{ "abstract": "Background\n\nDiabetes-associated neurodegeneration is amplified by methylglyoxal (MGO)-driven dicarbonyl stress linking hyperglycemia to neuronal insulin resistance and maladaptive neuroinflammation. We tested the neuroprotective activity of MNP-021, a non-electrophilic transient receptor potential ankyrin 1 (TRPA1) modulator, in neurons and glial cells in vitro.Methods\n\nSH-SY5Y neurons were pretreated with MNP-021 and challenged with MGO, then profiled by high-content imaging, RNA-seq, Seahorse Oxygen Consumption Rate (OCR) and Extracellular Acidification Rate (ECAR), glycolytic stress assays, and immunoblotting for AKT, ERK, and cAMP response element-binding protein (CREB). In an additional sustained glucotoxicity paradigm, differentiated SH-SY5Y cells were exposed to high glucose for 7 days and viability was assessed by LIVE/DEAD™ high-content imaging. HMC3 glial cells were treated with MNP-021, exposed to Lipopolysaccharide (LPS), Tumor Necrosis Factor-α (TNF-α) or Aβ(25-35), and tested for viability and inflammatory markers by Enzyme-Linked Immunosorbent Assay (ELISA) and RT-qPCR.Results\n\nMGO increased nucleus-to-cytoplasm area ratio by 49% and dysregulated glucose handling, increasing 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) uptake by ~ 25%, with GLUT1/GLUT4 membrane redistribution; MNP-021 normalized morphology, glucose uptake, and transporter localization without cytotoxicity up to 10 µM. RNA-seq identified 754 MGO-deregulated genes, including ISR/metabolic nodes such as glucokinase (GCK), Sestrin-2 (SESN2), phosphoglycerate dehydrogenase (PHGDH), Phosphoserine Aminotransferase 1 (PSAT1), phosphoenolpyruvate carboxykinase 2 (PCK2); MNP-021 buffered stress-induced transcription with limited baseline effects, modulated mitochondrial morphology and redox-associated fluorescence while preserving overall respiratory flux and blunting stress-evoked compensatory glycolysis. MNP-021 restored pro-survival signaling (pAKT/pERK and nuclear pCREB), including insulin responsiveness during MGO exposure. In a sustained high-glucose model, MNP-021 reduced the high-glucose-associated increase in cell death, extending its protective effects beyond the acute MGO paradigm. MNP-021 reduced Interleukine-6 (IL-6)/TNF-α release while increasing Interleukine-10 (IL-10) and Arginase 1 (ARG1) (~ 1.9-fold vs. LPS/TNF-α) in HMC3 glial cells, shifting them toward a pro-resolving IL-10/ARG1 program with reduced amyloid β-peptide ₂₅₋₃₅ (Aβ₍₂₅₋₃₅₎)-evoked cytokine release and Glucagon-Like Peptide-1 (GLP-1) remaining very low (≤ 10 pg/mL) and not significantly increased in this system.Conclusions\n\nMNP-021 coordinates transcriptomic restraint, transporter-level glucose handling, mitochondrial resilience, and pro-survival/pro-resolving signaling in neuron-microglia cell models. These findings support further preclinical evaluation of MNP-021 in dicarbonyl-linked neuro-metabolic stress and provide pharmacological evidence consistent with a TRPA1-linked component of its activity.", "abstract_shown": true, "affiliations": [ "Retrovirus Center, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.", "Centre for Instrumentation Sharing, University of Pisa (CISUP), Pisa, Italy.", "Department of Surgical, Medical, Molecular and Critical Care Pathology, University of Pisa, Pisa, Italy.", "Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.", "CNR, Institute of Neuroscience, Padua Branch, Padua, Italy.", "Department of Pharmacy, University of Pisa, Pisa, Italy.", "Department of Health Sciences, University of Milan, Milan, Italy.", "Unit of Pathology, Azienda Socio-Sanitaria Territoriale (ASST) dei Sette Laghi, Varese, Italy.", "Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.", "Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.", "Fondazione Umberto Di Mario ONLUS c/o Toscana Life Science, Siena, Italy.", "Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy.", "Centre for Instrumentation Sharing, University of Pisa (CISUP), Pisa, Italy. giuseppe.daniele@unipi.it.", "Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. giuseppe.daniele@unipi.it." ], "article_type": "research article", "arxiv": null, "author_total": 20, "authors": [ { "affs": [ 0, 1 ], "name": "Alessandro De Carli", "orcid": "0000-0001-5022-4764" }, { "affs": [ 0 ], "name": "Carolina Filipponi", "orcid": "0009-0002-1529-2862" }, { "affs": [ 2 ], "name": "Beatrice Polini", "orcid": "0000-0002-2664-6091" }, { "affs": [ 3 ], "name": "Veronica Sancho-Bornez", "orcid": "0000-0002-8563-4568" }, { "affs": [ 4 ], "name": "Emy Basso", "orcid": "0000-0003-2962-7213" }, { "affs": [ 0 ], "name": "Fabio Filippini", "orcid": "0009-0006-3309-763X" }, { "affs": [ 3 ], "name": "Angela Dardano", "orcid": "0000-0001-6176-4379" }, { "affs": [ 5 ], "name": "Francesca Sardelli", "orcid": "0009-0001-6926-8094" }, { "affs": [ 5 ], "name": "Simona Daniele", "orcid": "0000-0001-7391-3087" }, { "affs": [ 5 ], "name": "Martina Contestabile" }, { "affs": [ 6 ], "name": "Franco Folli", "orcid": "0000-0001-9824-5222" }, { "affs": [ 7 ], "name": "Giovanna Finzi", "orcid": "0000-0003-0253-8835" }, { "affs": [ 8 ], "name": "Sara De Martin", "orcid": "0000-0001-6398-8237" }, { "affs": [ 9, 10, 11 ], "name": "Giuseppina Emanuela Grieco", "orcid": "0000-0001-7325-6128" }, { "affs": [ 9, 10, 11 ], "name": "Francesco Dotta", "orcid": "0000-0003-4947-7478" }, { "affs": [ 9, 10, 11 ], "name": "Guido Sebastiani", "orcid": "0000-0003-4374-8564" }, { "affs": [ 2 ], "name": "Grazia Chiellini", "orcid": "0000-0001-6703-5820" }, { "affs": [ 5 ], "name": "Mauro Pineschi", "orcid": "0000-0001-6063-2198" }, { "affs": [ 0, 1 ], "name": "Michele Lai", "orcid": "0000-0001-7597-123X" }, { "affs": [ 12, 13 ], "name": "Giuseppe Daniele", "orcid": "0000-0001-6301-9161" } ], "bibtex": "https://research.draconitic.com/paper/bm5vxfn7k7q61.bib", "cited_by": 0, "doi": "10.1186/s12967-026-09028-7", "fulltext_url": "https://europepmc.org/articles/PMC13721280", "id": "bm5vxfn7k7q61", "issns": [ "1479-5876" ], "landing_url": "https://europepmc.org/article/MED/42958409", "language": "eng", "licence": "CC-BY-NC-ND", "licence_label": "CC BY-NC-ND", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Research" ], [ "openalex", "2737|Pain Mechanisms and Treatments" ] ], "openalex": "W7223996301", "pdf_url": "https://europepmc.org/articles/PMC13721280?pdf=render", "pmcid": "PMC13721280", "pmid": "42958409", "published": "2026-10-27", "publisher": "BMC", "ris": "https://research.draconitic.com/paper/bm5vxfn7k7q61.ris", "sources": [ { "first_seen": "2026-11-01T00:20:36Z", "native_id": "MED:42958409", "source": "europepmc", "url": "https://europepmc.org/article/MED/42958409" }, { "first_seen": "2026-11-03T12:22:00Z", "native_id": "PMC13721280", "source": "pmc", "url": "https://doi.org/10.1186/s12967-026-09028-7" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2737|Pain Mechanisms and Treatments", "subfield": "physiology" } ], "title": "Non-electrophilic TRPA1 modulator MNP-021 protects neuronal and glial function from diabetes-associated glucotoxicity and neuroinflammation.", "title_text": "Non-electrophilic TRPA1 modulator MNP-021 protects neuronal and glial function from diabetes-associated glucotoxicity and neuroinflammation.", "type": "peer-reviewed", "updated_at": "2026-11-03T12:22:00Z", "url": "https://research.draconitic.com/paper/bm5vxfn7k7q61", "venue": "Journal of translational medicine", "versions": [] }