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bioRxiv · 10.64898/2026.01.29.702298

Unconventional Small Molecule MNP-021 Protects Neuronal and Glial Function from Diabetes-Associated Glucotoxicity and Neuroinflammation

De Carli, A.·Filipponi, C.·Polini, B.·Sancho-Bornez, V.·Basso, E.·Filippini, F.·Dardano, A.·Sardelli, F.·Daniele, S.·Contestabile, M.·Grieco, G. E.·Dotta, F.·Sebastiani, G.·Chiellini, M. G.·Pineschi, M.·Lai, M.·Daniele, G.
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Abstract

BackgroundDiabetes-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 TRPA1 modulator, in neurons and glial cells in vitro. MethodsSH-SY5Y neurons were pretreated with MNP-021 and challenged with MGO, then profiled by high-content imaging, RNA-seq, Seahorse OCR/ECAR, glycolytic stress assays and AKT/ERK/CREB immunoblotting {+/-} insulin. In parallel, HMC3 glial cells were treated with MNP-021, exposed to LPS/TNF- or A{beta}(25-35) and tested for viability and inflammatory markers by ELISA and qRT-PCR. ResultsMGO increased nucleus-to-cytoplasm area ratio by 49% and dysregulated glucose handling, increasing 2-NBDG uptake by [~]25%, with GLUT1/GLUT4 membrane redistribution; MNP-021 normalized morphology, uptake, and transporter localization without cytotoxicity up to 10 {micro}M. RNA-seq identified 754 MGO-deregulated genes, including ISR/metabolic nodes (GCK, SESN2, PHGDH/PSAT1, PCK2); MNP-021 buffered stress-induced transcription with limited baseline effects, remodeled mitochondrial redox readouts consistent with controlled ROS signaling, while improving mitochondrial content/architecture and blunting stress-evoked compensatory glycolysis. MNP-021 restored pro-survival signaling (pAKT/pERK and nuclear pCREB), including insulin responsiveness during MGO exposure. MNP-021 reduced IL-6/TNF- release while increasing IL-10 and ARG1 ([~]1.9-fold vs LPS/TNF-) in HMC3 glial cells, shifting them toward a pro-resolving IL-10/ARG1 program with reduced A{beta}(25-35)-evoked cytokine release with GLP-1 remaining very low ([≤]10 pg/mL) and not significantly increased in this system. ConclusionsMNP-021 coordinates transcriptomic restraint, transporter-level glucose handling, mitochondrial resilience, and pro-survival/pro-resolving signaling across neuron-microglia compartments, supporting TRPA1-tuned small-molecule modulation as a candidate strategy against dicarbonyl-linked neuro-metabolic stress.

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De Carli, A., Filipponi, C., Polini, B., Sancho-Bornez, V., Basso, E., Filippini, F., Dardano, A., Sardelli, F., Daniele, S., Contestabile, M., Grieco, G. E., Dotta, F., Sebastiani, G., Chiellini, M. G., Pineschi, M., Lai, M., Daniele, G.. 2026-02-02. Unconventional Small Molecule MNP-021 Protects Neuronal and Glial Function from Diabetes-Associated Glucotoxicity and Neuroinflammation. https://doi.org/10.64898/2026.01.29.702298

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