher","first-page":"109610","DOI":"10.1016\/j.ejrad.2021.109610","article-title":"Altered in vivo brain GABA and glutamate levels are associated with multiple sclerosis central fatigue","volume":"137","author":"Arm","year":"2021","journal-title":"Eur. J. Radiology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"503650","DOI":"10.1016\/j.mrgentox.2023.503650","article-title":"The small molecule Erk1\/2 signaling pathway inhibitor PD98059 improves DNA repair in an experimental autoimmune encephalomyelitis SJL\/J mouse model of multiple sclerosis","volume":"889","author":"Attia","year":"2023","journal-title":"Mutat. Res. - Genet. Toxicol. Environ. Mutagen."},{"key":"B8","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1016\/j.neuron.2018.01.021","article-title":"Multiple sclerosis: mechanisms and immunotherapy","volume":"97","author":"Baecher-Allan","year":"2018","journal-title":"Neuron"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1038\/s41591-022-01956-3","article-title":"Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1\/2a trial","volume":"28","author":"Baloh","year":"2022","journal-title":"Nat. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"104662","DOI":"10.1016\/j.ebiom.2023.104662","article-title":"Articles blood neuro fi lament light levels predict non-relapsing progression following anti-CD20 therapy in relapsing and primary progressive multiple sclerosis: fi ndings from the ocrelizumab randomised, double-blind phase 3 clinical trials","volume":"93","author":"Bar-or","year":"2023","journal-title":"eBioMedicine"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1002\/ana.27200","article-title":"Vitamin B12 levels association with functional and structural biomarkers of central nervous system injury in older adults","volume":"97","author":"Beaudry-richard","year":"2025","journal-title":"Ann. Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e107","DOI":"10.14440\/jbm.2019.265","article-title":"A minimally-invasive serial cerebrospinal fluid sampling model in conscious g\u00f6ttingen minipigs","volume":"6","author":"Bergadano","year":"2019","journal-title":"J. Biol. Methods"},{"key":"B13","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/j.jmb.2003.08.031","article-title":"Structural characterization of the GSK-3\u03b2 active site using selective and non-selective ATP-Mimetic inhibitors","volume":"333","author":"Bertrand","year":"2003","journal-title":"J. Mol. Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"102296","DOI":"10.1016\/j.npep.2022.102296","article-title":"4-hydroxyisoleucine mediated IGF-1\/GLP-1 signalling activation prevents propionic acid-induced autism-like behavioural phenotypes and neurochemical defects in experimental rats","volume":"96","author":"Bhalla","year":"2022","journal-title":"Neuropeptides"},{"key":"B15","doi-asserted-by":"publisher","first-page":"103006","DOI":"10.1016\/j.msard.2021.103006","article-title":"Interleukin-1 receptor antagonist: an exploratory plasma biomarker that correlates with disabilty and provides pathophysiological insights in relapsing-remitting multiple sclerosis","volume":"52","author":"Blandford","year":"2021","journal-title":"Multiple Scler. Relat. Disord."},{"key":"B16","doi-asserted-by":"publisher","first-page":"241","DOI":"10.33594\/000000368","article-title":"Vitamin B12 induces hepatic fatty infiltration through altered fatty acid metabolism","volume":"55","author":"Boachie","year":"2021","journal-title":"Cell. Physiology Biochem."},{"key":"B17","first-page":"1365","article-title":"Oxidative stress markers in cerebrospinal fluid of newly diagnosed multiple sclerosis patients and their link to iron deposition and atrophy","volume-title":"Diagnostics","author":"Burgetova","year":"2022"},{"key":"B18","doi-asserted-by":"publisher","first-page":"825","DOI":"10.3892\/ijmm.2017.3076","article-title":"Paeoniflorin exerts neuroprotective effects against glutamate-induced PC12 cellular cytotoxicity by inhibiting apoptosis","volume":"40","author":"Chen","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"545","DOI":"10.3390\/md18110545","article-title":"Recent advances in molecular docking for the research and discovery of potential marine drugs","volume":"18","author":"Chen","year":"2020","journal-title":"Mar. Drugs"},{"key":"B20","doi-asserted-by":"publisher","first-page":"6922","DOI":"10.3390\/molecules28196922","article-title":"New monoterpene glycoside paeoniflorin derivatives as NO and IL-1\u03b2 inhibitors: synthesis and biological evaluation","volume":"28","author":"Chen","year":"2023","journal-title":"Molecules"},{"key":"B21","doi-asserted-by":"publisher","first-page":"114046","DOI":"10.1016\/j.jep.2021.114046","article-title":"Paeoniflorin exerts antidepressant-like effects through enhancing neuronal FGF-2 by microglial inactivation","volume":"274","author":"Cheng","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1007\/s11011-023-01214-6","article-title":"Matrine exerts its neuroprotective effects by modulating multiple neuronal pathways","volume":"38","author":"Chhabra","year":"2023","journal-title":"Metab. Brain Dis."},{"key":"B23","doi-asserted-by":"publisher","first-page":"578200","DOI":"10.1016\/j.jneuroim.2023.578200","article-title":"Matrine mediated neuroprotective potential in experimental multiple sclerosis: evidence from CSF, blood markers, brain samples and in-silico investigations","volume":"384","author":"Chhabra","year":"2023","journal-title":"J. Neuroimmunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"593","DOI":"10.4162\/nrp.2020.14.6.593","article-title":"Paeoniflorin ameliorates A\u03b2-stimulated neuroinflammation via regulation of NF-\u03baB signaling pathway and A\u03b2 degradation in C6 glial cells","volume":"14","author":"Cho","year":"2020","journal-title":"Nutr. Res. Pract."},{"key":"B25","doi-asserted-by":"publisher","first-page":"177417","DOI":"10.1016\/j.ejphar.2025.177417","article-title":"Navigating the complexities of neuronal signaling and targets in neurological disorders: from pathology to therapeutics","volume":"995","author":"Choudhary","year":"2025","journal-title":"Eur. J. Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/S0165-5728(02)00467-8","article-title":"Caspase inhibitors protect against neuronal apoptosis induced by cerebrospinal fluid from multiple sclerosis patients","volume":"136","author":"Cid","year":"2003","journal-title":"J. Neuroimmunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"102437","DOI":"10.1016\/j.pmedr.2023.102437","article-title":"Short communication A pilot study evaluating the prefeasibility of a behavioral weight loss program in people with multiple sclerosis","volume":"36","author":"Cozart","year":"2023","journal-title":"Prev. Med. Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1007\/978-1-4939-2269-7_19","article-title":"Small-molecule library screening by docking with PyRx","volume":"1263","author":"Dallakyan","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2020.588405","article-title":"Impact of persistent anemia on systemic inflammation and tuberculosis outcomes in persons living with HIV","volume":"11","author":"Demitto","year":"2020","journal-title":"Front. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms17122009","article-title":"Dysregulated homeostasis of acetylcholine levels in immune cells of RR-multiple sclerosis patients","volume":"17","author":"Di Bari","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/ene.13819","article-title":"Multiple sclerosis \u2013 a review","volume":"26","author":"Dobson","year":"2019","journal-title":"Eur. J. Neurology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"9523","DOI":"10.1073\/pnas.1301816110","article-title":"Preventing Alzheimer\u2019s disease-related gray matter atrophy by B-vitamin treatment","volume":"110","author":"Douaud","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/cddis.2016.263","article-title":"Ret is essential to mediate GDNF\u2019s neuroprotective and neuroregenerative effect in a parkinson disease mouse model","volume":"7","author":"Drinkut","year":"2016","journal-title":"Cell Death Dis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"601","DOI":"10.2174\/1567205017666201007120112","article-title":"Investigation of low dose cabazitaxel potential as microtubule stabilizer in experimental model of alzheimer\u2019s disease: restoring neuronal cytoskeleton","volume":"17","author":"Duggal","year":"2020","journal-title":"Curr. Alzheimer Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/nsb0697-435","article-title":"X-ray structure of glial cell-derived neurotrophic factor at 1.9 \u00c5 resolution and implications for receptor binding","volume":"4","author":"Eigenbrot","year":"1997","journal-title":"Nat. Struct. Biol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"200","DOI":"10.55782\/ane-2015-2028","article-title":"Effects of intracortical microinjection of vitamin B12 on penicillin-induced epileptiform activity in rats","author":"Erfanparast","year":"2015","journal-title":"Acta Neurobiol. Exp"},{"key":"B37","doi-asserted-by":"publisher","first-page":"101974","DOI":"10.1016\/j.toxrep.2025.101974","article-title":"Betaine alleviates deficits in motor behavior, neurotoxic effects, and neuroinflammatory responses in a rat model of demyelination","volume":"14","author":"Essawy","year":"2025","journal-title":"Toxicol. Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1007\/s11418-024-01781-7","article-title":"Paeoniflorin attenuates cuproptosis and ameliorates left ventricular remodeling after AMI in hypobaric hypoxia environments","volume":"78","author":"Fang","year":"2024","journal-title":"J. Nat. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.jns.2015.01.030","article-title":"Interleukin-10 but not transforming growth factor-\u03b21 gene expression is up-regulated by vitamin D treatment in multiple","volume":"350","author":"Farsani","year":"2015","journal-title":"J. Neurological Sci."},{"key":"B40","first-page":"1","article-title":"Aline fernanda ferreira","volume":"55","author":"Ferreira","year":"2014","journal-title":"arXiv"},{"key":"B41","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.neulet.2011.04.024","article-title":"GSK3\u03b2 genetic variability in patients with multiple sclerosis","volume":"497","author":"Galimberti","year":"2011","journal-title":"Neurosci. Lett."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1431349","DOI":"10.1155\/2016\/1431349","article-title":"GDNF enhances therapeutic efficiency of neural stem cells-based therapy in chronic experimental allergic encephalomyelitis in rat","volume":"2016","author":"Gao","year":"2016","journal-title":"Stem Cells Int."},{"key":"B43","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1097\/nen.0b013e3181461f54","article-title":"Extensive hippocampal demyelination in multiple sclerosis","volume":"66","author":"Geurts","year":"2007","journal-title":"J. Neuropathology Exp. Neurology"},{"key":"B44","doi-asserted-by":"publisher","first-page":"115831","DOI":"10.1016\/j.bcp.2023.115831","article-title":"Melatonin-mediated IGF-1\/GLP-1 activation in experimental OCD rats: evidence from CSF, blood plasma, brain and in-silico investigations","volume":"217","author":"Giri","year":"2023","journal-title":"Biochem. Pharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"2923","DOI":"10.1007\/s11064-016-2011-0","article-title":"Neuroprotective effects of paeoniflorin on 6-OHDA-Lesioned rat model of parkinson\u2019s disease","volume":"41","author":"Gu","year":"2016","journal-title":"Neurochem. Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1218506","DOI":"10.3389\/fphar.2023.1218506","article-title":"Renal mitochondrial restoration by gymnemic acid in gentamicin-mediated experimental nephrotoxicity: evidence from serum, kidney and histopathological alterations","volume":"14","author":"Gumbar","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B49","first-page":"14627","article-title":"Exploring the connection between BDNF\/TrkB and AC\/cAMP\/PKA\/CREB signaling pathways: potential for neuroprotection and therapeutic targets for neurological disorders","volume-title":"Mol. Neurobiol","author":"Gupta","year":"2025"},{"key":"B50","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.neuroscience.2025.01.021","article-title":"Disruptions in cellular communication: molecular interplay between glutamate\/NMDA signalling and MAPK pathways in neurological disorders","volume":"569","author":"Gupta","year":"2025","journal-title":"Neuroscience"},{"key":"B51","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1093\/brain\/awv398","article-title":"The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain","volume":"139","author":"Haider","year":"2016","journal-title":"Brain"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13287-024-03765-6","article-title":"Efficacy of intrathecal mesenchymal stem cell-neural progenitor therapy in progressive MS: results from a phase II, randomized, placebo-controlled clinical trial","volume":"15","author":"Harris","year":"2024","journal-title":"Stem Cell Res. Ther."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1007\/s11011-022-00937-2","article-title":"Paeoniflorin ameliorates cognitive impairment in Parkinson\u2019s disease via JNK\/p53 signaling","volume":"37","author":"He","year":"2022","journal-title":"Metab. Brain Dis."},{"key":"B54","doi-asserted-by":"publisher","first-page":"4978","DOI":"10.1021\/acs.jmedchem.8b00421","article-title":"Fragment-based discovery of a potent, orally bioavailable inhibitor that modulates the phosphorylation and catalytic activity of ERK1\/2","volume":"61","author":"Heightman","year":"2018","journal-title":"J. Med. Chem."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1742-2094-10-120","article-title":"Inflammatory demyelination induces glia alterations and ganglion cell loss in the retina of an experimental autoimmune encephalomyelitis model","volume":"10","author":"Horstmann","year":"2013","journal-title":"J. Neuroinflammation"},{"key":"B56","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.jns.2015.04.052","article-title":"Neuroprotective effect of ultra-high dose methylcobalamin in wobbler mouse model of amyotrophic lateral sclerosis","volume":"354","author":"Ikeda","year":"2015","journal-title":"J. Neurological Sci."},{"key":"B58","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1007\/s11596-022-2496-x","article-title":"Neuroprotective effect of chrysophanol as a PI3K\/AKT\/mTOR signaling inhibitor in an experimental model of autologous blood-induced intracerebral hemorrhage","volume":"42","author":"Jadaun","year":"2022","journal-title":"Curr. Med. Sci."},{"key":"B59","doi-asserted-by":"publisher","first-page":"14921","DOI":"10.1038\/s41598-018-33354-6","article-title":"Identification of novel acetylcholinesterase inhibitors designed by pharmacophore-based virtual screening, molecular docking and bioassay","volume":"8","author":"Jang","year":"2018","journal-title":"Sci. Rep."},{"key":"B60","doi-asserted-by":"publisher","first-page":"6532","DOI":"10.1074\/jbc.RA119.011802","article-title":"Cro Small-molecule agonists of the RET receptor tyrosine kinase activate biased trophic signals that are influenced by the presence of GFRa1 co-receptors","volume":"295","author":"Jmaeff","year":"2020","journal-title":"J. Biol. Chem."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-022-24550-6","article-title":"Peripheral blood mononuclear cell phenotype and function are maintained after overnight shipping of whole blood","volume":"12","author":"Johnson","year":"2022","journal-title":"Sci. Rep."},{"key":"B62","doi-asserted-by":"publisher","first-page":"113545","DOI":"10.1016\/j.celrep.2023.113545","article-title":"FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis","volume":"42","author":"Jonnalagadda","year":"2023","journal-title":"Cell Rep."},{"key":"B63","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fncel.2022.709596","article-title":"Cuprizone intoxication results in myelin vacuole formation","volume":"16","author":"Joost","year":"2022","journal-title":"Front. Cell. Neurosci."},{"key":"B64","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/jcm13133693","article-title":"TNF-alfa gene polymorphism associations with multiple sclerosis","volume":"13","author":"Kalvaitis","year":"2024","journal-title":"J. Clin. Med."},{"key":"B65","doi-asserted-by":"publisher","first-page":"31","DOI":"10.2174\/1570163817666200207100903","article-title":"Neuroprotective methodologies in the treatment of multiple sclerosis current status of clinical and pre-clinical findings","author":"Kapoor","year":"2020","journal-title":"Curr. Drug Discov. Technol"},{"key":"B66","doi-asserted-by":"publisher","first-page":"2771","DOI":"10.3390\/cells11182771","article-title":"Forskolin, an Adenylcyclase\/cAMP\/CREB signaling activator restoring myelin-associated oligodendrocyte destruction in experimental ethidium bromide model of multiple sclerosis","volume":"11","author":"Kapoor","year":"2022","journal-title":"Cells"},{"key":"B67","doi-asserted-by":"publisher","first-page":"4393","DOI":"10.1038\/s41598-021-83312-y","article-title":"To determine the effect of long-term antiepileptic drug on the serum folate and vitamin B12 among epileptic patients","volume":"11","author":"Kathiravan","year":"2021","journal-title":"Sci. Rep."},{"key":"B68","doi-asserted-by":"crossref","first-page":"192","DOI":"10.5567\/pharmacologia.2015.192.212","article-title":"Precautionary ellagic acid treatment ameliorates chronically administered scopolamine induced alzheimer\u2019s type memory and cognitive dysfunctions in rats","volume":"6","author":"Kaur","year":"2015","journal-title":"Pharmacologia"},{"key":"B69","doi-asserted-by":"publisher","first-page":"4319","DOI":"10.3390\/molecules27134319","article-title":"Anti-inflammatory and anti-rheumatic potential of selective plant compounds by targeting TLR-4\/AP-1 signaling: a comprehensive molecular docking and simulation approaches","volume":"27","author":"Khan","year":"2022","journal-title":"Molecules"},{"key":"B70","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.neuroscience.2024.04.004","article-title":"Immune system dysregulation in the progression of multiple sclerosis: molecular insights and therapeutic implications","volume":"548","author":"Khan","year":"2024","journal-title":"Neuroscience"},{"key":"B71","doi-asserted-by":"publisher","first-page":"102516","DOI":"10.1016\/j.npep.2025.102516","article-title":"Molecular mechanisms of GDNF\/GFRA1\/RET and PI3K\/AKT\/ERK signaling interplay in neuroprotection: therapeutic strategies for treating neurological disorders","volume":"111","author":"Khan","year":"2025","journal-title":"Neuropeptides"},{"key":"B72","doi-asserted-by":"publisher","first-page":"889","DOI":"10.3390\/molecules27030889","article-title":"Guggulsterone mediated JAK\/STAT and PPAR-gamma modulation prevents neurobehavioral and neurochemical abnormalities in propionic acid-induced experimental model of autism","volume":"27","author":"Khera","year":"2022","journal-title":"Molecules"},{"key":"B73","doi-asserted-by":"publisher","first-page":"369","DOI":"10.3390\/md21070369","article-title":"Antioxidant, antiviral, and anti-inflammatory activities of lutein-enriched extract of tetraselmis species","volume":"21","author":"Kim","year":"2023","journal-title":"Mar. Drugs"},{"key":"B74","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1523\/ENEURO.0149-16.2017","article-title":"Activation of Ras-ERK signaling and GSK-3 by amyloid precursor protein and amyloid beta facilitates neurodegeneration in Alzheimer\u2019s disease","volume":"4","author":"Kirouac","year":"2017","journal-title":"eNeuro"},{"key":"B75","doi-asserted-by":"publisher","first-page":"66","DOI":"10.4161\/pri.23499","article-title":"Grey matter damage in multiple sclerosis A pathology perspective","volume":"7","author":"Klaver","year":"2013","journal-title":"Prion"},{"key":"B76","doi-asserted-by":"publisher","first-page":"33577","DOI":"10.1074\/jbc.M605604200","article-title":"Structure and chemical inhibition of the RET tyrosine kinase domain","volume":"281","author":"Knowles","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B77","doi-asserted-by":"publisher","first-page":"105619","DOI":"10.1016\/j.jbc.2023.105619","article-title":"Akt activation ameliorates de fi cits in hippocampal-dependent memory and activity-dependent synaptic protein synthesis in an Alzheimer\u2019s disease mouse model","volume":"300","author":"Kommaddi","year":"2024","journal-title":"J. Biol. Chem."},{"key":"B78","doi-asserted-by":"publisher","first-page":"135016","DOI":"10.1016\/j.neulet.2020.135016","article-title":"Paeoniflorin exerts neuroprotective effects in a transgenic mouse model of Alzheimer\u2019s disease via activation of adenosine A1 receptor","volume":"730","author":"Kong","year":"2020","journal-title":"Neurosci. Lett."},{"key":"B79","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-020-73671-3","article-title":"Membrane stiffness and myelin basic protein binding strength as molecular origin of multiple sclerosis","volume":"10","author":"Krugmann","year":"2020","journal-title":"Sci. Rep."},{"key":"B80","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1016\/j.cell.2024.02.030","article-title":"Resource cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology ll ll cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology","volume":"187","author":"Kukanja","year":"2024","journal-title":"Cell"},{"key":"B81","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1007\/s11011-021-00691-x","article-title":"Guggulsterone ameliorates ethidium bromide-induced experimental model of multiple sclerosis via restoration of behavioral, molecular, neurochemical and morphological alterations in rat brain","volume":"36","author":"Kumar","year":"2021","journal-title":"Metab. Brain Dis."},{"key":"B82","doi-asserted-by":"publisher","first-page":"104547","DOI":"10.1016\/j.msard.2023.104547","article-title":"The importance of gut-brain axis and use of probiotics as a treatment strategy for multiple sclerosis","volume":"71","author":"Kumar","year":"2023","journal-title":"Multiple Scler. Relat. Disord."},{"key":"B83","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1080\/08927022.2023.2256624","article-title":"In-silico and in-vitro identification of triazole based compounds as potential EGFR inhibitors targeting lung cancer","volume":"49","author":"Kumar","year":"2023","journal-title":"Mol. Simul."},{"key":"B84","doi-asserted-by":"publisher","first-page":"527","DOI":"10.2174\/0118722105268801231203144554","article-title":"Formulation of solid lipid nanoparticles loaded with rosiglitazone and probiotic: optimization and in-vitro characterization","volume":"18","author":"Kumar","year":"2024","journal-title":"Recent Pat. Nanotechnol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"5161","DOI":"10.1007\/s12035-023-03902-x","article-title":"Guggulsterone selectively modulates STAT-3, mTOR, and PPAR-gamma signaling in a methylmercury-exposed experimental neurotoxicity: evidence from CSF, blood plasma, and brain samples","volume":"61","author":"Kumar","year":"2024","journal-title":"Mol. Neurobiol."},{"key":"B86","doi-asserted-by":"publisher","first-page":"149251","DOI":"10.1016\/j.brainres.2024.149251","article-title":"Therapeutic efficacy of genistein in activation of neuronal AC\/cAMP\/CREB\/PKA and mitochondrial ETC-complex pathways in experimental model of autism: evidence from CSF, blood plasma and brain analysis","volume":"1846","author":"Kumar","year":"2025","journal-title":"Brain Res."},{"key":"B162","doi-asserted-by":"publisher","first-page":"8783","DOI":"10.1038\/s41598-023-35975-y","article-title":"Necrosulfonamide exerts neuroprotective effect by inhibiting necroptosis, neuroinflammation, and \u03b1\u2010synuclein oligomerization in a subacute MPTP mouse model of Parkinson\u2019s disease","volume":"13","author":"Leem","year":"2023","journal-title":"Scientific reports"},{"key":"B88","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1073\/pnas.1621225114","article-title":"Boosting CNS axon regeneration by harnessing antagonistic effects of GSK3 activity","volume":"114","author":"Leibinger","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B89","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1038\/sj.emboj.7600174","article-title":"The structure of GFR\u03b11 domain 3 reveals new insights into GDNF binding and RET activation","volume":"23","author":"Lepp\u00e4nen","year":"2004","journal-title":"EMBO J."},{"key":"B90","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13024-021-00510-y","article-title":"Edaravone activates the GDNF\/RET neurotrophic signaling pathway and protects mRNA-induced motor neurons from iPS cells","volume":"17","author":"Li","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"B91","doi-asserted-by":"publisher","first-page":"1122969","DOI":"10.3389\/fphar.2023.1122969","article-title":"Protective effects of paeoniflorin on cardiovascular diseases: a pharmacological and mechanistic overview","volume":"14","author":"Li","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B92","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1038\/sj.bjp.0706732","article-title":"Paeoniflorin attenuates neuroinflammation and dopaminergic neurodegeneration in the MPTP model of Parkinson\u2019s disease by activation of adenosine A 1 receptor","volume":"148","author":"Liu","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"B93","doi-asserted-by":"publisher","first-page":"290","DOI":"10.4103\/1673-5374.200812","article-title":"Adenyl cyclase activator forskolin protects against Huntington\u2019s disease-like neurodegenerative disorders","volume":"12","author":"Mehan","year":"2017","journal-title":"Neural Regen. Res."},{"key":"B94","doi-asserted-by":"publisher","first-page":"309","DOI":"10.4103\/ijp.IJP_11_18","article-title":"Neuroprotective effect of solanesol against 3-nitropropionic acid-induced Huntington\u2019s disease-like behavioral, biochemical, and cellular alterations: restoration of coenzyme-Q10-mediated mitochondrial dysfunction","volume":"50","author":"Mehan","year":"2018","journal-title":"Indian J. Pharmacol."},{"key":"B95","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.4103\/1673-5374.270316","article-title":"Adenylate cyclase activator forskolin alleviates intracerebroventricular propionic acid-induced mitochondrial dysfunction of autistic rats","volume":"15","author":"Mehan","year":"2020","journal-title":"Neural Regen. Res."},{"key":"B96","doi-asserted-by":"publisher","first-page":"6417","DOI":"10.1016\/j.sjbs.2021.07.010","article-title":"Neuroprotective efficacy of 4-Hydroxyisoleucine in experimentally induced intracerebral hemorrhage","volume":"28","author":"Mehmood Siddiqui","year":"2021","journal-title":"Saudi J. Biol. Sci."},{"key":"B97","doi-asserted-by":"publisher","first-page":"920408","DOI":"10.3389\/fneur.2022.920408","article-title":"Serotonergic drug repurposing in multiple sclerosis: a new possibility for disease-modifying therapy","volume":"13","author":"Melnikov","year":"2022","journal-title":"Front. Neurology"},{"key":"B98","doi-asserted-by":"publisher","first-page":"103684","DOI":"10.1016\/j.mcn.2021.103684","article-title":"\u2018Long-term exposure to GDNF induces dephosphorylation of ret, AKT, and ERK1\/2, and is ineffective at protecting midbrain dopaminergic neurons in cellular models of Parkinson\u2019s disease","volume":"118","author":"Mesa-Infante","year":"2022","journal-title":"Mol. Cell. Neurosci."},{"key":"B99","doi-asserted-by":"publisher","first-page":"6214","DOI":"10.1523\/jneurosci.21-16-06214.2001","article-title":"Acute neuronal apoptosis in a rat model of multiple sclerosis","volume":"21","author":"Meyer","year":"2001","journal-title":"J. Neurosci."},{"key":"B100","doi-asserted-by":"publisher","first-page":"2867","DOI":"10.1007\/s11064-021-03366-2","article-title":"Nrf2\/HO-1 signaling activator Acetyl-11-keto-beta boswellic acid (AKBA)-mediated neuroprotection in methyl mercury-induced experimental model of ALS","volume":"46","author":"Minj","year":"2021","journal-title":"Neurochem. Res."},{"key":"B101","doi-asserted-by":"publisher","first-page":"104258","DOI":"10.1016\/j.msard.2022.104258","article-title":"Quantifying lower extremity inter-segmental coordination variability during walking in people with multiple sclerosis with high and low fear of falling","volume":"68","author":"Mofateh","year":"2022","journal-title":"Multiple Scler. Relat. Disord."},{"key":"B102","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1007\/s12079-023-00726-1","article-title":"A network map of GDNF\/RET signaling pathway in physiological and pathological conditions","volume":"17","author":"Mol","year":"2023","journal-title":"J. Cell Commun. Signal."},{"key":"B103","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2010","journal-title":"J. Computational Chemistry"},{"key":"B45","first-page":"16","article-title":"A focus on the normal - appearing white and gray matter within the multiple sclerosis brain: a link to smoldering progression","volume-title":"Acta Neuropathol","author":"Mu\u00f1oz Gonz\u00e1lez","year":"2025"},{"key":"B104","first-page":"7597","article-title":"Investigating the interplay between the Nrf2\/Keap1\/HO\u20101\/SIRT\u20101 pathway and the p75NTR\/PI3K\/akt\/MAPK Cascade in neurological disorders: mechanistic insights and therapeutic innovations","volume-title":"Mol. Neurobio.","author":"Mukherjee","year":"2025"},{"key":"B163","first-page":"e2679","article-title":"Grey matter atrophy in patients with benign multiple sclerosis","volume-title":"Brain and behavior","author":"Niiranen","year":"2022"},{"key":"B106","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1002\/jnr.21946","article-title":"Cuprizone treatment induces demyelination and astrocytosis in the mouse hippocampus","volume":"87","author":"Norkute","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"B107","doi-asserted-by":"publisher","first-page":"e41735","DOI":"10.34172\/ipp.2025.41735","article-title":"Exploring the therapeutic potential of Cerebrolysin-loaded exosomes in multiple sclerosis; an experimental study on neuroprotection and immune modulation","volume":"11","author":"Omrani","year":"2025","journal-title":"Immunopathol. Persa"},{"key":"B108","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2196\/56074","article-title":"Mobile health app (DIGICOG-MS) for self-assessment of cognitive impairment in people with multiple sclerosis: instrument validation and usability study","volume":"8","author":"Podda","year":"2024","journal-title":"JMIR Form. Res."},{"key":"B109","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1007\/s13205-023-03525-y","article-title":"Vitamin B6, B12 and folate modulate deregulated pathways and protein aggregation in yeast model of huntington disease","volume":"13","author":"Pradhan","year":"2023","journal-title":"3 Biotech."},{"key":"B110","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.5530\/ctbp.2023.3s.49","article-title":"In-silico screening of some isolated compounds of Hemidesmus indicus and evaluation of its antidiabetic potential","author":"Pratihar","year":"2023","journal-title":"Curr. Trends Biotechnol. Pharm"},{"key":"B111","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.ibror.2020.03.001","article-title":"Neuroprotective potential of solanesol in a combined model of intracerebral and intraventricular hemorrhage in rats","volume":"8","author":"Rajdev","year":"2020","journal-title":"IBRO Rep."},{"key":"B113","doi-asserted-by":"publisher","first-page":"5468","DOI":"10.1007\/s12035-023-03408-6","article-title":"Homocysteine may decrease glucose uptake and alter the Akt\/GSK3\u03b2\/GLUT1 signaling pathway in hippocampal slices: neuroprotective effects of rivastigmine and ibuprofen","volume":"60","author":"Ramires J\u00fanior","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"B114","doi-asserted-by":"publisher","first-page":"115545","DOI":"10.1016\/j.bbr.2025.115545","article-title":"Molecular mechanisms of neuroprotection: the interplay of klotho, SIRT-1, Nrf2, and HO-1 in neurological health","volume":"485","author":"Rana","year":"2025","journal-title":"Behav. Brain Res."},{"key":"B115","doi-asserted-by":"publisher","first-page":"12656","DOI":"10.3390\/ijms131012656","article-title":"Relation between pro-inflammatory cytokines and acetylcholine levels in relapsing-remitting multiple sclerosis patients","volume":"13","author":"Reale","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"B116","doi-asserted-by":"publisher","first-page":"115253","DOI":"10.1016\/j.biopha.2023.115253","article-title":"Paeoniflorin alleviates AngII-induced cardiac hypertrophy in H9c2 cells by regulating oxidative stress and Nrf2 signaling pathway","volume":"165","author":"Ren","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"B117","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s00415-005-0965-y","article-title":"Glatiramer acetate induces pro-apoptotic mechanisms involving Bcl-2, bax and Cyt-c in peripheral lymphocytes from multiple sclerosis patients","volume":"253","author":"Ruggieri","year":"2006","journal-title":"J. Neurology"},{"key":"B118","doi-asserted-by":"publisher","first-page":"151179","DOI":"10.1016\/j.ejcb.2021.151179","article-title":"Inhibition of extracellular regulated kinase (ERK)-1\/2 signaling pathway in the prevention of ALS: target inhibitors and influences on neurological dysfunctions","volume":"100","author":"Sahu","year":"2021","journal-title":"Eur. J. Cell Biol."},{"key":"B119","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1016\/j.toxrep.2022.04.023","article-title":"Effect of alpha-mangostin in the prevention of behavioural and neurochemical defects in methylmercury-induced neurotoxicity in experimental rats","volume":"9","author":"Sahu","year":"2022","journal-title":"Toxicol. Rep."},{"key":"B120","volume-title":"Applied sciences Ghost-ResNeXt: an effective deep learning based on mature and immature WBC classification","author":"Sambasiva","year":"2023"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.51126\/revsalus.v7i1.868","article-title":"Proposal of an unstable neuromuscular training protocol for a patient with multiple sclerosis: case-report Proposta de protocolo de treino neuromuscular inst\u00e1vel para uma utente com esclerose m\u00faltipla: estudo de caso Proposal of an unstable neuromuscula","author":"Santos","year":"2025","journal-title":"arXiv"},{"key":"B122","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s41422-019-0153-8","article-title":"Vitamin B 12 modulates Parkinson\u2019s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection","volume":"29","author":"Schaffner","year":"2019","journal-title":"Cell Res."},{"key":"B123","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/S0165-5728(02)00222-9","article-title":"The expression of apoptosis-regulatory proteins in B lymphocytes from patients with multiple sclerosis","volume":"130","author":"Seidi","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"B124","doi-asserted-by":"publisher","first-page":"3878","DOI":"10.3390\/molecules27123878","article-title":"Activation of IGF-1\/GLP-1 signalling via 4-Hydroxyisoleucine prevents motor neuron impairments in experimental ALS-rats exposed to methylmercury-induced neurotoxicity","volume":"27","author":"Shandilya","year":"2022","journal-title":"Molecules"},{"key":"B125","doi-asserted-by":"publisher","first-page":"105067","DOI":"10.1016\/j.neuint.2021.105067","article-title":"Targeting PI3K-AKT\/mTOR signaling in the prevention of autism","volume":"147","author":"Sharma","year":"2021","journal-title":"Neurochem. Int."},{"key":"B126","doi-asserted-by":"publisher","first-page":"100051","DOI":"10.1016\/j.phyplu.2021.100051","article-title":"Neuroprotection by solanesol against ethidium bromide-induced multiple sclerosis-like neurobehavioral, molecular, and neurochemical alterations in experimental rats","volume":"1","author":"Sharma","year":"2021","journal-title":"Phytomedicine Plus"},{"key":"B127","doi-asserted-by":"publisher","first-page":"105876","DOI":"10.1016\/j.neuint.2024.105876","article-title":"Therapeutic potential of oleanolic acid in modulation of PI3K\/Akt\/mTOR\/STAT-3\/GSK-3\u03b2 signaling pathways and neuroprotection against methylmercury-induced neurodegeneration","volume":"180","author":"Sharma","year":"2024","journal-title":"Neurochem. Int."},{"key":"B128","doi-asserted-by":"publisher","first-page":"359","DOI":"10.2174\/0115672026336440240822063430","article-title":"Targeting oligodendrocyte dynamics and remyelination: emerging therapies and personalized approaches in multiple sclerosis management","volume":"21","author":"Sharma","year":"2024","journal-title":"Curr. Neurovascular Res."},{"key":"B129","doi-asserted-by":"publisher","first-page":"100139","DOI":"10.1016\/j.phyplu.2021.100139","article-title":"Inhibition of c-JNK\/p38MAPK signaling pathway by apigenin prevents neurobehavioral and neurochemical defects in ethidium bromide-induced experimental model of multiple sclerosis in rats: evidence from CSF, blood plasma and brain samples","volume":"1","author":"Singh","year":"2021","journal-title":"Phytomedicine Plus"},{"key":"B130","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1056\/NEJMoa2201904","article-title":"Ublituximab versus teriflunomide in relapsing multiple sclerosis","volume":"387","author":"Steinman","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"B131","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3892\/etm.2024.12485","article-title":"CNPY2 governs PDGF-BB-treated vascular smooth muscle cell proliferation, migration and phenotypic transformation via the Akt\/mTOR\/GSK-3\u03b2 signaling pathway","volume":"27","author":"Sun","year":"2024","journal-title":"Exp. Ther. Med."},{"key":"B132","doi-asserted-by":"publisher","first-page":"e70111","DOI":"10.1111\/cns.70111","article-title":"Phospholipase D family member 4 regulates microglial phagocytosis and remyelination via the AKT pathway in a cuprizone-induced multiple sclerosis mouse model","volume":"30","author":"Sun","year":"2024","journal-title":"CNS Neuroscience and Therapeutics"},{"key":"B133","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/advs.202400812","article-title":"GFR \u03b1 1 promotes axon regeneration after peripheral nerve injury by functioning as a ligand","volume":"12","author":"Suzuki","year":"2025","journal-title":"Adv. Sci."},{"key":"B134","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fnana.2015.00010","article-title":"GDNF-based therapies, GDNF-producing interneurons, and trophic support of the dopaminergic nigrostriatal pathway","volume":"9","author":"Tassigny","year":"2015","journal-title":"Implic. Park. Disease\u2019"},{"key":"B135","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/npp.2017.187","article-title":"Failure to inactivate nuclear GSK3 \u03b2 by ser 389 -Phosphorylation leads to focal neuronal death and prolonged fear response","volume":"43","author":"Thornton","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"B136","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/brainsci11030288","article-title":"Neuroprotective effect of \u03b1\u2010mangostin in the ameliorating propionic acid\u2010induced experimental model of autism in wistar rats","volume":"11","author":"Tiwari","year":"2021","journal-title":"Brain Sci."},{"key":"B137","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/eLife.01936","article-title":"Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis","volume":"3","author":"Tritsch","year":"2014","journal-title":"Elife"},{"key":"B138","doi-asserted-by":"publisher","first-page":"100019","DOI":"10.1016\/j.dscb.2021.100019","article-title":"Targeting Nrf2\/HO-1 anti-oxidant signaling pathway in the progression of multiple sclerosis and influences on neurological dysfunctions","volume":"3","author":"Upadhayay","year":"2021","journal-title":"Brain Disord."},{"key":"B139","first-page":"1324","article-title":"Nrf2\/HO-1 signaling stimulation through Acetyl-11-Keto-Beta-Boswellic Acid (AKBA) provides neuroprotection in ethidium bromide-induced experimental model of multiple sclerosis. Basel:","volume-title":"Genes","author":"Upadhayay","year":"2022"},{"key":"B140","doi-asserted-by":"publisher","first-page":"2283","DOI":"10.1038\/s41380-025-03374-6","article-title":"Dopaminergic tone inhibits spontaneous glutamate release and augments homeostatic synaptic plasticity","volume":"31","author":"Uzay","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"B141","doi-asserted-by":"publisher","first-page":"488","DOI":"10.3389\/fneur.2020.00488","article-title":"Association between vitamins and amyotrophic lateral sclerosis: a center-based survey in mainland China","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Neurology"},{"key":"B142","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1007\/s11011-020-00571-w","article-title":"Paeoniflorin attenuates early brain injury through reducing oxidative stress and neuronal apoptosis after subarachnoid hemorrhage in rats","volume":"35","author":"Wang","year":"2020","journal-title":"Metab. Brain Dis."},{"key":"B143","doi-asserted-by":"publisher","first-page":"102103","DOI":"10.1016\/j.jchemneu.2022.102103","article-title":"The neuroprotective effects of paeoniflorin against MPP+-Induced damage to dopaminergic neurons via the Akt\/Nrf2\/GPX4 pathway","volume":"122","author":"Wang","year":"2022","journal-title":"J. Chem. Neuroanat."},{"key":"B144","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms252312543","article-title":"Paeoniflorin inhibits the activation of microglia and alleviates depressive behavior by regulating SIRT1-NF-kB-NLRP3\/Pyroptosis pathway","volume":"25","author":"Wang","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B145","doi-asserted-by":"publisher","first-page":"e12913","DOI":"10.1371\/journal.pone.0012913","article-title":"Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition","volume":"5","author":"Wu","year":"2010","journal-title":"PLoS ONE"},{"key":"B146","doi-asserted-by":"publisher","first-page":"696158","DOI":"10.3389\/fphar.2021.696158","article-title":"Evaluations and mechanistic interrogation of natural products isolated from Paeonia suffruticosa for the treatment of inflammatory bowel disease","volume":"12","author":"Wu","year":"","journal-title":"Front. Pharmacol."},{"key":"B147","doi-asserted-by":"publisher","first-page":"873","DOI":"10.3760\/cma.j.cn115354-20210215-00104","article-title":"Effect of paeoniflorin on motor behavior and dopamine neurons of mice with Parkinson\u2019s disease by activating autophagy","author":"Wu","year":"","journal-title":"Chin. J. Neuromedicine"},{"key":"B148","first-page":"31447","article-title":"Resolvin D1 combined with exercise rehabilitation alleviates neurological injury in mice with intracranial hemorrhage via the BDNF\/TrkB\/PI3K\/AKT pathway","volume-title":"Sci. Rep","author":"Xiaoyu","year":"2024"},{"key":"B149","first-page":"30051","article-title":"Perampanel reduces seizure frequency in patients with developmental and epileptic encephalopathy for a long term","volume-title":"Sci. Rep.","author":"Yamagishi","year":"2024"},{"key":"B150","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41392-020-00435-w","article-title":"G protein-coupled receptors: structure- and function-based drug discovery","volume":"6","author":"Yang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"B151","doi-asserted-by":"publisher","first-page":"e30555","DOI":"10.1016\/j.heliyon.2024.e30555","article-title":"Paeoniflorin inhibits the inflammation of rheumatoid arthritis fibroblast-like synoviocytes by downregulating hsa_circ_009012","volume":"10","author":"Yang","year":"2024","journal-title":"Heliyon"},{"key":"B152","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep13249","article-title":"Inhibition of glycogen synthase kinase-3 beta induces apoptosis and mitotic catastrophe by disrupting centrosome regulation in cancer cells","volume":"5","author":"Yoshino","year":"2015","journal-title":"Nat. Publ. Group"},{"key":"B153","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.bbr.2012.08.006","article-title":"Possible interaction of cholinergic and GABAergic systems between MS and CA1 upon memory acquisition in rats","volume":"235","author":"Yousefi","year":"2012","journal-title":"Behav. Brain Res."},{"key":"B154","doi-asserted-by":"publisher","first-page":"681","DOI":"10.7150\/ijms.69289","article-title":"Paeoniflorin attenuates monocrotaline-induced pulmonary arterial hypertension in rats by suppressing TAK1-MAPK\/NF-\u03baB pathways","volume":"19","author":"Yu","year":"2022","journal-title":"Int. J. Med. Sci."},{"key":"B155","doi-asserted-by":"publisher","first-page":"107452","DOI":"10.1016\/j.pharmthera.2019.107452","article-title":"Anti-inflammatory and immunoregulatory effects of paeoniflorin and total glucosides of paeony","volume":"207","author":"Zhang","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"B156","doi-asserted-by":"publisher","first-page":"e0146797","DOI":"10.1371\/journal.pone.0146797","article-title":"Decreased brain levels of vitamin B12 in aging, autism and schizophrenia","volume":"11","author":"Zhang","year":"2016","journal-title":"PLoS ONE"},{"key":"B157","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep41887","article-title":"Paeoniflorin ameliorates experimental autoimmune encephalomyelitis via inhibition of dendritic cell function and Th17 cell differentiation","volume":"7","author":"Zhang","year":"2017","journal-title":"Sci. Rep."},{"key":"B158","doi-asserted-by":"publisher","first-page":"116422","DOI":"10.1016\/j.jep.2023.116422","article-title":"Paeoniflorin protects against cisplatin-induced acute kidney injury through targeting Hsp90AA1-Akt protein-protein interaction","volume":"310","author":"Zhang","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"B159","doi-asserted-by":"publisher","first-page":"e21800","DOI":"10.1016\/j.heliyon.2023.e21800","article-title":"Network pharmacology and in vivo studies reveal the neuroprotective effects of paeoniflorin on Alzheimer\u2019s disease","volume":"9","author":"Zhang","year":"2023","journal-title":"Heliyon"},{"key":"B160","doi-asserted-by":"publisher","first-page":"7448","DOI":"10.1039\/d1fo01421h","article-title":"Inhibitory effect of paeoniflorin on IgE-dependent and IgE-independent mast cell degranulation: in vitro and vivo","volume":"12","author":"Zhao","year":"2021","journal-title":"Food Funct."},{"key":"B161","doi-asserted-by":"publisher","first-page":"469580251368004","DOI":"10.1177\/00469580251368004","article-title":"Chronic disease management: associations with doctors\u2019 intentions and perceived treatment effectiveness","volume":"62","author":"Zhou","year":"2025","journal-title":"Inquiry."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1792674\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:01:03Z","timestamp":1775800863000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1792674\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,10]]},"references-count":159,"alternative-id":["10.3389\/fphar.2026.1792674"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1792674","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,10]]},"article-number":"1792674"}}