Mechanisms associated with diabetic peripheral neuralgia and potential interventions

Main Article Content

Yudie Du
He Xiao
Xinting Huang
Yiming Shao
Ke Song

Abstract

Diabetes mellitus (DM), the most prevalent metabolic disorder globally, has been extensively investigated due to its significant clinical implications. Among its most common complications is diabetic peripheral neuropathy (DPN), which predominantly manifests as bilateral limb pain, numbness, and paresthesia. In advanced cases, DPN may progress to foot ulceration and potentially necessitate limb amputation. The precise etiology and pathogenesis of diabetic neuropathy remain incompletely understood; however, sustained hyperglycemia, dysregulated lipid metabolism, and impaired insulin signaling are recognized as key triggers for the cascade of pathophysiological alterations in DPN. Under these metabolic disturbances, the peripheral nervous system’s structural and functional integrity—encompassing myelinated and unmyelinated axons, neuronal somata, neurovascular units, and glial cells—is progressively undermined. This review synthesizes recent mechanistic advances in DPN research, centering on the sigma-1 receptor’s modulatory orchestration, SGC dysfunction and GalCer metabolic dysregulation in DPN pathogenesis, inhibition of neuroinflammation and apoptosis by microRNA-146a, nerve damage due to Ca²⁺ overload, and dorsal root ganglia neuronal apoptosis resulting from SFA, and summarize possible interventions based on these mechanisms. A systems-level understanding of how these mechanisms collectively drive neuropathy pathogenesis is critical for advancing both early diagnostic tools and pathway-selective therapeutics.
Views: 1060Downloads: 91

Article Details

Section

Computer Science and Artificial Intelligence

How to Cite

Du, Y., Xiao, H., Huang, X., Shao, Y., & Song, K. (2025). Mechanisms associated with diabetic peripheral neuralgia and potential interventions. AI Med, 1(3). https://doi.org/10.71423/aimed.20251106

References

Callaghan, B. C.; Gallagher, G.; Fridman, V.; Feldman, E. L. Diabetic neuropathy: what does the future hold? Diabetologia 2020, 63 (5), 891–897. DOI: 10.1007/s00125-020-05085-9

Smith, A. G.; Živković, S. The hidden costs of painful diabetic neuropathy revealed. Neurol Clin Pract 2020, 10 (1), 3–4. DOI: 10.1212/cpj.0000000000000759

Yeung, A. M.; Huang, J.; Nguyen, K. T.; Xu, N. Y.; Hughes, L. T.; Agrawal, B. K.; Ejskjaer, N.; Klonoff, D. C. Painful Diabetic Neuropathy: The Need for New Approaches. J Diabetes Sci Technol 2024, 18 (1), 159– 167. DOI: 10.1177/19322968221132252

Vlacho, B.; Bundó, M.; Llussà, J.; Real, J.; Mata-Cases, M.; Cos, X.; Tundidor, D.; Zaccardi, F.; Khunti, K.; Jude, E. B.; et al. Diabetic foot disease carries an intrinsic high risk of mortality and other severe outcomes in type 2 diabetes: a propensity score-matched retrospective population-based study. Cardiovasc Diabetol 2024, 23 (1), 209. DOI: 10.1186/s12933-024-02303-1

Savelieff, M. G.; Elafros, M. A.; Viswanathan, V.; Jensen, T. S.; Bennett, D. L.; Feldman, E. L. The global and regional burden of diabetic peripheral neuropathy. Nat Rev Neurol 2025, 21 (1), 17–31. DOI: 10.1038/s41582-024-01041-y

Javed, S.; Alam, U.; Malik, R. A. Treating Diabetic Neuropathy: Present Strategies and Emerging Solutions. Rev Diabet Stud 2015, 12 (1–2), 63–83. DOI: 10.1900/rds.2015.12.63

Scholz, J.; Woolf, C. J. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 2007, 10 (11), 1361–1368. DOI: 10.1038/nn1992

Wei, Z.; Fei, Y.; Su, W.; Chen, G. Emerging Role of Schwann Cells in Neuropathic Pain: Receptors, Glial Mediators and Myelination. Front Cell Neurosci 2019, 13, 116. DOI: 10.3389/fncel.2019.00116

Palacios, G.; Muro, A.; Verdú, E.; Pumarola, M.; Vela, J. M. Immunohistochemical localization of the sigma1 receptor in Schwann cells of rat sciatic nerve. Brain Res 2004, 1007 (1–2), 65–70. DOI: 10.1016/j.brainres.2004.02.013

Shen, B.; Behera, D.; James, M. L.; Reyes, S. T.; Andrews, L.; Cipriano, P. W.; Klukinov, M.; Lutz, A. B.; Mavlyutov, T.; Rosenberg, J.; et al. Visualizing Nerve Injury in a Neuropathic Pain Model with [(18)F]FTC-146 PET/MRI. Theranostics 2017, 7 (11), 2794–2805. DOI: 10.7150/thno.19378

Ji, R. R.; Chamessian, A.; Zhang, Y. Q. Pain regulation by non-neuronal cells and inflammation. Science 2016, 354 (6312), 572–577. DOI: 10.1126/science.aaf8924

Sikandar, S.; Minett, M. S.; Millet, Q.; Santana-Varela, S.; Lau, J.; Wood, J. N.; Zhao, J. Brain-derived neurotrophic factor derived from sensory neurons plays a critical role in chronic pain. Brain 2018, 141 (4), 1028–1039. DOI: 10.1093/brain/awy009

Zhu, W.; Frost, E. E.; Begum, F.; Vora, P.; Au, K.; Gong, Y.; MacNeil, B.; Pillai, P.; Namaka, M. The role of dorsal root ganglia activation and brain-derived neurotrophic factor in multiple sclerosis. J Cell Mol Med 2012, 16 (8), 1856–1865. DOI: 10.1111/j.1582-4934.2011.01481.x

Souza, G. R.; Talbot, J.; Lotufo, C. M.; Cunha, F. Q.; Cunha, T. M.; Ferreira, S. H. Fractalkine mediates inflammatory pain through activation of satellite glial cells. Proc Natl Acad Sci U S A 2013, 110 (27), 11193– 11198. DOI: 10.1073/pnas.1307445110

Vega-Avelaira, D.; Géranton, S. M.; Fitzgerald, M. Differential regulation of immune responses and macrophage/neuron interactions in the dorsal root ganglion in young and adult rats following nerve injury. Mol Pain 2009, 5, 70. DOI: 10.1186/1744-8069-5-70

Raoof, R.; Willemen, H.; Eijkelkamp, N. Divergent roles of immune cells and their mediators in pain. Rheumatology (Oxford) 2018, 57 (3), 429–440. DOI: 10.1093/rheumatology/kex308

Cobos, E. J.; Nickerson, C. A.; Gao, F.; Chandran, V.; Bravo-Caparrós, I.; González-Cano, R.; Riva, P.; Andrews, N. A.; Latremoliere, A.; Seehus, C. R.; et al. Mechanistic Differences in Neuropathic Pain Modalities Revealed by Correlating Behavior with Global Expression Profiling. Cell Rep 2018, 22 (5), 1301–1312. DOI: 10.1016/j.celrep.2018.01.006

Bravo-Caparrós, I.; Ruiz-Cantero, M. C.; Perazzoli, G.; Cronin, S. J. F.; Vela, J. M.; Hamed, M. F.; Penninger, J. M.; Baeyens, J. M.; Cobos, E. J.; Nieto, F. R. Sigma-1 receptors control neuropathic pain and macrophage infiltration into the dorsal root ganglion after peripheral nerve injury. Faseb j 2020, 34 (4), 5951–5966. DOI: 10.1096/fj.201901921R

Sánchez-Fernández, C.; Montilla-García, Á.; González-Cano, R.; Nieto, F. R.; Romero, L.; Artacho-Cordón, A.; Montes, R.; Fernández-Pastor, B.; Merlos, M.; Baeyens, J. M.; et al. Modulation of peripheral μ-opioid analgesia by σ1 receptors. J Pharmacol Exp Ther 2014, 348 (1), 32– 45. DOI: 10.1124/jpet.113.208272

Shin, S. M.; Wang, F.; Qiu, C.; Itson-Zoske, B.; Hogan, Q. H.; Yu, H. Sigma-1 receptor activity in primary sensory neurons is a critical driver of neuropathic pain. Gene Ther 2022, 29 (1–2), 1–15. DOI: 10.1038/s41434-020-0157-5

Bravo-Caparrós, I.; Perazzoli, G.; Yeste, S.; Cikes, D.; Baeyens, J. M.; Cobos, E. J.; Nieto, F. R. Sigma-1 Receptor Inhibition Reduces Neuropathic Pain Induced by Partial Sciatic Nerve Transection in Mice by Opioid-Dependent and -Independent Mechanisms. Front Pharmacol 2019, 10, 613. DOI: 10.3389/fphar.2019.00613

Goldin, A.; Beckman, J. A.; Schmidt, A. M.; Creager, M. A. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 2006, 114 (6), 597–605. DOI: 10.1161/circulationaha.106.621854

Vincent, A. M.; Russell, J. W.; Low, P.; Feldman, E. L. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 2004, 25 (4), 612–628. DOI: 10.1210/er.2003-0019

Hanani, M.; Verkhratsky, A. Satellite Glial Cells and Astrocytes, a Comparative Review. Neurochem Res 2021, 46 (10), 2525–2537. DOI: 10.1007/s11064-021-03255-8

Hanani, M. Satellite glial cells in sensory ganglia: from form to function. Brain Res Brain Res Rev 2005, 48 (3), 457–476. DOI: 10.1016/j.brainresrev.2004.09.001

Feldman-Goriachnik, R.; Hanani, M. The effects of sympathetic nerve damage on satellite glial cells in the mouse superior cervical ganglion. Auton Neurosci 2019, 221, 102584. DOI: 10.1016/j.autneu.2019.102584

Hanani, M.; Spray, D. C. Emerging importance of satellite glia in nervous system function and dysfunction. Nat Rev Neurosci 2020, 21 (9), 485–498. DOI: 10.1038/s41583-020-0333-z

Ayoub, S.; Berbéri, A.; Fayyad-Kazan, M. Cytokines, Masticatory Muscle Inflammation, and Pain: an Update. J Mol Neurosci 2020, 70 (5), 790–795. DOI: 10.1007/s12031-020-01491-1

Boggs, J. M.; Gao, W.; Zhao, J.; Park, H. J.; Liu, Y.; Basu, A. Participation of galactosylceramide and sulfatide in glycosynapses between oligodendrocyte or myelin membranes. FEBS Lett 2010, 584 (9), 1771–1778. DOI: 10.1016/j.febslet.2009.11.074

Eckhardt, M. The role and metabolism of sulfatide in the nervous system. Mol Neurobiol 2008, 37 (2–3), 93–103. DOI: 10.1007/s12035-008-8022-3

Gault, C. R.; Obeid, L. M.; Hannun, Y. A. An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol 2010, 688, 1–23. DOI: 10.1007/978-1-4419-6741-1_1

Parpura, V.; Heneka, M. T.; Montana, V.; Oliet, S. H.; Schousboe, A.; Haydon, P. G.; Stout, R. F., Jr.; Spray, D. C.; Reichenbach, A.; Pannicke, T.; et al. Glial cells in (patho)physiology. J Neurochem 2012, 121 (1), 4–27. DOI: 10.1111/j.1471-4159.2012.07664.x

Xu, X.; Zhang, Y.; Li, S.; Liao, C.; Yang, X.; Zhang, W. Role of Galactosylceramide Metabolism in Satellite Glial Cell Dysfunction and Neuron-Glia Interactions in Painful Diabetic Peripheral Neuropathy. Cells 2025, 14 (6). DOI: 10.3390/cells14060393

Zhang, J. M.; An, J. Cytokines, inflammation, and pain. Int Anesthesiol Clin 2007, 45 (2), 27–37. DOI: 10.1097/AIA.0b013e318034194e

Zheng, Y. N.; Zheng, Y. L.; Wang, X. Q.; Chen, P. J. Role of Exercise on Inflammation Cytokines of Neuropathic Pain in Animal Models. Mol Neurobiol 2024, 61 (12), 10288–10301. DOI: 10.1007/s12035-024-04214-4

Calvo, M.; Bennett, D. L. The mechanisms of microgliosis and pain following peripheral nerve injury. Exp Neurol 2012, 234 (2), 271–282. DOI: 10.1016/j.expneurol.2011.08.018

Block, L. Glial dysfunction and persistent neuropathic postsurgical pain. Scand J Pain 2016, 10, 74–81. DOI: 10.1016/j.sjpain.2015.10.002

Xie, S. Z.; Kaufmann, K. B.; Wang, W.; Chan-Seng-Yue, M.; Gan, O. I.; Laurenti, E.; Garcia-Prat, L.; Takayanagi, S. I.; Ng, S. W. K.; Xu, C.; et al. Sphingosine-1-phosphate receptor 3 potentiates inflammatory programs in normal and leukemia stem cells to promote differentiation. Blood Cancer Discov 2021, 2 (1), 32–53. DOI: 10.1158/2643-3230.Bcd-20-0155

Lee, K.; Escobar, I.; Jang, Y.; Kim, W.; Ausubel, F. M.; Mylonakis, E. In the Model Host Caenorhabditis elegans, Sphingosine-1-Phosphate-Mediated Signaling Increases Immunity toward Human Opportunistic Bacteria. Int J Mol Sci 2020, 21 (21). DOI: 10.3390/ijms21217813

Kong, T.; He, Z.; Wang, S.; Jiang, C.; Zhu, F.; Gao, J.; Li, L.; Wang, Y.; Xie, Q.; Li, Y. Diterpenoid DGA induces apoptosis via endoplasmic reticulum stress caused by changes in glycosphingolipid composition and inhibition of STAT3 in glioma cells. Biochem Pharmacol 2022, 205, 115254. DOI: 10.1016/j.bcp.2022.115254

Hanani, M.; Blum, E.; Liu, S.; Peng, L.; Liang, S. Satellite glial cells in dorsal root ganglia are activated in streptozotocin-treated rodents. J Cell Mol Med 2014, 18 (12), 2367–2371. DOI: 10.1111/jcmm.12406

El-Sitt, S.; Soueid, J.; Maalouf, K.; Makhoul, N.; Al Ali, J.; Makoukji, J.; Asser, B.; Daou, D.; Harati, H.; Boustany, R. M. Exogenous Galactosylceramide as Potential Treatment for CLN3 Disease. Ann Neurol 2019, 86 (5), 729–742. DOI: 10.1002/ana.25573

Ustjanzew, A.; Sencio, V.; Trottein, F.; Faber, J.; Sandhoff, R.; Paret, C. Interaction between Bacteria and the Immune System for Cancer Immunotherapy: The α- GalCer Alliance. Int J Mol Sci 2022, 23 (11). DOI: 10.3390/ijms23115896

Greenberg, D. S.; Soreq, H. MicroRNA therapeutics in neurological disease. Curr Pharm Des 2014, 20 (38), 6022–6027. DOI: 10.2174/1381612820666140314151924

Li, Y. Y.; Cui, J. G.; Dua, P.; Pogue, A. I.; Bhattacharjee, S.; Lukiw, W. J. Differential expression of miRNA-146a-regulated inflammatory genes in human primary neural, astroglial and microglial cells. Neurosci Lett 2011, 499 (2), 109–113. DOI: 10.1016/j.neulet.2011.05.044

Sonkoly, E.; Ståhle, M.; Pivarcsi, A. MicroRNAs and immunity: novel players in the regulation of normal immune function and inflammation. Semin Cancer Biol 2008, 18 (2), 131–140. DOI: 10.1016/j.semcancer.2008.01.005

Taganov, K. D.; Boldin, M. P.; Chang, K. J.; Baltimore, D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 2006, 103 (33), 12481–12486. DOI: 10.1073/pnas.0605298103

Juźwik, C. A.; S, S. D.; Zhang, Y.; Paradis-Isler, N.; Sylvester, A.; Amar-Zifkin, A.; Douglas, C.; Morquette, B.; Moore, C. S.; Fournier,A. E. microRNAdysregulation in neurodegenerative diseases: A systematic review. Prog Neurobiol 2019, 182, 101664. DOI: 10.1016/j.pneurobio.2019.101664

Shomali, N.; Mansoori, B.; Mohammadi, A.; Shirafkan, N.; Ghasabi, M.; Baradaran, B. MiR-146a functions as a small silent player in gastric cancer. Biomed Pharmacother 2017, 96, 238–245. DOI: 10.1016/j.biopha.2017.09.138

Cui, L.; Li, Y.; Ma, G.; Wang, Y.; Cai, Y.; Liu, S.; Chen, Y.; Li, J.; Xie, Y.; Liu, G.; et al. A functional polymorphism in the promoter region of microRNA-146a is associated with the risk of Alzheimer disease and the rate of cognitive decline in patients. PLoS One 2014, 9 (2), e89019. DOI: 10.1371/journal.pone.0089019

Cui, L.; Tao, H.; Wang, Y.; Liu, Z.; Xu, Z.; Zhou, H.; Cai, Y.; Yao, L.; Chen, B.; Liang, W.; et al. A functional polymorphism of the microRNA-146a gene is associated with susceptibility to drug-resistant epilepsy and seizures frequency. Seizure 2015, 27, 60–65. DOI: 10.1016/j.seizure.2015.02.032

Zhang, L.; Chopp, M.; Liu, X.; Teng, H.; Tang, T.; Kassis, H.; Zhang, Z. G. Combination therapy with VELCADE and tissue plasminogen activator is neuroprotective in aged rats after stroke and targets microRNA-146a and the toll-like receptor signaling pathway. Arterioscler Thromb Vasc Biol 2012, 32 (8), 1856–1864. DOI: 10.1161/atvbaha.112.252619

Fan, W.; Liang, C.; Ou, M.; Zou, T.; Sun, F.; Zhou, H.; Cui, L. MicroRNA-146a Is a Wide-Reaching Neuroinflammatory Regulator and Potential Treatment Target in Neurological Diseases. Front Mol Neurosci 2020, 13, 90. DOI: 10.3389/fnmol.2020.00090

Baldeón, R. L.; Weigelt, K.; de Wit, H.; Ozcan, B.; van Oudenaren, A.; Sempértegui, F.; Sijbrands, E.; Grosse, L.; Freire, W.; Drexhage, H. A.; et al. Decreased serum level of miR-146a as sign of chronic inflammation in type 2 diabetic patients. PLoS One 2014, 9 (12), e115209. DOI: 10.1371/journal.pone.0115209

Jia, L.; Wang, L.; Chopp, M.; Zhang, Y.; Szalad, A.; Zhang, Z. G. MicroRNA 146a locally mediates distal axonal growth of dorsal root ganglia neurons under high glucose and sildenafil conditions. Neuroscience 2016, 329, 43–53. DOI: 10.1016/j.neuroscience.2016.05.005

Liu, X. S.; Fan, B.; Szalad, A.; Jia, L.; Wang, L.; Wang, X.; Pan, W.; Zhang, L.; Zhang, R.; Hu, J.; et al. MicroRNA-146a Mimics Reduce the Peripheral Neuropathy in Type 2 Diabetic Mice. Diabetes 2017, 66 (12), 3111–3121. DOI: 10.2337/db16-1182

Wang, L.; Chopp, M.; Szalad, A.; Zhang, Y.; Wang, X.; Zhang, R. L.; Liu, X. S.; Jia, L.; Zhang, Z. G. The role of miR-146a in dorsal root ganglia neurons of experimental diabetic peripheral neuropathy. Neuroscience 2014, 259, 155–163. DOI: 10.1016/j.neuroscience.2013.11.057

Luo, Q.; Feng, Y.; Xie, Y.; Shao, Y.; Wu, M.; Deng, X.; Yuan, W. E.; Chen, Y.; Shi, X. Nanoparticle-microRNA- 146a-5p polyplexes ameliorate diabetic peripheral neuropathy by modulating inflammation and apoptosis. Nanomedicine 2019, 17, 188–197. DOI: 10.1016/j.nano.2019.01.007

Burgoyne, R. D.; Haynes, L. P. Understanding the physiological roles of the neuronal calcium sensor proteins. Mol Brain 2012, 5 (1), 2. DOI: 10.1186/1756-6606-5-2

Fernyhough, P.; Calcutt, N. A. Abnormal calcium homeostasis in peripheral neuropathies. Cell Calcium 2010, 47 (2), 130–139. DOI: 10.1016/j.ceca.2009.11.008

Huang, T. J.; Sayers, N. M.; Fernyhough, P.; Verkhratsky, A. Diabetes-induced alterations in calcium homeostasis in sensory neurones of streptozotocin-diabetic rats are restricted to lumbar ganglia and are prevented by neurotrophin-3. Diabetologia 2002, 45 (4), 560–570. DOI: 10.1007/s00125-002-0785-x

Kostyuk, E.; Svichar, N.; Shishkin, V.; Kostyuk, P. Role of mitochondrial dysfunction in calcium signalling alterations in dorsal root ganglion neurons of mice with experimentally-induced diabetes. Neuroscience 1999, 90 (2), 535–541. DOI: 10.1016/s0306-4522(98)00471-0

Levy, J.; Gavin, J. R., 3rd; Sowers, J. R. Diabetes mellitus: a disease of abnormal cellular calcium metabolism? Am J Med 1994, 96 (3), 260–273. DOI: 10.1016/0002-9343(94)90152-x

Ighodaro, O. M.; Adeosun, A. M.; Akinloye, O. A. Alloxan-induced diabetes, a common model for evaluating the glycemic-control potential of therapeutic compounds and plants extracts in experimental studies. Medicina (Kaunas) 2017, 53 (6), 365–374. DOI: 10.1016/j.medici.2018.02.001

Lowery, J. M.; Eichberg, J.; Saubermann, A. J.; LoPachin, R. M., Jr. Distribution of elements and water in peripheral nerve of streptozocin-induced diabetic rats. Diabetes 1990, 39 (12), 1498–1503. DOI: 10.2337/diab.39.12.1498

(66) O'Brien, P. D.; Hinder, L. M.; Sakowski, S. A.; Feldman, E. L. ER stress in diabetic peripheral neuropathy: A new therapeutic target. Antioxid Redox Signal 2014, 21 (4), 621–633. DOI: 10.1089/ars.2013.5807

Amran, M. S.; Homma, N.; Hashimoto, K. Pharmacology of KB-R7943: a Na+-Ca2+ exchange inhibitor. Cardiovasc Drug Rev 2003, 21 (4), 255–276. DOI: 10.1111/j.1527-3466.2003.tb00121.x

Obradovic, A.; Hwang, S. M.; Scarpa, J.; Hong, S. J.; Todorovic, S. M.; Jevtovic-Todorovic, V. CaV3.2 T-type calcium channels in peripheral sensory neurons are important for mibefradil-induced reversal of hyperalgesia and allodynia in rats with painful diabetic neuropathy. PLoS One 2014, 9 (4), e91467. DOI: 10.1371/journal.pone.0091467

Lu, J.; Yang, L.; Xu, Y.; Ai, L.; Chen, J.; Xiong, F.; Hu, L.; Chen, H.; Liu, J.; Yan, X.; et al. The Modulatory Effect of Motor Cortex Astrocytes on Diabetic Neuropathic Pain. J Neurosci 2021, 41 (24), 5287–5302. DOI: 10.1523/jneurosci.2566-20.2021

Vargas-Soria, M.; García-Alloza, M.; Corraliza-Gómez, M. Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies. J Neuroinflammation 2023, 20 (1), 57. DOI: 10.1186/s12974-023-02740-x

Annunziato, L.; Pignataro, G.; Di Renzo, G. F. Pharmacology of brain Na+/Ca2+ exchanger: from molecular biology to therapeutic perspectives. Pharmacol Rev 2004, 56 (4), 633–654. DOI: 10.1124/pr.56.4.5

Iwamoto, T.; Shigekawa, M. Differential inhibition of Na+/Ca2+ exchanger isoforms by divalent cations and isothiourea derivative. Am J Physiol 1998, 275 (2), C423– 430. DOI: 10.1152/ajpcell.1998.275.2.C423

Li, Y.; Woo, V.; Bose, R. Platelet hyperactivity and abnormal Ca(2+) homeostasis in diabetes mellitus. Am J Physiol Heart Circ Physiol 2001, 280 (4), H1480–1489. DOI: 10.1152/ajpheart.2001.280.4.H1480

Vincent, A. M.; Hinder, L. M.; Pop-Busui, R.; Feldman, E. L. Hyperlipidemia: a new therapeutic target for diabetic neuropathy. J Peripher Nerv Syst 2009, 14 (4), 257–267. DOI: 10.1111/j.1529-8027.2009.00237.x

Boden, G. Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc Am Physicians 1999, 111 (3), 241–248. DOI: 10.1046/j.1525-1381.1999.99220.x

Nolan, C. J.; Larter, C. Z. Lipotoxicity: why do saturated fatty acids cause and monounsaturates protect against it? J Gastroenterol Hepatol 2009, 24 (5), 703–706. DOI: 10.1111/j.1440-1746.2009.05823.x

Rumora, A. E.; Lentz, S. I.; Hinder, L. M.; Jackson, S. W.; Valesano, A.; Levinson, G. E.; Feldman, E. L. Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons. Faseb j 2018, 32 (1), 195– 207. DOI: 10.1096/fj.201700206R

Feldman, E. L.; Nave, K. A.; Jensen, T. S.; Bennett, D. L. H. New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain. Neuron 2017, 93 (6), 1296–1313. DOI: 10.1016/j.neuron.2017.02.005

Papamandjaris, A. A.; MacDougall, D. E.; Jones, P. J. Medium chain fatty acid metabolism and energy expenditure: obesity treatment implications. Life Sci 1998, 62 (14), 1203–1215. DOI: 10.1016/s0024-3205(97)01143-0

Schönfeld, P.; Wojtczak, L. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J Lipid Res 2016, 57 (6), 943–954. DOI: 10.1194/jlr.R067629

Rumora, A. E.; LoGrasso, G.; Haidar, J. A.; Dolkowski, J. J.; Lentz, S. I.; Feldman, E. L. Chain length of saturated fatty acids regulates mitochondrial trafficking and function in sensory neurons. J Lipid Res 2019, 60 (1), 58– 70. DOI: 10.1194/jlr.M086843

An, Y.; Cao, S.; Shi, L.; Zhang, Y.; Wang, X.; Yuan, S.; Shi, Y.; Wang, B.; Liu, J.; Han, C. J. Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway. Brain Res Bull 2025, 221, 111226. DOI: 10.1016/j.brainresbull.2025.111226

Liu, D.; Yang, L.; Liu, P.; Ji, X.; Qi, X.; Wang, Z.; Chi, T.; Zou, L. Sigma-1 receptor activation alleviates blood-brain barrier disruption post cerebral ischemia stroke by stimulating the GDNF-GFRα1-RET pathway. Exp Neurol 2022, 347, 113867. DOI: 10.1016/j.expneurol.2021.113867

Bhat, N. R.; Feinstein, D. L.; Shen, Q.; Bhat, A. N. p38 MAPK-mediated transcriptional activation of inducible nitric-oxide synthase in glial cells. Roles of nuclear factors, nuclear factor kappa B, cAMP response element-binding protein, CCAAT/enhancer-binding protein-beta, and activating transcription factor-2. J Biol Chem 2002, 277 (33), 29584–29592. DOI: 10.1074/jbc.M204994200

Chen, L.; Wang, H.; Xing, J.; Shi, X.; Huang, H.; Huang, J.; Xu, C. Silencing P2X7R Alleviates Diabetic Neuropathic Pain Involving TRPV1 via PKCε/P38MAPK/NF-κB Signaling Pathway in Rats. Int J Mol Sci 2022, 23 (22). DOI: 10.3390/ijms232214141

Shen, Y. C.; Wang, Y. H.; Chou, Y. C.; Liou, K. T.; Yen, J. C.; Wang, W. Y.; Liao, J. F. Dimemorfan protects rats against ischemic stroke through activation of sigma-1 receptor-mediated mechanisms by decreasing glutamate accumulation. J Neurochem 2008, 104 (2), 558–572. DOI: 10.1111/j.1471-4159.2007.05058.x

Yang, W.; Liu, Y.; Xu, Q. Q.; Xian, Y. F.; Lin, Z. X. Sulforaphene Ameliorates Neuroinflammation and Hyperphosphorylated Tau Protein via Regulating the PI3K/Akt/GSK-3β Pathway in Experimental Models of Alzheimer's Disease. Oxid Med Cell Longev 2020, 2020, 4754195. DOI: 10.1155/2020/4754195

Wang, M. J.; Huang, H. Y.; Chen, W. F.; Chang, H. F.; Kuo, J. S. Glycogen synthase kinase-3β inactivation inhibits tumor necrosis factor-α production in microglia by modulating nuclear factor κB and MLK3/JNK signaling cascades. J Neuroinflammation 2010, 7, 99. DOI: 10.1186/1742-2094-7-99

Zhang, L. Y.; Liu, Z. H.; Zhu, Q.; Wen, S.; Yang, C. X.; Fu, Z. J.; Sun, T. Resolvin D2 Relieving Radicular Pain is Associated with Regulation of Inflammatory Mediators, Akt/GSK-3β Signal Pathway and GPR18. Neurochem Res 2018, 43 (12), 2384–2392. DOI: 10.1007/s11064-018-2666-9

Wang, Y.; Guo, L.; Jiang, H. F.; Zheng, L. T.; Zhang, A.; Zhen, X. C. Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity. CNS Neurosci Ther 2016, 22 (5), 368–377. DOI: 10.1111/cns.12502

Gao, T.; Gao, C.; Liu, Z.; Wang, Y.; Jia, X.; Tian, H.; Lu, Q.; Guo, L. Inhibition of Noncanonical Ca(2+) Oscillation/Calcineurin/GSK-3β Pathway Contributes to Anti-Inflammatory Effect of Sigma-1 Receptor Activation. Neurochem Res 2022, 47 (2), 264–278. DOI: 10.1007/s11064-021-03439-2

Gris, G.; Portillo-Salido, E.; Aubel, B.; Darbaky, Y.; Deseure, K.; Vela, J. M.; Merlos, M.; Zamanillo, D. The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats. Sci Rep 2016, 6, 24591. DOI: 10.1038/srep24591

Paniagua, N.; Girón, R.; Goicoechea, C.; López-Miranda, V.; Vela, J. M.; Merlos, M.; Martín Fontelles, M. I. Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats. Eur J Pain 2017, 21 (1), 61– 72. DOI: 10.1002/ejp.897

Romero, L.; Merlos, M.; Vela, J. M. Antinociception by Sigma-1 Receptor Antagonists: Central and Peripheral Effects. Adv Pharmacol 2016, 75, 179–215. DOI: 10.1016/bs.apha.2015.11.003

Romero, L.; Zamanillo, D.; Nadal, X.; Sánchez-Arroyos, R.; Rivera-Arconada, I.; Dordal, A.; Montero, A.; Muro, A.; Bura, A.; Segalés, C.; et al. Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization. Br J Pharmacol 2012, 166 (8), 2289–2306. DOI: 10.1111/j.1476-5381.2012.01942.x

Bura, A. S.; Guegan, T.; Zamanillo, D.; Vela, J. M.; Maldonado, R. Operant self-administration of a sigma ligand improves nociceptive and emotional manifestations of neuropathic pain. Eur J Pain 2013, 17 (6), 832–843. DOI: 10.1002/j.1532-2149.2012.00251.x

Mazo, I.; Roza, C.; Zamanillo, D.; Merlos, M.; Vela, J. M.; Lopez-Garcia, J. A. Effects of centrally acting analgesics on spinal segmental reflexes and wind-up. Eur J Pain 2015, 19 (7), 1012–1020. DOI: 10.1002/ejp.629

Vidal-Torres,A.; Fernández-Pastor, B.; Carceller, A.; Vela, J. M.; Merlos, M.; Zamanillo, D. Effects of the selective sigma-1 receptor antagonist S1RA on formalin-induced pain behavior and neurotransmitter release in the spinal cord in rats. J Neurochem 2014, 129 (3), 484–494. DOI: 10.1111/jnc.12648

Gálvez, R.; Mayoral, V.; Cebrecos, J.; Medel, F. J.; Morte, A.; Sust, M.; Vaqué, A.; Montes-Pérez, A.; Neira-Reina, F.; Cánovas, L.; et al. E-52862-A selective sigma-1 receptor antagonist, in peripheral neuropathic pain: Two randomized, double-blind, phase 2 studies in patients with chronic postsurgical pain and painful diabetic neuropathy. Eur J Pain 2025, 29 (1). DOI: 10.1002/ejp.4755

Ahmadi, S. A.; Sabahi, M.; Haddadi, R. The effect of acute and repeated administration of buspirone, 8- OHDPAT and fluoxetine on haloperidol-induced extrapyramidal symptoms. Neuropsychopharmacol Hung 2019, 21 (2), 59–68

Ventura-Martínez, R.; Ángeles-López, G. E.; González-Ugalde, D.; Domínguez-Páez, T.; Navarrete-Vázquez, G.; Jaimez, R.; Déciga-Campos, M. Antinociceptive effect of LMH-2, a new sigma-1 receptor antagonist analog of haloperidol, on the neuropathic pain of diabetic mice. Biomed Pharmacother 2024, 174, 116524. DOI: 10.1016/j.biopha.2024.116524

Cameron, N. E.; Cotter, M. A. The relationship of vascular changes to metabolic factors in diabetes mellitus and their role in the development of peripheral nerve complications. Diabetes Metab Rev 1994, 10 (3), 189– 224. DOI: 10.1002/dmr.5610100302

Kwon, S. G.; Roh, D. H.; Yoon, S. Y.; Choi, S. R.; Choi, H. S.; Moon, J. Y.; Kang, S. Y.; Kim, H. W.; Han, H. J.; Beitz, A. J.; et al. Role of peripheral sigma-1 receptors in ischaemic pain: Potential interactions with ASIC and P2X receptors. Eur J Pain 2016, 20 (4), 594–606. DOI: 10.1002/ejp.774

Naseri, R.; Farzaei, F.; Fakhri, S.; El-Senduny, F. F.; Altouhamy, M.; Bahramsoltani, R.; Ebrahimi, F.; Rahimi, R.; Farzaei, M. H. Polyphenols for diabetes associated neuropathy: Pharmacological targets and clinical perspective. Daru 2019, 27 (2), 781–798. DOI: 10.1007/s40199-019-00289-w

Qi, M. Y.; Wang, X. T.; Xu, H. L.; Yang, Z. L.; Cheng, Y.; Zhou, B. Protective effect of ferulic acid on STZ-induced diabetic nephropathy in rats. Food Funct 2020, 11 (4), 3706–3718. DOI: 10.1039/c9fo02398d

Saraswat, N.; Sachan, N.; Chandra, P. Anti-diabetic, diabetic neuropathy protective action and mechanism of action involving oxidative pathway of chlorogenic acid isolated from Selinum vaginatum roots in rats. Heliyon 2020, 6 (10), e05137. DOI: 10.1016/j.heliyon.2020.e05137

Sosnik, A. Alginate Particles as Platform for Drug Delivery by the Oral Route: State-of-the-Art. ISRN Pharm 2014, 2014, 926157. DOI: 10.1155/2014/926157

Tønnesen, H. H.; Karlsen, J. Alginate in drug delivery systems. Drug Dev Ind Pharm 2002, 28 (6), 621–630. DOI: 10.1081/ddc-120003853

Tusi, S. K.; Khalaj, L.;Ashabi, G.; Kiaei, M.; Khodagholi, F. Alginate oligosaccharide protects against endoplasmic reticulum- and mitochondrial-mediated apoptotic cell death and oxidative stress. Biomaterials 2011, 32 (23), 5438–5458. DOI: 10.1016/j.biomaterials.2011.04.024

Guo, J. J.; Xu, F. Q.; Li, Y. H.; Li, J.; Liu, X.; Wang, X. F.; Hu, L. G.; An, Y. Alginate oligosaccharide alleviates myocardial reperfusion injury by inhibiting nitrative and oxidative stress and endoplasmic reticulum stress-mediated apoptosis. Drug Des Devel Ther 2017, 11, 2387–2397. DOI: 10.2147/dddt.S142118

Mohamed, N. A.; Shouran, N. M.; Essawy, A. E.; Abdel-Moneim, A. M.; Abdel Salam, S. Mitigative effect of sodium alginate on streptozotocin (STZ)-induced diabetic neuropathy through regulation of redox status and miR- 146a in the rat sciatic nerve. PeerJ 2025, 13, e19046. DOI: 10.7717/peerj.19046

Zhao, H.; Gao, X.; Liu, Z.; Zhang, L.; Fang, X.; Sun, J.; Zhang, Z.; Sun, Y. Sodium Alginate Prevents Non-Alcoholic Fatty Liver Disease by Modulating the Gut-Liver Axis in High-Fat Diet-Fed Rats. Nutrients 2022, 14 (22). DOI: 10.3390/nu14224846

Andreeva-Gateva, P.; Hristov, M.; Strokova-Stoilova, M.; Ivanova, N.; Sabit, Z.; Surcheva, S.; Beliakov, M.; Karakashev, G.; Sukhov, I.; Belinskaya, D.; et al. Therapeutic potential of orally applied KB-R7943 in streptozotocin-induced neuropathy in rats. Heliyon 2024, 10 (6), e27367. DOI: 10.1016/j.heliyon.2024.e27367

Bobylev, I.; Maru, H.; Joshi, A. R.; Lehmann, H. C. Toxicity to sensory neurons and Schwann cells in experimental linezolid-induced peripheral neuropathy. J Antimicrob Chemother 2016, 71 (3), 685–691. DOI: 10.1093/jac/dkv386

Ivanova, N.; Hristov, M.; Gateva, P. Rodent Models of Diabetic Neuropathy, Role of Calcium Homeostasis in Pain and KB-R7943 as a Potential Therapeutic. Int J Mol Sci 2025, 26 (5). DOI: 10.3390/ijms26052094

Tsuda, M.; Ueno, H.; Kataoka, A.; Tozaki-Saitoh, H.; Inoue, K. Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling. Glia 2008, 56 (4), 378–386. DOI: 10.1002/glia.20623

Wu, J.; Ding, D. H.; Li, Q. Q.; Wang, X. Y.; Sun, Y. Y.; Li, L. J. Lipoxin A4 Regulates Lipopolysaccharide-Induced BV2 Microglial Activation and Differentiation via the Notch Signaling Pathway. Front Cell Neurosci 2019, 13, 19. DOI: 10.3389/fncel.2019.00019

Shu, B.; He, S. Q.; Guan, Y. Spinal Cord Stimulation Enhances Microglial Activation in the Spinal Cord of Nerve-Injured Rats. Neurosci Bull 2020, 36 (12), 1441– 1453. DOI: 10.1007/s12264-020-00568-6

Yuan, J.; Fei, Y. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization. Open Med (Wars) 2022, 17 (1), 897–906. DOI: 10.1515/med-2022-0480

Zhang, Y.; Chen, Q.; Nai, Y.; Cao, C. Suppression of miR- 155 attenuates neuropathic pain by inducing an M1 to M2 switch in microglia. Folia Neuropathol 2020, 58 (1), 70– 82. DOI: 10.5114/fn.2020.94008

Kim, H.; Wang, S. Y.; Kwak, G.; Yang, Y.; Kwon, I. C.; Kim, S. H. Exosome-Guided Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing. Adv Sci (Weinh) 2019, 6 (20), 1900513. DOI: 10.1002/advs.201900513

Kalluri, R.; LeBleu, V. S. The biology, function, and biomedical applications of exosomes. Science 2020, 367 (6478). DOI: 10.1126/science.aau6977

Wei, W.; Fang, J.; Yang, B.; Cui, C.; Wei, J.; Xue, Y. Temporal therapy utilizing exosomes derived from M2 macrophages demonstrates enhanced efficacy in alleviating neuropathic pain in diabetic rats. Korean J Pain 2025, 38 (1), 14–28. DOI: 10.3344/kjp.24244

Shiue, S. J.; Rau, R. H.; Shiue, H. S.; Hung, Y. W.; Li, Z. X.; Yang, K. D.; Cheng, J. K. Mesenchymal stem cell exosomes as a cell-free therapy for nerve injury-induced pain in rats. Pain 2019, 160 (1), 210–223. DOI: 10.1097/j.pain.0000000000001395

Sun, G.; Li, G.; Li, D.; Huang, W.; Zhang, R.; Zhang, H.; Duan, Y.; Wang, B. hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation. Mater Sci Eng C Mater Biol Appl 2018, 89, 194–204. DOI: 10.1016/j.msec.2018.04.006

Raposo, G.; Stahl, P. D. Extracellular vesicles: a new communication paradigm? Nat Rev Mol Cell Biol 2019, 20 (9), 509–510. DOI: 10.1038/s41580-019-0158-7

Tran, P. H.; Xiang, D.; Nguyen, T. N.; Tran, T. T.; Chen, Q.; Yin, W.; Zhang, Y.; Kong, L.; Duan, A.; Chen, K.; et al. Aptamer-guided extracellular vesicle theranostics in oncology. Theranostics 2020, 10 (9), 3849–3866. DOI: 10.7150/thno.39706

Lin, P.; Yang, M.; Huang, D.; Lin, H.; Wang, J.; Zhong, C.; Guan, L. Effect of proprioceptive neuromuscular facilitation technique on the treatment of frozen shoulder: a pilot randomized controlled trial. BMC Musculoskelet Disord 2022, 23 (1), 367. DOI: 10.1186/s12891-022-05327-4

Chittrakul, J.; Siviroj, P.; Sungkarat, S.; Sapbamrer, R. Multi-System Physical Exercise Intervention for Fall Prevention and Quality of Life in Pre-Frail Older Adults: A Randomized Controlled Trial. Int J Environ Res Public Health 2020, 17 (9), 3102. DOI: 10.3390/ijerph17093102

Haleem, F.; Saeed, A.; Kundi, M.; Jalal, A.; Bilal, M.; Jalal, M. Combined effects of strength and balance training versus aerobic training on balance, neuropathy symptoms and quality of life in patients with diabetic peripheral neuropathy. Physiother Res Int 2024, 29 (3), e2103. DOI: 10.1002/pri.2103

Khurshid, S.; Saeed, A.; Kashif, M.; Nasreen, A.; Riaz, H. Effects of multisystem exercises on balance, postural stability, mobility, walking speed, and pain in patients with diabetic peripheral neuropathy: a randomized controlled trial. BMC Neurosci 2025, 26 (1), 16. DOI: 10.1186/s12868-024-00924-6

Akhtar, S. Diabetes-induced peripheral neuropathy: Is prescribing physical exercise the answer? Biomol Biomed 2024, 24 (3), 436–439. DOI: 10.17305/bb.2023.10188

Gozzi, N.; Chee, L.; Odermatt, I.; Kikkert, S.; Preatoni, G.; Valle, G.; Pfender, N.; Beuschlein, F.; Wenderoth, N.; Zipser, C.; et al. Wearable non-invasive neuroprosthesis for targeted sensory restoration in neuropathy. Nat Commun 2024, 15 (1), 10840. DOI: 10.1038/s41467-024-55152-7

Melzack, R.; Wall, P. D. Pain mechanisms: a new theory. Science 1965, 150 (3699), 971–979. DOI: 10.1126/science.150.3699.971

Li, Y.; Sun, S.; Li, B.; Li, Y.; Liu, C.; Ta, D. Low-intensity pulsed ultrasound relieved the diabetic peripheral neuropathy in mice via anti-oxidative stress mechanism. Ultrasonics 2025, 150, 107618. DOI: 10.1016/j.ultras.2025.107618

Most read articles by the same author(s)

Similar Articles

You may also start an advanced similarity search for this article.