Oxidative Stress in Peripheral Diabetic Neuropathy: Key Mechanisms and Therapeutic Targets

Oxidative Stress in Peripheral Diabetic Neuropathy: Key Mechanisms and Therapeutic Targets | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 1 November 2025 V1 Latest version Share on Oxidative Stress in Peripheral Diabetic Neuropathy: Key Mechanisms and Therapeutic Targets Authors : Tarek El-Masri [email protected] , Franck Sturtz 0000-0001-6428-5162 , and Mirella Hage Authors Info & Affiliations https://doi.org/10.22541/au.176199324.45430645/v1 586 views 183 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Oxidative stress plays a central and multifaceted role in the pathogenesis of diabetic peripheral neuropathies (DPN), one of the most common and disabling complications of diabetes mellitus. Chronic hyperglycemia initiates a cascade of interrelated metabolic disturbances including activation of the polyol, hexosamine, protein kinase C, mitogen-activated protein kinase, and advanced glycation end-product pathways, all of which converge to increase reactive oxygen species production, disrupt mitochondrial function, and overwhelm antioxidant defenses. These mechanisms lead to axonal degeneration, Schwann cell dysfunction, vascular impairment, and ultimately, irreversible nerve damage. At present, DPN remains largely untreatable, with available therapies offering only symptomatic relief. Increasing attention has been directed toward targeting the oxidative stress response as a potential disease-modifying strategy. Central to the antioxidant defence is the nuclear factor erythroid 2–related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) pathway signalling pathway, a critical regulator of cellular redox homeostasis. Current research highlights several therapeutic candidates including aldose reductase inhibitors, α-lipoic acid, benfotiamine, GLP-1 receptor agonists, DPP-4 inhibitors, and Nrf2 activators like curcumin and bardoxolone methyl, that aim to restore redox balance and mitigate neuronal injury. This review comprehensively discusses the molecular underpinnings of oxidative stress in DN and evaluates emerging antioxidant-based strategies that hold promise for preventing or slowing disease progression. Oxidative Stress in Peripheral Diabetic Neuropathy: Key Mechanisms and Therapeutic Targets Tarek El-Masri 1* , Franck G. Sturtz 1,2 Mirella Hage 3,4 1 UR 20218 - NeurIT, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France 2 Department of Biochemistry and Molecular Genetics, University Hospital of Limoges, Limoges, France. 3 Department of Endocrinology, Diabetology, and Nutrition, Ambroise Paré University Hospital, Assistance Publique-Hôpitaux de Paris, F-92100 Boulogne Billancourt, France. 4 University of Versailles Saint-Quentin-en-Yvelines, UFR of Health Sciences Simone Veil, F-78423 Montigny-le-Bretonneux, France. Tarek El Masri: corresponding author , UR 20218 - NeurIT, Faculties of Medicine and Pharmacy, University of Limoges, Limoges, France. Email: [email protected] Key words: oxidative stress, diabetic neuropathy, antioxidant, Nrf2 Short running title: oxidative stress and diabetic neuropathy Word count: 4818 words in manuscript, 120 references, 3 figures, 2 tables Abstract Oxidative stress plays a central and multifaceted role in the pathogenesis of diabetic peripheral neuropathies (DPN), one of the most common and disabling complications of diabetes mellitus. Chronic hyperglycemia initiates a cascade of interrelated metabolic disturbances including activation of the polyol, hexosamine, protein kinase C, mitogen-activated protein kinase, and advanced glycation end-product pathways, all of which converge to increase reactive oxygen species production, disrupt mitochondrial function, and overwhelm antioxidant defenses. These mechanisms lead to axonal degeneration, Schwann cell dysfunction, vascular impairment, and ultimately, irreversible nerve damage. At present, DPN remains largely untreatable, with available therapies offering only symptomatic relief. Increasing attention has been directed toward targeting the oxidative stress response as a potential disease-modifying strategy. Central to the antioxidant defence is the nuclear factor erythroid 2–related factor 2 (Nrf2)–Kelch-like ECH-associated protein 1 (Keap1) pathway signalling pathway, a critical regulator of cellular redox homeostasis. Current research highlights several therapeutic candidates including aldose reductase inhibitors, α-lipoic acid, benfotiamine, GLP-1 receptor agonists, DPP-4 inhibitors, and Nrf2 activators like curcumin and bardoxolone methyl, that aim to restore redox balance and mitigate neuronal injury. This review comprehensively discusses the molecular underpinnings of oxidative stress in DN and evaluates emerging antioxidant-based strategies that hold promise for preventing or slowing disease progression. Introduction The global incidence of diabetes mellitus (DM) is significantly on the rise. In 2021, around 10.5% of the world’s population, equivalent to 537 million individuals, were living with either type 1 or type 2 diabetes mellitus 1,2 . This number is expected to grow to 643 million by 2030 and 783 million by 2045 3 . Additionally, more than 4 million deaths were attributed to complications related to diabetes 1 . Among the complications of diabetes, diabetic neuropathy is the most prevalent, affecting more than half of patients with DM after two decades of disease progression 4 . Several clinical subtypes of diabetic neuropathy have been identified, including autonomic neuropathy, mononeuropathy, multiple mononeuropathy, motor neuropathy, and sensory neuropathy. Among these, distal symmetric polyneuropathy, primarily affecting sensory fibers, is by far the most prevalent form and will be the focus of this review 5 \sout. Diabetic neuropathy substantially compromises patients’ quality of life and functional independence, contributing to chronic pain, gait instability, sleep disturbances, and increased vulnerability to foot ulcers and lower-limb amputations. As the disease progresses, it imposes a considerable personal and socioeconomic burden, underscoring the urgent need for disease-modifying interventions 6 . At present, there is no definitive treatment for diabetic peripheral neuropathy (DPN), as current therapies mainly offer symptomatic relief. The pathophysiology of DPN remains complex and not fully understood, with oxidative stress recognized as a key contributing factor. A deeper understanding of these mechanisms is essential for the development of effective disease-modifying treatments. Thus, the present review aims to comprehensively examine the molecular mechanisms by which hyperglycemia-induced oxidative stress contributes to the development and progression of diabetic peripheral neuropathy. The roles of key metabolic pathways will be examined in propagating oxidative stress. Furthermore, we will explore the critical contribution of mitochondrial dysfunction as a major source of reactive oxygen species, and describe the protective mechanisms of the Nuclear factor erythroid 2–related factor 2/ Kelch-like ECH-associated protein 1 (Nrf2/Keap1) pathway and its dysregulation in diabetes. Finally, we will discuss current and emerging therapeutic strategies that specifically target these oxidative stress-related pathways, offering insights into potential disease-modifying interventions for diabetic neuropathy. Oxidative stress Oxidative stress (OS) refers to a state where the production of reactive oxygen species (ROS) exceeds the capacity of the antioxidant defense systems, leading to cellular damage. The body often produces a variety of free radical species to carry out particular tasks. Three free radical reactive oxygen species: superoxide (O 2 ), hydrogen peroxide (H 2 O 2 ), and nitric oxide (NO) are necessary for normal metabolism but are also thought to hasten aging and induce cellular degeneration in pathological situations. When combined, these substances create very potent singlet oxygen, hydroxyl radicals, and peroxynitrite that may damage DNA, lipids, and proteins 7 . Furthermore, secondary reactive species like hypochlorous acid, lipid peroxyl and alkoxyl radicals, generated through inflammatory enzymes or lipid peroxidation, exacerbate oxidative damage and amplify injury to neuronal membranes and structures 8 . Extensive research supports the critical role of hyperglycemia-induced oxidative stress in the development of diabetic neuropathy. Chronically elevated blood glucose levels increase oxidative stress, which contributes to nerve damage by harming various cell types, including endothelial, retinal, mesangial, and neural cells 4,9–11 . Impaired mitochondrial glucose oxidation is considered a primary source of ROS production in diabetes 4,9,12 (Table 1). Under normal conditions, glucose is metabolized through glycolysis and mitochondrial oxidation to generate adenosine triphosphate (ATP), the primary energy carrier in all living cells, with minimal ROS production efficiently managed by cellular antioxidants. In diabetes, however, chronic hyperglycemia leads to an overload of reducing equivalents in the mitochondrial electron transport chain, particularly affecting Complexes I and III. This causes electron leakage and excessive superoxide production, which damages mitochondrial and nuclear DNA, impairs ETC function, and further amplifies oxidative stress 10 . Additionally, excess glucose is diverted into alternative pathways such as the Polyol pathway, the Hexosamine pathway, Advanced Glycation End-Products (AGE) and Protein kinase C (PKC) pathways, Mitogen-Activated Protein Kinase (MAPK pathways), all of which contribute to mitochondrial dysfunction and ROS overproduction (Figure 1). The resulting oxidative imbalance plays a central role in diabetic neuropathy. Axons, which depend on local mitochondrial ATP production and have limited antioxidant capacity, are particularly vulnerable, making oxidative stress a central contributor to Schwann cell and axonal degeneration in diabetic neuropathy 13–16 . Mechanisms involved in increasing oxidative stress during hyperglycemia In the following paragraph we will describe several metabolic pathways are implicate in the development of oxidative stress during hyperglycemia (Summarized in figure 2) The Polyol Pathway The polyol pathway, primarily driven by aldose reductase (AR) and sorbitol dehydrogenase (SD), is significantly upregulated in diabetic conditions due to chronic hyperglycemia. AR catalyzes the conversion of excess glucose to sorbitol, consuming Nicotinamide Adenine Dinucleotide Phosphate (NADPH) in the process. Subsequently, SD transforms sorbitol into fructose, utilizing NAD+. While this pathway metabolizes a minor portion of glucose under normal physiological concentrations, its accelerated activity during hyperglycemia leads to a critical decline in cellular NADPH levels 17,18 . This depletion of NADPH is detrimental as it reduces the availability of reduced glutathione (GSH), a paramount antioxidant in the nervous system. The subsequent decrease in GSH compromises the cellular redox equilibrium, contributing to endothelial nerve injury and a loss of NO-mediated vasodilation 19 . Beyond the impact on redox balance, the elevated intracellular accumulation of sorbitol induces significant osmotic stress 12,18 . This stress triggers the compensatory efflux and subsequent depletion of crucial osmolytes, such as taurine and myoinositol 20 . These metabolic disturbances severely affect Schwann cells in peripheral neurons, which are particularly susceptible to sorbitol accumulation 12,21 . Furthermore, the build-up of sorbitol and fructose directly inhibits the vital Na+/K+-ATPase pump, leading to an increase in intracellular sodium, axon enlargement, axon-glia dysfunction, and a decrease in nerve conduction velocity (NCV) 22–24 . Beyond metabolic disruption, AR overactivity initiates several inflammatory and stress-related pathways. It stimulates protein kinases, PolyADP-ribose polymerase (PARP), Cyclooxygenase-2 (COX-2), and MAPK, and activates transcription factors such as Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and tumor protein p53. This leads to increased activity of inflammatory molecules like inducible nitric oxide synthase (iNOS), and endothelin-1 and 12/15-lipoxygenase (12/15-LOX) further contributing to neural damage and endothelial dysfunction, including reduced NO-mediated vasodilation 25,26 . AR activation also contributes to the upregulation of COX-2 and 12/15-LOX in nerve cells 26 . Evidence from transgenic mouse models corroborates this, showing that higher AR levels correlate with lower GSH content and more severe neuropathic damage 17 , while AR-deficient mice exhibit improved motor and sensory nerve function 27 . Genetic studies have further linked variations in the AR gene ( AKR1B1 ) to a two- to threefold increase in AR gene expression and a higher risk of diabetic neuropathy 28,29 . Overall, the polyol pathway undermines cellular redox equilibrium by encouraging the production of ROS and reducing the availability of molecules necessary for glutathione recycling, thereby acting as a major contributor to the oxidative stress-induced damage observed in diabetic neuropathy 30 . The Hexosamine pathway The hexosamine pathway (HP) plays a significant role in promoting oxidative stress and contributing to both direct and indirect neuronal damage. Excess intracellular glucose is diverted into the HP, where fructose-6-phosphate is converted into glucosamine-6-phosphate by the rate-limiting enzyme glucosamine-6-phosphate amidotransferase (GFAT), ultimately producing uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc). This metabolite drives aberrant O-GlcNAcylation of key neuronal proteins, disrupting intracellular signaling, gene expression, mitochondrial integrity, and antioxidant defenses, which in turn promotes oxidative stress, pro-inflammatory cytokine expression, synaptic dysfunction, and neuronal apoptosis via NF-κB and caspase activation. Indirectly, increased UDP-GlcNAc also activates the transcription factor Specificity Protein 1 (Sp1), stimulating the expression of Transforming Growth Factor Beta 1 (TGF-β1) and Plasminogen Activator Inhibitor-1 (PAI-1) 31 . TGF-β1 induces vascular fibrosis, while PAI-1 promotes atherosclerosis, both of which compromise blood flow to peripheral nerves and exacerbate oxidative damage and neuronal dysfunction. Moreover, overexpression of GFAT elevates hydrogen peroxide levels and downregulates genes essential for glucose metabolism, further contributing to β-cell dysfunction and metabolic stress. Together, these mechanisms highlight the dual role of the hexosamine pathway in directly impairing neuronal viability and indirectly worsening neurodegeneration via vascular compromise and oxidative stress 32,33 . The PKC pathway PKC is a family of roughly 15 serine/threonine kinases categorized into classical, novel, and atypical isoforms based on their activation requirements 34 . In diabetes, chronic hyperglycemia elevates intracellular diacylglycerol (DAG), persistently activating several PKC isoforms (especially α, βI, βII, γ, δ, and ε) in neural and vascular tissues 34–36 . This aberrant activation stimulates enzymes such as NADPH oxidase, leading to excessive generation of reactive oxygen species 21,37 . The resulting oxidative stress damages lipids, proteins, and DNA in peripheral nerves, contributing to axonal dysfunction and demyelination 37,38 . Moreover, ROS accumulation disrupts mitochondrial function by impairing oxidative phosphorylation and reducing ATP production, which compromises axonal transport and neuronal viability 39 . This oxidative environment further enhances DAG synthesis and PKC activity, establishing a vicious cycle that perpetuates neuronal injury 21,37 . Additionally, redox-sensitive transcription factors such as NF-κB are activated under these conditions, amplifying inflammatory signaling and exacerbating oxidative damage 37,40,41 . Altogether, PKC-driven oxidative stress represents a central mechanism in the pathogenesis of diabetic neuropathy 42 . The MAPK pathway MAPKs are critical signaling molecules that mediate cellular responses to various stimuli, with three primary subfamilies: extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 MAPKs. While ERK signaling supports neuronal survival, JNK and p38 pathways are linked to apoptosis, contributing to oxidative stress 43 . In diabetic conditions, particularly in streptozotocin (STZ)-induced diabetic rat models, there is an upregulation of all three MAPK subfamilies — ERKs, JNKs, and p38 MAPKs — in neurons within the dorsal root ganglia 44 . Clinical studies of diabetic patients also show increased activation of p38 and JNK pathways in sural nerve biopsies, correlating oxidative stress with neuronal damage 43 . JNK activation, in particular, has been linked to the abnormal modification of neurofilament proteins, and inhibiting JNK signaling in diabetic models can improve peripheral nerve regeneration, suggesting a therapeutic potential for mitigating oxidative damage in diabetic neuropathy 45–47 . Next to that, AGEs restrict the phosphorylation of ERK, which typically facilitates the transcription of growth factors leading to proliferation. Lastly, by decreasing the availability of antioxidant enzymes, AGEs can cause ROS production, which directly damages proteins and DNA 48 . Advanced Glycation End-Products AGEs are a complex and heterogeneous group of molecules that result from non-enzymatic reactions between reducing sugars and the free amino groups of proteins, lipids, or nucleic acids. Elevated glucose causes proteins to become glycated and undergo further changes, forming AGEs. Reactive compounds from lipid oxidation also contribute to this process. Importantly, AGEs are often irreversible, and accumulate over time, altering tissue structure and function by cross-linking proteins like collagen, leading to stiffness, inflammation, fibrosis, and calcification 48,49 . The pathogenic role of AGEs in diabetes extends to both microvascular and macrovascular complications. In hyperglycemic conditions, excessive glucose undergoes glycation, forming AGEs that disrupt cellular functions through multiple mechanisms 50 . One of the primary pathways involves the activation of the Receptor for Advanced Glycation End Products (RAGE), a transmembrane receptor expressed on endothelial cells, neurons, and immune cells. RAGE activation triggers intracellular signaling cascades, including NF-κB, MAPKs, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways, all of which contribute to inflammation, oxidative stress, and cellular dysfunction 51,52 . AGEs have been shown to exacerbate oxidative stress by depleting intracellular levels of GSH, a key antioxidant that plays a central role in maintaining redox homeostasis in mammalian cells 53 . In SH-SY5Y human neuroblastoma cells, this oxidative imbalance contributes directly to AGE-induced cytotoxicity 54 . The reduction in GSH levels triggered by AGEs can be mitigated by antioxidant agents such as N-acetylcysteine, alpha-lipoic acid, 17β-estradiol, and by the enzymatic activity of catalase, indicating that the production of ROS, specifically superoxide and hydrogen peroxide, precedes GSH depletion 53 . These findings support the notion that oxidative stress driven by hyperglycemia accelerates AGE formation, which in turn amplifies oxidative damage in peripheral nerves, disrupting neuronal and Schwann cell signaling. This vicious cycle contributes to progressive axonal loss and impaired nerve regeneration in diabetic neuropathy. Moreover, recent data from long-term diabetic rat models revealed a simultaneous increase in AGE accumulation, neuronal nitric oxide synthase (nNOS) expression, and oxidative stress-induced apoptosis in pelvic ganglion neurons. These findings suggest a synergistic interaction between AGEs and endogenous nitric oxide in promoting oxidative injury and irreversible nitrergic neuron degeneration in experimental diabetic autonomic neuropathy 55 . In addition, AGE-RAGE interactions initiate intracellular signaling cascades that activate NADPH oxidase and disrupt mitochondrial function, leading to excessive ROS production 52 . The resulting oxidative stress causes lipid peroxidation, DNA damage, and oxidation of proteins critical for neuronal integrity, exacerbating nerve dysfunction 56 . Additionally, AGEs impair antioxidant defense mechanisms by depleting glutathione and inhibiting superoxide dismutase and catalase activity, increasing neuronal susceptibility to metabolic stress 12 . AGEs also contribute to neuronal injury by modifying key structural proteins such as neurofilaments and myelin basic protein, leading to cytoskeletal instability and myelin degeneration 57 . These changes disrupt axonal transport, reduce conduction velocity, and ultimately promote neuronal apoptosis, all of these being hallmarks of diabetic neuropathy 58 . Antioxidant Defense Mechanisms in Diabetic Neuropathy Classical antioxidant mechanisms The human body is equipped with robust endogenous antioxidant defense systems that play a fundamental role in counteracting the harmful effects of ROS, which are continuously generated during normal metabolic processes and in response to environmental stressors. This defense network consists of both enzymatic and non-enzymatic components that act synergistically to maintain redox homeostasis and protect cellular structures from oxidative damage. Non-enzymatic antioxidants play a central role in directly and very rapidly scavenging free radicals, maintaining redox status, and regenerating oxidized forms of other antioxidants. These molecules include Glutathione also known as GSH 59 , Vitamin E and Vitamin C, coenzyme Q10 and several others. On the other hand, key enzymatic antioxidants include superoxide dismutases (SOD), which catalyze the dismutation of superoxide radicals into hydrogen peroxide; catalase, which rapidly decomposes hydrogen peroxide into water and oxygen 60,61 ; and glutathione peroxidases (GPx), which reduce hydrogen peroxide and lipid peroxides using GSH as a substrate 62 . These systems are not static; they are finely regulated in response to changes in cellular redox status, highlighting their importance in adaptive and protective responses. A key orchestrator of this regulation is the transcription factor Nrf2 (nuclear factor erythroid 2–related factor 2), which serves as a master regulator of antioxidant and cytoprotective gene expression 63 . By modulating the transcription of numerous detoxifying and antioxidant genes, Nrf2 links upstream oxidative signals to a broad and coordinated cellular defense response, bridging the gap between oxidative stress and the activation of endogenous antioxidant mechanisms. In diabetes, however, chronic hyperglycemia overwhelms these defenses, leading to persistent oxidative stress that contributes to endothelial dysfunction, axonal degeneration, and Schwann cell injury in peripheral nerves 11,61 . Nrf2, a major switch of antioxidant mechanisms Nrf2 and its negative regulator Keap1 form a crucial defense pathway against oxidative stress. As a central regulator of redox homeostasis, Nrf2 orchestrates the expression of over 50 genes critical for cellular defense against oxidative stress, a contributor to diverse pathologies including aging, obesity, cancer, diabetes, and neurodegenerative diseases 64 . Under physiological conditions, the transcription factor Nrf2 is retained in the cytoplasm by its negative regulator Keap1, which facilitates its ubiquitination and subsequent proteasomal degradation, thus maintaining low Nrf2 basal activity. Keap1 acts as a redox-sensitive sensor; it contains several cysteine residues —particularly Cys151, Cys273, and Cys288 — that are critical for sensing oxidative or electrophilic stress. Upon exposure to ROS or electrophiles, these cysteine residues undergo oxidative modification, causing a conformational change in Keap1 that disrupts its interaction with Nrf2. This allows newly synthesized Nrf2 to accumulate and translocate into the nucleus, where it forms heterodimers with small MAF (sMAF) proteins and binds to antioxidant responsive elements (AREs) located in the promoter regions of its target genes 65–68 (Figure 3). Through this mechanism, Nrf2 activates the transcription of a wide array of cytoprotective and antioxidant genes, including heme oxygenase-1 ( HMOX1 ), NAD(P)H quinone dehydrogenase 1 ( NQO1 ), glutamate-cysteine ligase ( GCL ) — comprising catalytic and modifier subunits — and thioredoxin ( TXN ), all of which play crucial roles in detoxification, redox regulation, and cellular defense against oxidative injury. In the context of chronic hyperglycemia, dysregulation of the Nrf2–Keap1 axis contributes to impaired antioxidant responses and heightened neuronal vulnerability 63 . Hyperglycemia significantly disrupts the Nrf2-Keap1 regulatory axis through multiple interconnected mechanisms that ultimately compromise cellular antioxidant defenses 69 . Chronic exposure to elevated glucose levels leads to increased production of ROS through several pathways, including enhanced mitochondrial oxidative phosphorylation, activation of NADPH oxidase, and non-enzymatic protein glycation 70 . While initial oxidative stress might be expected to activate Nrf2 through Keap1 modifications, prolonged hyperglycemic conditions paradoxically result in Nrf2 dysfunction and reduced its antioxidant capacity 71 . AGEs, formed under hyperglycemic conditions, can contribute to mechanisms that impair Nrf2 nuclear translocation and transcriptional activity 70 . Additionally, hyperglycemia-induced inflammatory pathways, particularly NF-κB activation, can interfere with Nrf2 signaling through competitive binding to transcriptional co-activators and promotion of Nrf2 degradation 72 . The persistent oxidative burden also leads to epigenetic modifications, including hypermethylation of the Nrf2 promoter region, further suppressing its expression 73–75 . This creates a vicious cycle where hyperglycemia-induced oxidative stress overwhelms and subsequently impairs the very pathway designed to counteract it, contributing to the progressive nature of diabetic complications including peripheral neuropathy 76 . In figure 3, we illustrate the mechanisms of Nrf2–ARE pathway activation. Targeting oxidative stress in DPN As such, targeting oxidative stress represents a promising disease-modifying approach in DPN, with both natural compounds and pharmacological agents under investigation for their ability to modulate antioxidant defenses, inhibit pro-oxidant pathways, and improve neural function (Table 2). 1/ Aldose Reductase inhibitors (ARIs) like sorbinil, fidarestat, and epalrestat have been studied for their effects on nerve conduction and regeneration. Some ARIs, like sorbinil and alrestatin, showed promise in animal studies but had side effects in humans 77 . Other ARIs, such as minalrestat and zenarestat, improved nerve function in rats but had mixed results in human trials due to side effects or lack of efficacy 73–75,78 . Epalrestat, a carboxylic acid ARI, showed fewer side effects in clinical trials and is approved for use in Japan and India 79 . Ranirestat, another ARI, improved nerve conduction in diabetic patients and is undergoing clinical trials 80,81 . Researchers are also exploring plant-based ARIs for better efficacy and safety 82,83 . Additionally, compounds like α-lipoic acid (ALA), L-carnitine, and synthetic derivatives have shown potential in alleviating neuropathic symptoms and improving glycemic control in diabetic patients. 84–86 . Some synthetic compounds, like pterin-7-carboxamides, have exhibited promising AR inhibition activity in vitro, with the potential for fewer side effects 87 . Several synthetic derivatives of ALA have been developed to enhance its therapeutic potential in DPN and oxidative stress-related conditions. Among these, N2L (ALA dimer) has demonstrated stronger antioxidant and neuroprotective effects by modulating key oxidative stress markers and apoptosis-related proteins in neuronal models 88 . Ester and amide derivatives of ALA, such as AN-7 and AN-8, have shown significantly improved cellular uptake and glucose-lowering effects in diabetic models, making them relevant for metabolic and neuropathic complications. Additionally, R-ALA prodrugs like PD-ALA4 HCl have been engineered for improved bioavailability and stability, showing efficacy in neuropathic pain models linked to oxidative stress. These advanced formulations aim to overcome ALA’s pharmacokinetic limitations while amplifying its antioxidant, anti-inflammatory, and neuroprotective actions specifically in the context of DPN and diabetes-induced oxidative damage 89 . 2/ Benfotiamine, a lipid-soluble derivative of thiamine (vitamin B1), inhibits three key hyperglycemia-driven pathways that contribute to oxidative stress: the hexosamine biosynthetic pathway, the AGE formation pathway, and the DAG–PKC pathway 90 . By blocking these mechanisms, Benfotiamine has been shown to alleviate symptoms of DPN, including a significant reduction in neuropathic pain. 91 . The therapeutic efficacy of benfotiamine in diabetic complications remains inconclusive, with clinical studies reporting non-definitive results. Accordingly, further investigations are ongoing to clarify its potential role and establish its effectiveness in the management of those conditions. 3/ Targeting the PKC pathway has been extensively investigated as a therapeutic strategy to combat oxidative stress in diabetic complications. The selective PKC-β inhibitor, ruboxistaurin (RBX), has been a key focus of clinical research. RBX showed promise in reducing progression of diabetic macular edema and improving visual acuity in patients with diabetic retinopathy 92 . A systematic review of randomized controlled trials evaluated the efficacy and safety of RBX in patients with diabetic neuropathy. All included trials lasted at least six months and compared RBX to placebo. The primary outcomes were changes in neurological function, assessed using the Neurological Total Symptom Score (NTSS) and Vibration Detection Threshold (VDT). All six studies reported improvements reported improvements in NTSS, with four demonstrating statistically significant benefits in the RBX group compared to placebo. However, the only study that assessed VDT found no significant difference between groups. Secondary outcomes included quality of life and microvascular blood flow. Two studies reported significant improvements in QoL with RBX. Safety data, available from two trials, indicated no RBX-related adverse effects. Overall, these findings suggest that ruboxistaurin may improve neurological symptoms and quality of life in patients with diabetic neuropathy, with a favorable safety profile 93 . 4/ Therapeutic approaches for diabetic neuropathy targeting the MAPK pathway involve both direct and indirect strategies. Direct inhibition aims to block specific MAPK enzymes (ERK, JNK, p38) 11 . While preclinical studies using direct inhibitors show promise in ameliorating nerve pathology, their translation to clinical use has faced challenges 94 . Indirect strategies, on the other hand, focus on reducing the upstream oxidative stress that activates MAPKs or modulating downstream effects. This includes the use of antioxidants to mitigate the initial insult, and certain antidiabetic drugs like metformin and Glucagon like peptide-1 (GLP-1) receptor agonists and to a lesser extent DPP-4 inhibitors (via increased endogenous GLP-1). These agents have demonstrated neuroprotective effects, partly by suppressing MAPK pathway activity and reducing oxidative stress and inflammation 95,96 . Additionally, studies have shown that GLP-1 receptor agonists and DPP-4 inhibitors possess pleiotropic effects, including anti-inflammatory and antioxidant actions, which are often independent of their glucose-lowering properties 97,98 . These molecules seem to activate the Nrf2 pathway 99 . This activation upregulates the expression of genes involved in GSH synthesis (e.g., GCLC and GCLM, the rate-limiting enzymes) and other antioxidant enzymes (like HO-1, SOD, and catalase), thereby increasing the production of GSH and other endogenous antioxidants 100 . Moreover, GLP-1 receptor agonists and DPP-4i can directly or indirectly reduce ROS production, notably by inhibiting enzymes like NADPH oxidase, a major ROS source. This action mitigates hyperglycemia-induced oxidative stress, thereby decreasing the demand on the cellular antioxidant system and potentially preserving GSH levels 100,101 . 5/AGE inhibitors, such as aminoguanidine, have shown promise in reducing AGE accumulation and oxidative damage 102 . Additionally, several RAGE-targeting strategies have demonstrated promising antioxidant effects in models of DPN. Genetic deletion of RAGE in streptozotocin-induced diabetic mice significantly reduced oxidative stress in peripheral nerves, likely by suppressing macrophage-mediated inflammation and ROS production, thereby preserving nerve conduction and axonal transport integrity 103 . Similarly, the small-molecule RAGE inhibitor FPS-ZM1 decreased oxidative stress markers in diabetic rats, including reductions in TNF-α, IL-6, and key NADPH oxidase subunits such as Nox1, Nox2, Nox4, and Cyba, which are primary contributors to ROS generation in diabetic tissues 104 . Furthermore, upregulation of RAGE and its ligand HMGB1 was associated with inflammatory activation in peripheral nerves of diabetic animals, which was attenuated through RAGE inhibition 105 . 6. Selective sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a class of therapeutic agents used in the management of type 2 diabetes mellitus. They lower blood glucose independently of insulin by enhancing urinary glucose excretion. Beyond their glucose-lowering effects, agents such as empagliflozin have demonstrated anti-glucotoxic properties, including the reversal of pro-inflammatory phenotypes, normalization of elevated aortic RAGE protein and mRNA expression, and reduction of AGE-positive proteins and the potent AGE precursor, methylglyoxal 106 . Furthermore, empagliflozin directly attenuates oxidative stress by lowering oxidative markers in aortic tissue and blood, normalizing the oxidative burst, and dose-dependently inhibiting both the activity and expression of NADPH oxidase isoforms (Nox1 and Nox2), key sources of reactive oxygen species. Additionally, empagliflozin helps preserve the activity of mitochondrial aldehyde dehydrogenase 2 (ALDH-2), a crucial antioxidant enzyme. 107,108 . SGLT2 inhibitors may be neuroprotective in patients with diabetic neuropathy, likely through a combination of improved glycemic control, anti-inflammatory, and antioxidant mechanisms 109,110 . However, clinical experience remains limited, and larger studies are needed to fully delineate their role in preventing or mitigating diabetic neuropathy. Compounds enhancing the Nrf2 antioxidant pathway Recent studies have shown that a variety of naturally occurring and synthetic compounds are capable of activating Nrf2 signaling pathway including taurine, sulforaphane, resveratrol, curcumin and others. Table 2 provides an overview of studied and investigational therapeutic compounds, highlighting their respective mechanisms of action. 1/ Curcumin, a bioactive polyphenol derived from Curcuma longa , has emerged as a potent activator of the Nrf2–ARE pathway, offering neuroprotective benefits in the context of neuropathy. Mechanistically, curcumin modifies critical cysteine residues on Keap1 (particularly Cys151), disrupting its bound to Nrf2 and promoting Nrf2 nuclear translocation and transcriptional activation of ARE-driven genes like HMOX1 and NQO1 111 . In STZ-induced diabetic rodents, curcumin administration restores HO‑1/Nrf2 expression, boosts glutathione (GSH) levels, reduces lipid peroxidation (MDA), and inhibits NF‑κB-driven inflammation in spinal cord and peripheral nerves 112 . These molecular changes translate into functional neuroprotection, evidenced by improved nerve conduction velocity, decreased mechanical and thermal hypersensitivity, and a reduction in apoptotic markers within the dorsal root ganglia and sciatic nerve tissues 111 . However, curcumin’s therapeutic potential is hampered by its poor bioavailability. To overcome this, nanoformulations such as NanoCur, self-nanoemulsifying drug delivery systems (SNEDDS), and curcumin-polybutylcyanoacrylate nanoparticles have been developed. These formulations markedly enhance the systemic and neural tissue levels of curcumin. In diabetic peripheral neuropathy models, they more effectively enhance Nrf2/HO‑1 signaling and alleviate neuropathic pain compared to unformulated curcumin. Beyond antioxidant support, curcumin also suppresses inflammation via NF‑κB inhibition, modulates Schwann cell survival and Nerve Growth Factor expression, and improves axonal integrity — all through Nrf2-dependent pathways 113 . These results support curcumin and its enhanced formulations as promising adjuvant therapies targeting the Nrf2 defense mechanism to prevent or delay progression of DPN. 2/ Sulforaphane, a naturally occurring isothiocyanate found in cruciferous vegetables, has been shown in STZ-induced diabetic rodents to increase expression of Nrf2 and its downstream targets HO‑1 and NQO1, while concurrently reducing markers of oxidative damage (malondialdehyde, MDA) and inflammation (NF‑κB, iNOS, COX‑2, TNF‑α, IL‑6). These molecular changes were accompanied by restored motor nerve conduction, improved nerve blood flow, and reduced neuropathic behavioral deficits 114 . 3/ Resveratrol, a natural polyphenol, demonstrated significant therapeutic potential in alleviating diabetic neuropathy in vivo by effectively counteracting high glucose-induced oxidative stress and endothelial dysfunction in part by inhibiting the DAG-PKC-NADPH oxidase pathway, which reduces ROS production and mitigates fibrotic complications relevant to diabetic neuropathy 115 . Interestingly, Resveratrol also activates the Nrf2 pathway, leading to upregulation of endogenous antioxidant defences and suppression of pro-inflammatory signaling, including inhibition of NF-κB and related cytokines such as TNF-α and IL-6 116 . These effects are complemented by improvements in microvascular function and nerve blood flow, as well as restoration of glutathione and other antioxidant enzyme levels 117 . 4/ Bardoxolone methyl (also known as CDDO-methyl ester or RTA 402) is another potent Nrf2 activator under investigation is, a synthetic oleanane triterpenoid that disrupts Keap1-Nrf2 interactions. In STZ-induced diabetic rat models, bardoxolone improved both motor and sensory nerve conduction velocities, increased nerve blood flow, and intraepidermal nerve fiber density compared to untreated diabetic controls. Mechanistically, it restored mitochondrial function (membrane potential, respiratory capacity), reduced ROS generation, and reactivated Nrf2 transcriptional activity to increase expression of key antioxidant and mitochondrial chaperone proteins 118 . Despite its promising therapeutic potential, bardoxolone has raised concerns due to an increased incidence of cardiovascular events reported in some clinical trials. 118,119 5/ Dihydroaustrasulfone alcohol (WA25), a Formosan soft coral synthetic precursor derived from Cladiella australis , has shown promising neuroprotective and analgesic properties in neuropathic pain models. In a study using rats with chronic constriction injury (CCI) to induce neuropathic pain, intrathecal administration of WA25 significantly alleviated CCI-induced nociceptive behaviors, reduced spinal neuroinflammation, and decreased oxidative stress accumulation. These effects were accompanied by enhanced expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the ipsilateral spinal cord dorsal horn. Importantly, co-administration of the HO-1 inhibitor ZnPP abolished the analgesic, anti-inflammatory, and antioxidant effects of WA25, confirming the central role of the Nrf2/HO-1 pathway in its mechanism of action. These findings highlight WA25 as a potential therapeutic candidate for managing neuropathic pain via modulation of oxidative stress and inflammation 120 . Conclusion Our understanding of the central role of oxidative stress in the pathogenesis of DPN has significantly advanced. Chronic hyperglycemia activates multiple metabolic pathways, including the polyol, AGE, hexosamine, PKC, and MAPK pathways, that increase ROS production, impair mitochondrial function, and damage peripheral nerves. Among emerging therapeutic targets, the Nrf2–Keap1 signaling pathway has gained attention as a key regulator of cellular antioxidant defenses. Both natural compounds and synthetic agents that activate Nrf2 have shown promising results in preclinical models. Clinical trials are currently underway to evaluate their safety and therapeutic efficacy. These antioxidant-based approaches, particularly those targeting Nrf2 modulation, hold great promise for the development of effective, disease-modifying treatments for DPN. Acknowledgments The authors used ChatGPT, an artificial intelligence language model developed by OpenAI, to assist with language refinement, text editing during the preparation of this manuscript. All content was reviewed, verified, and approved by the authors, who take full responsibility for the accuracy and integrity of the work. Authorship All authors meet the criteria for authorship. …conceived the review, conducted the literature search, and wrote the initial manuscript draft. Professor … and Dr. … provided critical revisions, intellectual input, and guidance to improve the manuscript. All authors reviewed and approved the final version of the manuscript, agree to be accountable for its content, and take responsibility for the integrity and accuracy of the work. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of Interest The authors declare that they have no conflicts of interest related to the content of this manuscript. References 1. Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract . 2019;157:107843. doi:10.1016/j.diabres.2019.1078432. Rooney MR, Fang M, Ogurtsova K, et al. Global Prevalence of Prediabetes. Diabetes Care . 2023;46(7):1388-1394. doi:10.2337/dc22-23763. International Diabetes Federation. (2021). IDF Diabetes Atlas, 10th ed. Brussels, Belgium. Retrieved from https://diabetesatlas.org.4. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care . 2016;40(1):136-154. doi:10.2337/dc16-20425. Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic neuropathy. Nat Rev Dis Primers . 2019;5(1):41. doi:10.1038/s41572-019-0092-16. Savelieff MG, Elafros MA, Viswanathan V, Jensen TS, Bennett DL, Feldman EL. The global and regional burden of diabetic peripheral neuropathy. Nat Rev Neurol . 2025;21(1):17-31. doi:10.1038/s41582-024-01041-y7. Radi R. Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine. Proc Natl Acad Sci U S A . 2018;115(23):5839-5848. doi:10.1073/pnas.18049321158. Jomova K, Raptova R, Alomar SY, et al. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Arch Toxicol . 2023;97(10):2499-2574. doi:10.1007/s00204-023-03562-99. Brownlee M., The pathobiology of diabetic complications: a unifying mechanism, Diabetes. (2005) 54, no. 6, 1615–1625, https://doi.org/10.2337/diabetes.54.6.1615, 2-s2.0-20044376702, 15919781.10. Newsholme P, Haber EP, Hirabara SM, et al. Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity. J Physiol . 2007;583(Pt 1):9-24. doi:10.1113/jphysiol.2007.13587111. Vincent AM, Russell JW, Low P, Feldman EL. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev . 2004;25(4):612-628. doi:10.1210/er.2003-001912. Brownlee M., Biochemistry and molecular cell biology of diabetic complications, Nature. (2001) 414, no. 6865, 813–820, https://doi.org/10.1038/414813a, 2-s2.0-0035856980, 11742414.13. Turrens J. F., Mitochondrial formation of reactive oxygen species, The Journal of Physiology. (2003) 552, no. 2, 335–344, https://doi.org/10.1113/jphysiol.2003.049478, 2-s2.0-0142150051, 14561818.14. Fernyhough P. and McGavock J., Mechanisms of disease: mitochondrial dysfunction in sensory neuropathy and other complications in diabetes, Handbook of Clinical Neurology. (2014) 126, 353–377, https://doi.org/10.1016/B978-0-444-53480-4.00027-8, 2-s2.0-84921972920.15. Nishikawa T., Edelstein D., du X. L., Yamagishi S. I., Matsumura T., Kaneda Y., Yorek M. A., Beebe D., Oates P. J., Hammes H. P., Giardino I., and Brownlee M., Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage, Nature. (2000) 404, no. 6779, 787–790, https://doi.org/10.1038/35008121, 2-s2.0-0034643340, 10783895.16. Li J, Guan R, Pan L. Mechanism of Schwann cells in diabetic peripheral neuropathy: A review. Medicine (Baltimore) . 2023;102(1):e32653. doi:10.1097/MD.000000000003265317. A.Y.W. Lee, S.S.M. Chung Contributions of polyol pathway to oxidative stress in diabetic cataract FASEB J., 13 (1999), pp. 23-30.18. Chung SSM, Ho ECM, Lam KSL, Chung SK. Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol . 2003;14(8 Suppl 3):S233-236. doi:10.1097/01.asn.0000077408.15865.0619. Niimi N, Yako H, Takaku S, Chung SK, Sango K. Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems. International Journal of Molecular Sciences . 2021;22(3):1031. doi:10.3390/ijms2203103120. Askwith T, Zeng W, Eggo MC, Stevens MJ. Oxidative stress and dysregulation of the taurine transporter in high-glucose-exposed human Schwann cells: implications for pathogenesis of diabetic neuropathy. Am J Physiol Endocrinol Metab . 2009;297(3):E620-628. doi:10.1152/ajpendo.00287.200921. N. Bhattacharjee, S. Barma, N. Konwar, S. Dewanjee, P. Manna Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: an update.22. Zenker et al., 2013 J. Zenker, D. Ziegler, R. Chrast Novel pathogenic pathways in diabetic neuropathy.23. Greene DA, Sima AA, Stevens MJ, Feldman EL, Lattimer SA. Complications: neuropathy, pathogenetic considerations. Diabetes Care . 1992;15(12):1902-1925. doi:10.2337/diacare.15.12.190224. Akamine T, Kusunose N, Matsunaga N, Koyanagi S, Ohdo S. Accumulation of sorbitol in the sciatic nerve modulates circadian properties of diabetes-induced neuropathic pain hypersensitivity in a diabetic mouse model. Biochem Biophys Res Commun . 2018;503(1):181-187. doi:10.1016/j.bbrc.2018.05.20925. Ramana KV, Friedrich B, Srivastava S, Bhatnagar A, Srivastava SK. Activation of nuclear factor-kappaB by hyperglycemia in vascular smooth muscle cells is regulated by aldose reductase. Diabetes . 2004;53(11):2910-2920. doi:10.2337/diabetes.53.11.291026. Stavniichuk R, Shevalye H, Hirooka H, Nadler JL, Obrosova IG. Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy. Biochem Pharmacol . 2012;83(7):932-940. doi:10.1016/j.bcp.2012.01.01527. Ho ECM, Lam KSL, Chen YS, et al. Aldose reductase-deficient mice are protected from delayed motor nerve conduction velocity, increased c-Jun NH2-terminal kinase activation, depletion of reduced glutathione, increased superoxide accumulation, and DNA damage. Diabetes . 2006;55(7):1946-1953. doi:10.2337/db05-149728. Kallinikou D, Tsentidis C, Kekou K, et al. Homozygosity of the Z-2 polymorphic variant in the aldose reductase gene promoter confers increased risk for neuropathy in children and adolescents with Type 1 diabetes. Pediatr Diabetes . 2022;23(1):104-114. doi:10.1111/pedi.1328529. Demaine AG. Polymorphisms of the aldose reductase gene and susceptibility to diabetic microvascular complications. Curr Med Chem . 2003;10(15):1389-1398. doi:10.2174/092986703345735930. Oates PJ, and Mylari BL. Aldose reductase inhibitors: therapeutic implications for diabetic complications. Expert Opinion on Investigational Drugs . 1999;8(12):2095-2119. doi:10.1517/13543784.8.12.209531. Du XL, Edelstein D, Rossetti L, et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A . 2000;97(22):12222-12226. doi:10.1073/pnas.97.22.1222232. H. Kaneto, G. Xu, K.H. Song, K. Suzuma, S. Bonner-Weir, A. Sharma, G.C. Weir Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress J. Biol. Chem., 276 (2001), pp. 31099-31104.33. P.P. Sayeski, J.E. Kudlow Glucose metabolism to glucosamine is necessary for glucose stimulation of transforming growth factor-alpha gene transcription.34. R.E. Roberts, W.G. McLean Protein kinase C isozyme expression in sciatic nerves and spinal cords of experimentally diabetic rats Brain Res., 754 (1997), pp. 147-156.35. P. Geraldes, G.L. King Activation of protein kinase C isoforms and its impact on diabetic complications Circ. Res., 106 (2010), pp. 1319-1331.36. S. Yamagishi, K. Uehara, S. Otsuki, S. Yagihashi Differential influence of increased polyol pathway on protein kinase C expressions between endoneurial and epineurial tissues in diabetic mice J. Neurochem., 87 (2003), pp. 497-507.37. K. Uehara, S. Yamagishi, S. Otsuki, S. Chin, S. Yagihashi Effects of polyol pathway hyperactivity on protein kinase C activity, nociceptive peptide expression, and neuronal structure in dorsal root ganglia in diabetic mice Diabetes, 53 (2004), pp. 3239-3247.38. R.N. Cortright, J.L. Azevedo Jr., Q. Zhou, M. Sinha, W.J. Pories, S.I. Itani, G.L. Dohm Protein kinase C modulates insulin action in human skeletal muscle Am. J. Physiol.-Endocrinol. Metab., 278 (2000), pp. E553-E562.39. J. Nakamura, K. Kato, Y. Hamada, M. Nakayama, S. Chaya, E. Nakashima, K. Naruse, Y. Kasuya, R. Mizubayashi, K. Miwa, Y. Yasuda, H. Kamiya, K. Ienaga, F. Sakakibara, N. Koh, N. Hotta A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats Diabetes, 48 (1999), pp. 2090-2095.40. B. Williams, B. Gallacher, H. Patel, C. Orme Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro Diabetes, 46 (1997), pp. 1497-.41. A.S. Edwards, M.C. Faux, J.D. Scott, A.C. Newton Carboxyl-terminal phosphorylation regulates the function and subcellular localization of protein kinase C betaII J. Biol. Chem., 274 (1999), pp. 6461-6468.42. Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res . 2010;106(8):1319-1331. doi:10.1161/CIRCRESAHA.110.21711743. Purves T, Middlemas A, Agthong S, et al. A role for mitogen-activated protein kinases in the etiology of diabetic neuropathy. FASEB J . 2001;15(13):2508-2514. doi:10.1096/fj.01-0253hyp44. Daulhac L, Mallet C, Courteix C, et al. Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms. Mol Pharmacol . 2006;70(4):1246-1254. doi:10.1124/mol.106.02547845. D.A. Greene, S. Lattimer, J. Ulbrecht, P. Carroll Glucose-induced alterations in nerve metabolism: current perspective on the pathogenesis of diabetic neuropathy and future directions for research and therapy Diabetes Care, 8 (1985), pp. 290-299.46. Fernyhough P, Gallagher A, Averill SA, et al. Aberrant neurofilament phosphorylation in sensory neurons of rats with diabetic neuropathy. Diabetes . 1999;48(4):881-889. doi:10.2337/diabetes.48.4.88147. Tu NH, Katano T, Matsumura S, et al. Role of c-Jun N-terminal kinase in late nerve regeneration monitored by in vivo imaging of thy1-yellow fluorescent protein transgenic mice. Eur J Neurosci . 2016;43(4):548-560. doi:10.1111/ejn.1313948. Zhang Y, Zhang Z, Tu C, Chen X, He R. Advanced Glycation End Products in Disease Development and Potential Interventions. Antioxidants . 2025;14(4):492. doi:10.3390/antiox1404049249. Twarda-Clapa A, Olczak A, Białkowska AM, Koziołkiewicz M. Advanced Glycation End-Products (AGEs): Formation, Chemistry, Classification, Receptors, and Diseases Related to AGEs. Cells . 2022;11(8):1312. doi:10.3390/cells1108131250. Goh SY, Cooper ME. Clinical review: The role of advanced glycation end products in progression and complications of diabetes. J Clin Endocrinol Metab . 2008;93(4):1143-1152. doi:10.1210/jc.2007-181751. Yan SF, Ramasamy R, Schmidt AM. The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Circ Res . 2010;106(5):842-853. doi:10.1161/CIRCRESAHA.109.21221752. Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol . 2014;18(1):1-14. doi:10.4196/kjpp.2014.18.1.153. Deuther-Conrad W, Loske C, Schinzel R, Dringen R, Riederer P, Münch G. Advanced glycation endproducts change glutathione redox status in SH-SY5Y human neuroblastoma cells by a hydrogen peroxide dependent mechanism. Neurosci Lett . 2001;312(1):29-32. doi:10.1016/s0304-3940(01)02174-754. Loske C, Neumann A, Cunningham AM, et al. Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress. J Neural Transm (Vienna) . 1998;105(8-9):1005-1015. doi:10.1007/s00702005010855. Cellek S, Qu W, Schmidt AM, Moncada S. Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: a new insight into selective nitrergic neuropathy in diabetes. Diabetologia . 2004;47(2):331-339. doi:10.1007/s00125-003-1298-y56. Schmidt AM, Hori O, Brett J, Yan SD, Wautier JL, Stern D. Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler Thromb . 1994;14(10):1521-1528. doi:10.1161/01.atv.14.10.152157. Advanced glycation end products in neurodegeneration: more than early markers of oxidative stress? - PubMed. Accessed August 12, 2025. https://pubmed.ncbi.nlm.nih.gov/9749578/58. Goh & Cooper, 2008 – (Goh, S. Y., & Cooper, M. E. (2008). The role of advanced glycation end products in progression and complications of diabetes. The Journal of Clinical Endocrinology & Metabolism, 93(4), 1143-1152.).59. Forman HJ, Zhang H, Rinna A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med . 2009;30(1-2):1-12. doi:10.1016/j.mam.2008.08.00660. Sies H, Berndt C, Jones DP. Oxidative Stress. Annu Rev Biochem . 2017;86:715-748. doi:10.1146/annurev-biochem-061516-04503761. Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry & Cell Biology . 2007;39(1):44-84. doi:10.1016/j.biocel.2006.07.00162. Brigelius-Flohé R, Maiorino M. Glutathione peroxidases. Biochim Biophys Acta . 2013;1830(5):3289-3303. doi:10.1016/j.bbagen.2012.11.02063. Tonelli C, Chio IIC, Tuveson DA. Transcriptional Regulation by Nrf2. Antioxid Redox Signal . 2018;29(17):1727-1745. doi:10.1089/ars.2017.734264. Yamamoto M, Kensler TW, Motohashi H. The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiol Rev . 2018;98(3):1169-1203. doi:10.1152/physrev.00023.201765. Ma Q. Role of Nrf2 in Oxidative Stress and Toxicity. Annual Review of Pharmacology and Toxicology . 2013;53(Volume 53, 2013):401-426. doi:10.1146/annurev-pharmtox-011112-14032066. Itoh K, Tong KI, Yamamoto M. Molecular mechanism activating nrf2–keap1 pathway in regulation of adaptive response to electrophiles. Free Radical Biology and Medicine . 2004;36(10):1208-1213. doi:10.1016/j.freeradbiomed.2004.02.07567. Zhang DD. Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway. Drug Metabolism Reviews . 2006;38(4):769-789. doi:10.1080/0360253060097197468. Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL. The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox Biology . 2013;1(1):45-49. doi:10.1016/j.redox.2012.10.00169. Yi M, Cruz Cisneros L, Cho EJ, et al. Nrf2 Pathway and Oxidative Stress as a Common Target for Treatment of Diabetes and Its Comorbidities. International Journal of Molecular Sciences . 2024;25(2):821. doi:10.3390/ijms2502082170. Jin Q, Liu T, Qiao Y, et al. Oxidative stress and inflammation in diabetic nephropathy: role of polyphenols. Front Immunol . 2023;14:1185317. doi:10.3389/fimmu.2023.118531771. A defect in Nrf2 signaling constitutes a mechanism for cellular stress hypersensitivity in a genetic rat model of type 2 diabetes. doi:10.1152/ajpendo.00047.201172. Bellezza I, Tucci A, Galli F, et al. Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity. The Journal of Nutritional Biochemistry . 2012;23(12):1583-1591. doi:10.1016/j.jnutbio.2011.10.01273. E.H. Akamine, T.C. Hohman, D. Nigro, C.M. Helena, Carvalho, R.D.C. Tostes, Z.B. Fortes Minalrestat, an aldose reductase inhibitor, corrects the impaired microvascular reactivity in diabetes.74. A.S. Grewal, S. Bhardwaj, D. Pandita, V. Lather, B.S. Sekhon Updates on aldose reductase inhibitors for management of diabetic complications and non-diabetic diseases.75. Y. Hamada, J. Nakamura Clinical potential of aldose reductase inhibitors in diabetic neuropathy Treat. Endocrinol., 3 (2004), pp. 245-255.76. Uruno A, Yagishita Y, Yamamoto M. The Keap1-Nrf2 system and diabetes mellitus. Arch Biochem Biophys . 2015;566:76-84. doi:10.1016/j.abb.2014.12.01277. Huang Q, Liu Q, Ouyang D. Sorbinil, an Aldose Reductase Inhibitor, in Fighting Against Diabetic Complications. Medicinal Chemistry . 15(1):3-7. doi:10.2174/157340641466618052408244578. J.L. Edwards, A. Vincent, T. Cheng, E.L. Feldman Diabetic neuropathy: mechanisms to management.79. Hotta N, Akanuma Y, Kawamori R, et al. Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial. Diabetes Care . 2006;29(7):1538-1544. doi:10.2337/dc05-237080. N. Hotta, Y. Akanuma, R. Kawamori, K. Matsuoka, Y. Oka, M. Shichiri, T. Toyota, M. Nakashima, I. Yoshimura, N. Sakamoto, Y. Shigeta Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative aldose reductase inhibitor-diabetes complications trial.81. N. Giannoukakis Ranirestat as a therapeutic aldose reductase inhibitor for diabetic complications.82. Veeresham C, Rama Rao A, Asres K. Aldose Reductase Inhibitors of Plant Origin. Phytotherapy Research . 2014;28(3):317-333. doi:10.1002/ptr.500083. Iyer S, Sam FS, DiPrimio N, et al. Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG. Dis Model Mech . 2019;12(11):dmm040584. doi:10.1242/dmm.04058484. D.Q. Jiang, M.X. Li, Y.J. Ma, Y. Wang, Y. Wang Efficacy and safety of prostaglandin E1 plus lipoic acid combination therapy versus monotherapy for patients with diabetic peripheral neuropathy.85. D.Q. Jiang, M.X. Li, Y. Wang, Y. Wang Effects of prostaglandin E1 plus methylcobalamin alone and in combination with lipoic acid on nerve conduction velocity in patients with diabetic peripheral neuropathy: a meta-analysis.86. A.R. Rahbar, R. Shakerhosseini, N. Saadat, F. Taleban, A. Pordal, B. Gollestan Effect of L-carnitine on plasma glycemic and lipidemic profile in patients with type II diabetes mellitus.87. Saito R, Suzuki S, Sasaki K. Pterin-7-carboxamides as a new class of aldose reductase inhibitors. Bioorganic & Medicinal Chemistry Letters . 2016;26(20):4870-4874. doi:10.1016/j.bmcl.2016.09.03388. N2L, a novel lipoic acid-niacin dimer protects HT22 cells against β-amyloid peptide-induced damage through attenuating apoptosis - PubMed. Accessed August 13, 2025. https://pubmed.ncbi.nlm.nih.gov/31478183/89. Zhang T, Zhang D, Zhang Z, et al. Alpha-lipoic acid activates AMPK to protect against oxidative stress and apoptosis in rats with diabetic peripheral neuropathy. Hormones (Athens) . 2023;22(1):95-105. doi:10.1007/s42000-022-00413-790. Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med . 2003;9(3):294-299. doi:10.1038/nm83491. Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel RG. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes . 2008;116(10):600-605. doi:10.1055/s-2008-106535192. Aiello LP, Vignati L, Sheetz MJ, et al. Oral protein kinase c β inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1,392 eyes) with diabetic retinopathy in the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study and the Protein Kinase C β Inhibitor-Diabetic Retinopathy Study 2. Retina . 2011;31(10):2084-2094. doi:10.1097/IAE.0b013e318211166993. Bansal D, Badhan Y, Gudala K, Schifano F. Ruboxistaurin for the Treatment of Diabetic Peripheral Neuropathy: A Systematic Review of Randomized Clinical Trials. Diabetes Metab J . 2013;37(5):375-384. doi:10.4093/dmj.2013.37.5.37594. Sweitzer SM, Medicherla S, Almirez R, et al. Antinociceptive action of a p38alpha MAPK inhibitor, SD-282, in a diabetic neuropathy model. Pain . 2004;109(3):409-419. doi:10.1016/j.pain.2004.02.01695. Pop-Busui R, Sima A, Stevens M. Diabetic neuropathy and oxidative stress. Diabetes Metab Res Rev . 2006;22(4):257-273. doi:10.1002/dmrr.62596. Wei J, Wei Y, Huang M, Wang P, Jia S. Is metformin a possible treatment for diabetic neuropathy? J Diabetes . 2022;14(10):658-669. doi:10.1111/1753-0407.1331097. Does Glucagon-like Peptide-1 Ameliorate Oxidative Stress in Diabetes? Evidence Based on Experimental and Clinical Studies | Bentham Science. Accessed July 28, 2025. https://www.eurekaselect.com/article/7050898. Xie D, Wang Q, Huang W, Zhao L. Dipeptidyl-peptidase-4 inhibitors have anti-inflammatory effects in patients with type 2 diabetes. Eur J Clin Pharmacol . 2023;79(10):1291-1301. doi:10.1007/s00228-023-03541-099. Fernández-Millán E, Martín MA, Goya L, et al. Glucagon-like peptide-1 improves beta-cell antioxidant capacity via extracellular regulated kinases pathway and Nrf2 translocation. Free Radical Biology and Medicine . 2016;95:16-26. doi:10.1016/j.freeradbiomed.2016.03.002100. Kawanami D, Takashi Y, Takahashi H, Motonaga R, Tanabe M. Renoprotective Effects of DPP-4 Inhibitors. Antioxidants . 2021;10(2):246. doi:10.3390/antiox10020246101. Pujadas G, De Nigris V, Prattichizzo F, La Sala L, Testa R, Ceriello A. The dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin functions as antioxidant on human endothelial cells exposed to chronic hyperglycemia and metabolic high-glucose memory. Endocrine . 2017;56(3):509-520. doi:10.1007/s12020-016-1052-0102. Thornalley, 2003 – (Thornalley, P. J. (2003). Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. Archives of Biochemistry and Biophysics, 419(1), 31-40.).103. Dong H, Zhang Y, Huang Y, Deng H. Pathophysiology of RAGE in inflammatory diseases. Front Immunol . 2022;13:931473. doi:10.3389/fimmu.2022.931473104. Shen C, Ma Y, Zeng Z, et al. RAGE-Specific Inhibitor FPS-ZM1 Attenuates AGEs-Induced Neuroinflammation and Oxidative Stress in Rat Primary Microglia. Neurochem Res . 2017;42(10):2902-2911. doi:10.1007/s11064-017-2321-x105. Singh H, Agrawal DK. Therapeutic Potential of Targeting the HMGB1/RAGE Axis in Inflammatory Diseases. Molecules . 2022;27(21):7311. doi:10.3390/molecules27217311106. Ganbaatar B, Fukuda D, Shinohara M, et al. Empagliflozin ameliorates endothelial dysfunction and suppresses atherogenesis in diabetic apolipoprotein E-deficient mice. Eur J Pharmacol . 2020;875:173040. doi:10.1016/j.ejphar.2020.173040107. Mone P, Varzideh F, Jankauskas SS, et al. SGLT2 Inhibition via Empagliflozin Improves Endothelial Function and Reduces Mitochondrial Oxidative Stress: Insights From Frail Hypertensive and Diabetic Patients. Hypertension . 2022;79(8):1633-1643. doi:10.1161/HYPERTENSIONAHA.122.19586108. Steven S, Oelze M, Hanf A, et al. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol . 2017;13:370-385. doi:10.1016/j.redox.2017.06.009109. Kandeel M. The Outcomes of Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2I) on Diabetes-Associated Neuropathy: A Systematic Review and meta-Analysis. Front Pharmacol . 2022;13:926717. doi:10.3389/fphar.2022.926717110. Panou T, Gouveri E, Popovic DS, Papazoglou D, Papanas N. The Therapeutic Potential of Sodium-Glucose Cotransporter-2 Inhibitors in Diabetic Neuropathy. Exp Clin Endocrinol Diabetes . Published online July 14, 2025. doi:10.1055/a-2640-9411111. Zhang WX, Lin ZQ, Sun AL, Shi YY, Hong QX, Zhao GF. Curcumin Ameliorates the Experimental Diabetic Peripheral Neuropathy through Promotion of NGF Expression in Rats. Chem Biodivers . 2022;19(6):e202200029. doi:10.1002/cbdv.202200029112. Nabawy A. Suppression of neuronal apoptosis and glial activation with modulation of Nrf2/HO-1 and NF-kB signaling by curcumin in streptozotocin-induced diabetic spinal cord central neuropathy. Frontiers in Neuroanatomy . Published online March 9, 2023. doi:10.3389/FNANA.2023.1094301113. Caillaud M, Aung Myo YP, McKiver BD, et al. Key Developments in the Potential of Curcumin for the Treatment of Peripheral Neuropathies. Antioxidants . 2020;9(10):950. doi:10.3390/antiox9100950114. Negi G, Kumar A, Sharma SS. Nrf2 and NF-κB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes. Curr Neurovasc Res . 2011;8(4):294-304. doi:10.2174/156720211798120972115. Kumar A, Negi G, Sharma SS. Neuroprotection by resveratrol in diabetic neuropathy: concepts & mechanisms. Curr Med Chem . 2013;20(36):4640-4645. doi:10.2174/09298673113209990151116. Zhang W, Yu H, Lin Q, Liu X, Cheng Y, Deng B. Anti-inflammatory effect of resveratrol attenuates the severity of diabetic neuropathy by activating the Nrf2 pathway. Aging (Albany NY) . 2021;13(7):10659-10671. doi:10.18632/aging.202830117. Kumar A, Kaundal RK, Iyer S, Sharma SS. Effects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy. Life Sci . 2007;80(13):1236-1244. doi:10.1016/j.lfs.2006.12.036118. Kalvala AK, Kumar R, Sherkhane B, Gundu C, Arruri VK, Kumar A. Bardoxolone Methyl Ameliorates Hyperglycemia Induced Mitochondrial Dysfunction by Activating the keap1-Nrf2-ARE Pathway in Experimental Diabetic Neuropathy. Mol Neurobiol . 2020;57(8):3616-3631. doi:10.1007/s12035-020-01989-0119. Zeeuw D de, Akizawa T, Audhya P, et al. Bardoxolone Methyl in Type 2 Diabetes and Stage 4 Chronic Kidney Disease. New England Journal of Medicine . 2013;369(26):2492-2503. doi:10.1056/NEJMoa1306033120. Sung CS, Cheng HJ, Yang SN, et al. Antinociceptive and anti-inflammatory effects of dihydroaustrasulfone alcohol in alleviating peripheral neuropathy via Nrf2/HO-1 pathway in rats. Neurochem Int . 2025;188:106010. doi:10.1016/j.neuint.2025.106010 Figure captions Figure 1: Hyperglycemia-induced oxidative stress pathways in diabetic neuropathy This figure illustrates the major molecular mechanisms through which chronic hyperglycemia contributes to oxidative stress in diabetic neuropathy. Sustained hyperglycemia simultaneously activates five distinct but interconnected biochemical pathways: the polyol pathway, which causes Nicotinamide adenine dinucleotide phosphate (NADPH) depletion and sorbitol accumulation; the advanced glycation end-products (AGE) pathway, leading to protein cross-linking and RAGE activation; the Hexosamine pathway, resulting in altered protein function through O-GlcNAcylation; the protein kinase C (PKC) pathway, affecting vascular function and inflammation; and the mitogen-activated protein kinase (MAPK) pathway, triggering inflammatory gene expression and cellular stress responses. These pathways converge to generate excessive reactive oxygen species (ROS) and impair endogenous antioxidant defenses, culminating in oxidative stress. This oxidative imbalance damages neuronal components, contributing to the pathogenesis and progression of diabetic peripheral neuropathy. Blue arrows indicate pathway activation by hyperglycemia, while gold arrows represent downstream effects leading to oxidative stress. Figure 2. Schematic overview of metabolic pathways contributing to oxidative stress in diabetes and diabetic peripheral neuropathy (DPN). Chronic hyperglycemia activates multiple glucose metabolism pathways that drive the generation of reactive oxygen species (ROS) and contribute to the pathogenesis of DPN. The polyol pathway reduces glucose to sorbitol via aldose reductase, consuming NADPH and lowering antioxidant defenses such as glutathione (GSH). This process also generates osmotic stress and reduces ATP availability, contributing to cellular dysfunction. The hexosamine biosynthetic pathway diverts fructose-6-phosphate to UDP-GlcNAc via GFAT, promoting protein glycosylation (O-GlcNAcylation) and altering protein function, further impacting cellular signaling and stress responses. The AGE pathway forms advanced glycation end products (AGEs) from reactive intermediates like methylglyoxal. AGEs induce structural and functional damage to proteins, lipids, and DNA, impair nerve regeneration, and activate pro-inflammatory signaling. Finally, the protein kinase C (PKC) pathway is activated by increased levels of diacylglycerol (DAG), leading to PKC isoform overactivation. This contributes to vascular dysfunction, apoptosis, and impaired nerve conduction velocity (NCV). MAPK pathways (ERK, p38, JNK) are activated downstream of both AGE–RAGE signaling and PKC activation, linking hyperglycemia-induced stress to oxidative damage, and apoptosis. Together, these interrelated pathways amplify oxidative stress, mitochondrial dysfunction, and inflammation, ultimately contributing to peripheral nerve damage in diabetes. HK, hexokinase; PGI, phosphoglucose isomerase; GFAT, glutamine:fructose-6-phosphate amidotransferase; GADPH, glyceraldehyde-3-phosphate dehydrogenase; PDH, pyruvate dehydrogenase; NADPH, nicotinamide adenine dinucleotide phosphate (reduced form); NADP⁺, nicotinamide adenine dinucleotide phosphate (oxidized form); NAD⁺, nicotinamide adenine dinucleotide (oxidized form); NADH, nicotinamide adenine dinucleotide (reduced form); GSH, reduced glutathione; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine; AGEs, advanced glycation end-products; RAGE, receptor for advanced glycation end-products; MAPK, mitogen-activated protein kinase; PKC, protein kinase C; NCV, nerve conduction velocity; ATP, adenosine triphosphate; CoA, coenzyme A. Figure 3. Mechanisms of Nrf2–ARE pathway activation. (a) Under normal physiological conditions, Nrf2 is bound to Keap1 in the cytosol, which promotes its ubiquitination and subsequent degradation by the proteasome, thereby maintaining low Nrf2 activity. (b) Activation of the Nrf2–ARE pathway by Michael acceptors involves the dissociation of the Nrf2–Keap1 complex through two primary mechanisms: 1- Direct modification of specific cysteine residues on Keap1 by electrophilic Michael acceptors, causing a conformational change in Keap1 that leads to the release of Nrf2. 2- Phosphorylation of Nrf2 by activated protein kinases, which disrupts the Nrf2–Keap1 interaction and prevents its degradation. Once liberated, Nrf2 translocates into the nucleus, where it binds to antioxidant response elements (AREs) in the promoter regions of target genes. This binding activates the expression of a broad array of genes involved in cellular detoxification, antioxidant defense, and anti-inflammatory responses. Nrf2: Nuclear factor erythroid 2-related factor 2, Keap1: Kelch-like ECH-associated protein 1, ARE: Antioxidant response element, Ub: Ubiquitin, P: Phosphate Supplementary Material File (table 1.docx) Download 29.25 KB File (table 2.docx) Download 17.68 KB Information & Authors Information Version history V1 Version 1 01 November 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Tarek El-Masri [email protected] Universite de Limoges Faculte de Pharmacie View all articles by this author Franck Sturtz 0000-0001-6428-5162 Universite de Limoges Faculte de Pharmacie View all articles by this author Mirella Hage Hopital Ambroise-Pare Endocrinologie diabetologie nutrition View all articles by this author Metrics & Citations Metrics Article Usage 586 views 183 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Tarek El-Masri, Franck Sturtz, Mirella Hage. Oxidative Stress in Peripheral Diabetic Neuropathy: Key Mechanisms and Therapeutic Targets. Authorea . 01 November 2025. DOI: https://doi.org/10.22541/au.176199324.45430645/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.176199324.45430645/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9ffaed3d9e0f1640',t:'MTc3OTQ0MzUzMg=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();