Search Results (109)

Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus which affects individuals with both type 1 and type 2 diabetes mellitus (T2DM), presenting with sensory loss, pain, and progressive nerve dysfunction. DPN pathogenesis is multifactorial: chronic hyperglycemia activates the polyol, hexosamine, and protein kinase C (PKC) pathways, increases advanced glycation end-products, and drives oxidative stress, mitochondrial dysfunction, inflammation, and impaired neurotrophic signaling. In addition to hyperglycemia-driven mechanisms, dyslipidemia and microvascular insufficiency exacerbate neural ischemia and metabolic stress. Recent mechanistic, animal, and associative human studies further implicate amyloidogenic toxicity, particularly from human islet amyloid polypeptide (hIAPP), as a plausible contributory factor in peripheral nerve degeneration in T2DM, linking protein misfolding and aggregation to axonal damage and demyelination in DPN. Despite increased understanding of these mechanisms, current treatments remain mainly symptomatic. Emerging therapeutic strategies, including antioxidants, anti-inflammatory agents, modulators of mitochondrial function, amyloid oligomer modulators, neurotrophic enhancers, and regenerative approaches such as stem cells and gene-based therapies, offer potential to modify disease progression. The strength of evidence across these methods varies, ranging from mechanistic and animal studies to early human research and, in some cases, randomized clinical trials. Therefore, although several candidates show potential to alter the disease, few have demonstrated consistent benefits on objective measures of nerve structure or function in large clinical trials. This review summarizes the key mechanisms driving DPN in T2DM and highlights promising therapeutic innovations poised for clinical translation. Full article

Background/Objectives: Self-mutilation behavior is often triggered by neuropathic pain associated with peripheral nerve injuries (PNIs). Polyethylene glycol (PEG)-fusion is a repair method that rapidly joins/fuses the open ends of closely apposed severed axons, greatly reduces Wallerian degeneration, and restores sensorimotor behavior much more rapidly than current clinical procedures. Here, we examined whether the improved sensorimotor behavior recovery following PEG-fusion repair of sciatic nerve injuries compared to Negative Controls (NC) correlated with self-mutilation. We also examined six variables (repair method, behavioral tests, sex, injury type, strain, and surgical experience) that could influence self-mutilation outcomes. Methods: The Sciatic Functional Index (SFI) and the Von Frey (VF) behavioral tests were performed and analyzed. Regression and other analyses were performed to determine the independent effect of six variables on self-mutilation rates and severity. Results: PEG-fused rats that had no self-mutilation had significantly better SFI scores than those that had self-mutilation. More rapid VF sensory recovery in PEG-fused rats was also associated with less self-mutilation. Self-mutilation rates and severity were: (1) significantly reduced following PEG-fusion repairs compared to NCs; (2) significantly increased following weekly VF tests; (3) not different between female and male rats or (4) between simple transection and segmental-loss PNIs; (5) non-existent in Lewis rats and significantly less severe in Sprague Dawley rats than Long Evans rats; and (6) significantly reduced in rats operated on by experienced PEG-fusion surgeons who historically achieved better SFI outcomes than trainee surgeons. Conclusions: Our data suggest potential clinical benefits of PEG-fusion repair to produce more rapid and better sensorimotor recoveries and reductions of self-mutilation behaviors. Full article

When nerves are severed, such as during traumatic injury, an acute injury state is induced, characterized by biological and physical changes in the proximal and distal stumps. Beyond the initial injury phase, over a time frame of weeks to months, nerves that remain unrepaired progressively enter a chronic injury state, characterized by a change in the extracellular matrix structure of the distal stump, the down-regulation of neurotrophic factors and the loss of macrophages’ and Schwann cells’ ability to clear out degraded axons and myelin. There are also potential systemic impacts away from the site of injury, including in end organs such as muscle and bone. The literature suggests that several of these processes may be strongly influenced by innate and adaptive immune system responses, including a major role for complement pathways. This review details evidence in favor of such a possibility, as well as knowledge gaps and areas for future investigation. Full article

Damage to the chorda tympani (CT) nerve through trauma or experimental nerve axotomy results in the degeneration of anterior taste buds and taste loss. Our previous work demonstrated that interleukin-1 receptor 1 (Il1r) signaling is required for taste bud regeneration and the recovery of taste function. However, the effects of experimental axotomy on immune responses in the absence of Il1r signaling remain unclear. Here we performed unilateral CT sectioning in Il1r KO or wild-type mice to observe changes in innate immune cell populations in the anterior taste field. We found that CD45+ immune cells, CD68+ and CD206+ M2-like macrophages are significantly increased near anterior taste buds at days two and five post-injury in wild-type but not Il1r KO mice. However, taste buds degenerated at similar time points in both strains, suggesting that a suppressed immune responses in the absence of Il1r signaling is not the primary reason for later functional deficits. The presence of pro-regenerative M2-like macrophages may play a role in later taste bud regeneration and functional recovery in the injured peripheral taste system. Full article

Background/Objectives: To date, few studies have reported the use of neurophysiological testing to assess the long-term progression of functional changes in median and ulnar nerve conduction in children and adolescents with mucopolysaccharidosis (MPS). This case series study aimed to perform an electroneurographic (ENG) assessment of the median and ulnar nerves in three young patients with MPS treated with enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) over a five-year observation period. Methods: Bilateral electroneurography of the motor and sensory fibers in the median and ulnar nerves, recording compound muscle action potential (CMAP) and sensory nerve action potential (SNAP), was performed twice in 5-, 7-, and 19-year-old males at two time points: before and five years after the application of ERT and HSCT. Results: In three MPS patients with Hurler or Hunter syndrome, ENG studies similarly demonstrated decreased amplitudes and prolonged distal latencies in their CMAP recordings, confirming the bilateral progression of axonal degeneration and demyelinating changes in the distal parts of the median nerves. The SNAP recordings revealed more severe degenerative processes of similar types in the sensory fibers of the median nerves. Nerve conduction studies in the ulnar nerve fibers bilaterally revealed analogous pathologies, but with a lesser degree of progression. Conclusions: This study confirms the progression of axonal degeneration and demyelinating changes in the distal parts of the median nerves, which were associated with decreased amplitudes and prolonged distal latencies in the CMAP recordings of the MPS patients. More expressed degeneration processes of a similar type were found in the sensory fibers of the median nerves. Ulnar nerve pathologies of neural conduction are less advanced in patients with Hurler and Hunter syndromes. It seems advisable to implement neurophysiological diagnostics as soon as possible to specify surgical or conservative therapy, which is crucial for maintaining hand function in the case of progressive peripheral neuropathies in patients with MPS. The timing of the treatment and the patient’s age may be factors influencing the effectiveness of treatment. Full article

2-acetylfuran is a product of the Maillard reaction and is widely found, especially in heat-processed foods such as grain products, baked goods, and dairy products. Although 2-acetylfuran contributes to flavor, high concentrations may be toxic. Its target organs and dose–response relationships remain poorly characterized. In this study, transgenic zebrafish with fluorescently labeled immune and neural systems were used to assess the effects of 2-acetylfuran on immune and neural development. Wild-type zebrafish were employed to assess the toxicity of 2-acetylfuran on locomotor ability, gastrointestinal development, and liver function. The maximum non-lethal concentration (MNLC) and the 10% lethal concentration (LC₁₀) for zebrafish embryos were 0.844 and 0.889 μL/mL, respectively. Regarding immunotoxicity, at concentrations of 0.281, 0.844, and 0.889 μL/mL, 2-acetylfuran significantly reduced the numbers of neutrophils, T cells, and macrophages. Regarding locomotor and neurotoxicity, motor speed and total locomotor distance were significantly reduced at 0.844 and 0.889 μL/mL. These findings were consistent with neurodevelopmental assessments, in which 0.844 μL/mL 2-acetylfuran resulted in a significant increase in apoptotic cells in the central nervous system and markedly shortened peripheral motor nerve lengths. Regarding gastrointestinal toxicity, 0.844 and 0.889 μL/mL 2-acetylfuran significantly reduced the gastrointestinal area, while neutrophil counts showed no significant changes, suggesting a relatively mild effect on the gastrointestinal tract. Regarding hepatic toxicity, all tested concentrations of 2-acetylfuran primarily increased the delayed yolk sac absorption area. Furthermore, at 0.844 μL/mL, histological examination revealed hepatic pathological changes characterized by hepatocyte nuclear swelling, vacuolar degeneration, and hepatocyte necrosis. In summary, this study reveals the multi-organ toxicity profile of 2-acetylfuran in the zebrafish model, with particularly high sensitivity in the immune system and liver. This research provides theoretical support for risk assessment and process control of 2-acetylfuran in foods. Full article

Peripheral nerve injuries affect 13–23 out of 100,000 people annually, with Wallerian degeneration and subsequent inflammatory/oxidative responses critically impacting recovery. Aloperine, a natural alkaloid from Sophora alopecuroides L., exhibits potent anti-inflammatory and antioxidant properties but has never been studied for nerve repair. In this study, we aimed to investigate whether aloperine could enhance peripheral nerve regeneration by modulating inflammation and oxidative stress in a rat sciatic nerve injury model. Thirty male Wistar rats underwent sciatic nerve neurotmesis with epineural repair. Animals were divided into surgical controls (Group A), aloperine-treated rats (Group B; single 100 mg/kg intraperitoneal dose), and intact controls (Group C). After 8 weeks, outcomes were assessed via functional tests (pinprick, hot plate, extensor postural thrust), biochemical analyses (TNF-α, IL-6, IL-10, TOS/TAS), and histomorphometric evaluations (axon counts, diameter indices, immunohistochemistry). Aloperine treatment significantly improved functional recovery, with near-normal hot plate latency and motor performance. Biochemically, it reduced pro-inflammatory markers (TNF-α) while elevating IL-10. Oxidative stress was attenuated. Histologically, treated nerves showed better-preserved axonal architecture (reduced inflammation). This first investigation of aloperine for nerve repair demonstrates its therapeutic potential through dual anti-inflammatory and antioxidant mechanisms, significantly improving functional and structural outcomes. These findings support its development as a novel treatment for peripheral nerve injuries. Full article

Peripheral nerve injuries, particularly those involving the sciatic nerve, remain a major clinical challenge due to incomplete functional recovery and the limited translation of preclinical advances into effective therapies. This review synthesizes current evidence on the phase-specific evaluation of sciatic nerve regeneration in preclinical models, integrating behavioral, sensory, electrophysiological, and morphological approaches across the acute, subacute (Wallerian degeneration), early regenerative, and late regenerative phases. By mapping functional readouts onto the underlying biological events of each phase, we highlight how tools such as the Sciatic Functional Index, Beam Walk test, Rotarod test, nerve conduction studies, and nociceptive assays provide complementary and often non-interchangeable information about motor, sensory, and neuromuscular recovery. We further examine emerging therapeutic strategies, including intraoperative electrical stimulation, immunomodulation, platelet-rich plasma, bioengineered scaffolds, conductive and piezoelectric conduits, exosome-based hydrogels, tacrolimus delivery systems, and small molecules, emphasizing the importance of aligning their mechanisms of action with the dynamic microenvironment of peripheral nerve repair. Despite substantial advancements in experimental models, an analysis of publication trends and registries reveals a persistent translational gap, with remarkably few clinical trials relative to the high volume of preclinical studies. To illustrate how mechanistic insights can be complemented by molecular-level characterization, we also present a targeted computational analysis of alpha-lipoic acid (ALA,) including frontier orbital energies, physicochemical descriptors, and docking interactions with IL-6, TGF-β, and a growth-factor receptor—performed solely for this molecule due to its documented structural availability and relevance. By presenting an integrated, phase-specific framework for functional assessment and therapeutic evaluation, this review underscores the need for standardized, biologically aligned methodologies to improve the rigor, comparability, and clinical relevance of future studies in sciatic nerve regeneration. Full article

Background/Objectives: Diabetic foot ulcers (DFUs) are one of the most debilitating complications of diabetes mellitus, characterized by impaired wound healing, chronic inflammation, and neuropathy. Peripheral nerve degeneration plays a critical role in delayed healing, but the molecular mediators linking hyperglycemia, neurodegeneration, and impaired DFU repair remain incompletely understood. This study aims to characterize the expression of activin A, which is a key regulator of fibroblast activity and neuronal growth, tumor necrosis factor receptor superfamily member 10B (TNFRSF10B), which mediates inflammatory and apoptotic signaling, and synaptophysin, which serves as a marker of axonal sprouting and synaptic remodeling in diabetic tissues. Methods: Skin tissues during wounding and after healing from control and diabetic Sprague–Dawley rats were analyzed using histological staining, immunohistochemistry, and quantitative real-time polymerase chain reactions. Additionally, rat fibroblasts were treated with hyperglycemic medium to evaluate gene and protein expression in vitro. Results: Histological analyses revealed impaired healing in diabetic wounds with reduced collagen deposition, loss of adnexal structures, and disorganized tissue architecture. Gene and protein expression of activin A, TNFRSF10B, and synaptophysin were significantly decreased in diabetic healed tissues compared to controls. In vitro, hyperglycemia induced transient upregulation of activin A and TNFRSF10B at 24 h, followed by a decline at 48 and 72 h. Conclusions: These findings indicate that hyperglycemia disrupts key mediators of axonal regeneration in DFUs, potentially contributing to impaired neuronal regeneration and delayed healing. Targeting these molecular pathways may offer therapeutic opportunities to enhance wound repair in DFUs. Full article

Background: Diabetic peripheral neuropathy (DPN) is one of the most common and debilitating complications of diabetes mellitus, for which current therapies do not prevent nerve degeneration. Chitosan, a biocompatible polysaccharide with antioxidant, anti-inflammatory, and lipid-lowering properties, may exert direct neuroprotective effects. This study evaluated the impact of oral administration of chitosan on peripheral nerve function and structure in a murine model of streptozotocin (STZ)-induced diabetes. Methods: Male C57BL/6 mice were divided into three groups: Sham, untreated diabetics (T1DM) and diabetics treated with chitosan (150 mg/kg/day, 12 weeks). Metabolic, behavioral (Open Field), nociceptive (Von Frey, Tail-Flick), electrophysiological (compound motor action potential—CMAP) and histological (intraepidermal nerve fiber density—IENF) parameters were analyzed. Results: Chitosan did not significantly modify blood glucose (p = 0.3366), but showed favorable metabolic effects, reducing LDL cholesterol in T1DM+Chitosan vs. T1DM mice (43.75 ± 5.62 mg/dL vs. 82.75 ± 7.65 mg/dL, p < 0.0001) as well as triglycerides (103.5 ± 12.8 mg/dL vs. 175.5 ± 22.8 mg/dL, p < 0.0001). In nociceptive tests, chitosan ameliorated thermal hyperalgesia (Tail-Flick: T1DM 1.25 ± 0.19 s vs. T1DM+Chitosan 1.54 ± 0.16 s; p = 0.0188) and mechanical allodynia (Von Frey: T1DM 0.16 ± 0.07 g vs. T1DM+Chitosan 0.38 ± 0.15 g, p = 0.0103). Electrodiagnostically, chitosan improved CMAP amplitude (T1DM 5.756 ± 0.706 mV vs. T1DM + Chitosan 6.756 ± 0.760 mV, p = 0.0409) and reduced CMAP duration (3.161 ± 0.217 ms vs. 2.900 ± 0.080 ms, p = 0.0273). Histologically, IENF density significantly increased in the treated group (0.01991 ± 0.00246 vs. 0.01512 ± 0.00253 in T1DM; p = 0.0200). Conclusions: Oral administration of chitosan confers functional and structural neuroprotection in STZ-induced diabetic neuropathy despite persistent hyperglycemia. Full article

Background: Amiodarone is a widely used class III antiarrhythmic agent, but its use can lead to peripheral neuropathy mediated by mitochondrial dysfunction, oxidative stress, and neuroinflammatory injury, while effective preventive options remain limited. Agents that support mitochondrial energy metabolism, sustain redox balance, and modulate inflammation, including adenosine triphosphate (ATP), melatonin, and thiamine pyrophosphate (TPP), may counteract these mechanisms; however, their relative neuroprotective potential in amiodarone-induced neuropathy remains unclear. This study aimed to comparatively evaluate the effects of ATP, melatonin, and TPP on amiodarone-induced peripheral neuropathy and neuropathic pain in rats. Methods: Thirty male albino Wistar rats were assigned to five groups: healthy; amiodarone (50 mg/kg/orally); amiodarone + ATP (5 mg/kg/intraperitoneally); amiodarone + melatonin (10 mg/kg/orally); or amiodarone + TPP (20 mg/kg/intraperitoneally). Treatments were given once daily for 14 days. Oxidative stress indices (malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT)) and proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-1 Beta (IL-1β), interleukin-6 (IL-6)) were quantified in sciatic nerve by Enzyme-Linked Immunosorbent Assay (ELISA). Paw withdrawal thresholds were measured with the Randall-Selitto test before and after treatment. Histopathology was performed using Hematoxylin-eosin staining. Results: Amiodarone exposure resulted in pronounced elevations in MDA and proinflammatory cytokine levels, accompanied by significant reductions in tGSH, SOD, CAT activities, and paw withdrawal thresholds. ATP, melatonin and TPP ameliorated these alterations to varying degrees. Among them, TPP provided the most robust antioxidant and anti-inflammatory effects, followed by ATP and melatonin. Histopathological examination confirmed most severe axonal degeneration, interstitial edema and Schwann cell proliferation in the amiodarone group, with substantial amelioration in the TPP-treated rats. Conclusions: Amiodarone induces neuropathic pain through oxidative and inflammatory injury to peripheral nerves. TPP exhibited superior neuroprotective efficacy compared with ATP and melatonin, highlighting its potential as a candidate therapeutic agent for amiodarone-related neuropathy. Further clinical research is warranted to support translational application of these findings. Full article

Corneal nerves play a crucial role in maintaining ocular surface homeostasis by supporting the functional integrity of corneal epithelial, stromal, and endothelial cells; modulating tear secretion; and facilitating sensory responses essential for overall ocular health. With advancing age, these highly specialized peripheral sensory fibers undergo progressive attrition and morphologic distortion driven by the canonical hallmarks of aging including genomic instability, impaired proteostasis, mitochondrial dysfunction, and chronic low-grade inflammation. The resulting neuro-immune dysregulation reduces trophic support, delays wound healing, and predisposes older adults to dry-eye disease, neurotrophic keratopathy, and postsurgical hypoesthesia. Age-exacerbating cofactors including diabetes, dyslipidemia, neurodegenerative disorders, topical preservatives, chronic contact-lens wear, herpes zoster ophthalmicus, and ocular-surface hypoxia further accelerate sub-basal nerve rarefaction and functional decline. This review provides an overview of age-related physiological alterations in ocular surface nerves, with a particular emphasis on corneal innervation. It also discusses risk factors that speed up these changes. Given the inherently limited regenerative capacity of corneal nerves and their inability to fully restore to baseline conditions following injury or degeneration, it is critical to identify and develop effective strategies aimed at mitigating or delaying physiological nerve degeneration and promoting nerve regeneration. This review also brings up emerging therapeutic strategies, including regenerative medicine, neuroprotective agents, and lifestyle interventions aimed at mitigating age-related corneal nerve degeneration. Full article

After peripheral nerve lesion, the role of reactive oxygen species (ROS) has not been clarified during Wallerian degeneration. The present study examined the participation of oxidant stress after rat sciatic nerve injury induced by two experimental models (crush and transection). Here, biochemical parameters indicative of oxidant stress, nitric oxide (NO) metabolism, cell proliferation, apoptosis, and bioenergetics were determined in injured and contralateral sciatic nerves and caudofemoralis muscle. After crushing, we found two peaks of increased lipid peroxidation (LP) by-products and carbonylation of proteins in crushed nerves. In transected nerves, increases in LP showed similar patterns in both proximal and distal nerve. In both models, NO production was decreased and accompanied by an early increase in cell proliferation. Moreover, caspase-3 activity increased later only in crushed nerves. NAD availability and mitochondrial cytochrome oxidase activity were increased in transected but not in crushed nerves. The contralateral nerves also had changes in these parameters, but in a differential manner depending on the type of nerve lesion. In conclusion, present data suggest that changes in the patterns of LP may play a regulatory role in cell damage and death, somehow exerting a control in the progression of Wallerian degeneration. Full article

Objective: Molecular biology techniques were employed to investigate the effects of thrombospondin-4 (Thbs4) expression in dorsal root ganglion (DRG) on peripheral nerve injury repair and regeneration, as well as to elucidate the underlying molecular mechanisms. Methods: A sciatic nerve transection model in rat was established to analyze Thbs4 expression and localization in DRG tissues after injury. Both siRNA and adeno-associated virus (AAV) were used to knockdown or overexpress Thbs4. The effects of knockdown and overexpression of Thbs4 on axon growth were assessed using immunofluorescence staining. The roles of Thbs4 in peripheral nerve injury repair and regeneration were determined using behavioral assays, electrophysiological recordings, and transmission electron microscopy. Results: Thbs4 was primarily localized in the cell membrane and cytoplasm of DRG neurons but was also found in the intercellular spaces. In vitro experiments demonstrated that Thbs4 overexpression promoted axonal regeneration and reduced neuronal apoptosis. They also showed that Thbs4 overexpression accelerated sciatic nerve regeneration and enhanced the recovery of motor and sensory functions. Conversely, Thbs4 knockdown had the opposite effects. This study also showed that the knockdown or overexpression of Thbs4 significantly altered the expression of NF-κB and ERK signaling pathways, suggesting their involvement in peripheral nerve repair and regeneration. Conclusions: Thbs4 expression in DRG tissues is significantly altered following sciatic nerve injury. The NF-κB and ERK may be involved in regulating the repair and regeneration of the peripheral nerve by Thbs4. Full article

Diabetic sensorimotor polyneuropathy (DSPN) is the most prevalent complication of diabetes, affecting nearly half of all persons with diabetes. It is characterized by nerve degeneration, progressive sensory loss and pain, with increased risk of ulceration and amputation. Despite its high prevalence, disease-modifying treatments for DSPN do not exist. Mitochondrial dysfunction and Ca²⁺ dyshomeostasis are key contributors to the pathophysiology of DSPN, disrupting neuronal energy homeostasis and initiating axonal degeneration. Recent findings have demonstrated that antagonism of the muscarinic acetylcholine type 1 receptor (M₁R) promotes restoration of mitochondrial function and axon repair in various neuropathies, including DSPN, chemotherapy-induced peripheral neuropathy (CIPN) and HIV-associated neuropathy. Pirenzepine, a selective M₁R antagonist with a well-established safety profile, is currently under clinical investigation for its potential to reverse neuropathy. The transient receptor potential melastatin-3 (TRPM3) channel, a Ca²⁺-permeable ion channel, has recently emerged as a downstream effector of G protein-coupled receptor (GPCR) pathways, including M₁R. TRPM3 activation enhanced mitochondrial Ca²⁺ uptake and bioenergetics, promoting axonal sprouting. This review highlights mitochondrial and Ca²⁺ signaling imbalances in DSPN and presents M₁R antagonism and TRPM3 activation as promising neuro-regenerative strategies that shift treatment from symptom control to nerve restoration in diabetic and other peripheral neuropathies. Full article