Search Results (608)

Diabetic neuropathy (DN) is a multifactorial complication of diabetes mellitus driven by chronic hyperglycemia, insulin resistance, and disturbed metabolic homeostasis, leading to progressive injury of both the peripheral and central nervous systems. This study investigated whether L-serine supplementation could attenuate DN through dose-dependent metabolic and neuroprotective mechanisms in a high-fat diet (HFD) plus streptozotocin (STZ)-induced diabetic rat model. Male Wistar rats (n = 8 per group) were allocated to five groups: normal control (NC), diabetic control (DC), pioglitazone (PIO; 1.5 mg/kg/day), low-dose L-serine (S1; 200 mg/kg/day), and high-dose L-serine (S2; 400 mg/kg/day). After 60 days of oral gavage, behavioural testing, glucose and insulin profiling, HOMA-IR calculation, brain histopathology, nerve growth factor (NGF) immunohistochemistry, and LC–MS/MS-based proteomic analysis of cerebral tissue were performed. Diabetic rats exhibited marked hyperglycaemia (355.33 ± 4.72 mg/dL), hyperinsulinaemia, severe insulin resistance (HOMA-IR 16.8 ± 3.2; a 14-fold increase), impaired thermal nociception, motor dysfunction, and pronounced neuronal degeneration. L-serine supplementation significantly improved metabolic status: S1 reduced HOMA-IR by 77.4% and S2 by 87.5% relative to diabetic controls (p < 0.001). High-dose L-serine produced greater improvements in thermal sensitivity, motor coordination (rotarod latency 26.67 ± 1.52 s vs. 16.1 ± 0.85 s in DC; p < 0.05), and NGF expression (8.6-fold increase vs. DC). Histopathology confirmed attenuation of neuronal injury and gliosis in both treatment groups. Exploratory, group-level proteomic profiling identified dose-specific molecular signatures: S1 was predominantly associated with carbohydrate, lipid, and biosynthetic pathways, whereas S2 was associated with synaptic, neurotransmission-related, and proteostasis pathways. Within the constraints of an exploratory design—group-level pooled proteomics, analysis of cerebral rather than peripheral-nerve tissue, and only two doses—these findings indicate that L-serine attenuates the metabolic and behavioural features of experimental diabetic neuropathy and generates the testable hypothesis of dose-dependent neuro-metabolic remodelling. The proteomic signatures are hypothesis-generating and require orthogonal validation before any mechanistic or translational inference can be drawn. Full article

Diabetic neuropathy is typically diagnosed with distal sensory and nerve conduction abnormalities. These symptoms may reflect earlier disturbances of axonal maintenance. This review examines axonal transport and cytoskeletal failure as convergent cellular mechanisms of diabetic axonopathy. Long peripheral axons are particularly vulnerable to damage because their integrity depends on continuous communication between the neuronal soma and distal terminals. This process involves the continuous renewal of cytoskeletal and functional proteins and the involvement of organelles such as mitochondria. Diabetes in experimental models disrupts this system at several levels. It slows cargo transport. The supply of neurofilaments, tubulin and retrograde signaling is reduced, and regenerative growth after injury is weakened. Carbonyl stress and AGEs cause modifications of neural proteins, the extracellular matrix, vascular barriers, and the excitability of sensory neurons. RAGE ligands, including AGEs and the proteins HMGB1 and S100, link the diabetic tissue environment to redox and inflammatory signaling. This occurs in neural and glial compartments, as well as in vascular tissue and the immune system. RAGE interacts with DIAPH1 to activate GTPase signaling and remodel the cytoskeleton. The RAGE–DIAPH1 interaction provides a plausible route from diabetic ligand accumulation to cytoskeletal remodeling. These observations provide a mechanistic context for axonal transport, although not all represent direct measurements of cargo movement. Direct evidence for transport impairment comes mainly from experimental studies showing altered slow cytoskeletal transport, impaired retrograde signaling, and weakened regenerative responses. This work highlights the possibility of developing therapies that go beyond symptomatic relief. Verifying the effectiveness of interventions in protecting axonal transport and nerve fiber integrity in diabetic neuropathy may be therapeutically beneficial. Full article

Background and Objectives: Brachial plexus birth injury (BPBI) is a peripheral nerve injury occurring during birth that may result in upper-extremity weakness and functional impairment. This systematic review aimed to evaluate the effects of neuromuscular electrical stimulation (NMES) on motor function, muscle strength, range of motion, and upper-extremity function in children with BPBI. Materials and Methods: This systematic review was conducted according to PRISMA guidelines and registered in PROSPERO. PubMed, CINAHL, Scopus, Web of Science, PEDro, and the Cochrane Library were searched from inception to 5 May 2026. Only randomized controlled trials were included. Methodological quality was assessed using the PEDro scale, and risk of bias was evaluated using the RoB 2 tool. Results: Seven randomized controlled trials involving 197 participants were included. Several studies reported improvements in shoulder abduction, elbow flexion, wrist extension, muscle strength, and motor function following NMES compared with conventional therapy. The combination of NMES and constraint-induced movement therapy demonstrated favorable outcomes in functional performance. However, substantial heterogeneity was observed across studies regarding participant characteristics, NMES parameters, treatment duration, and outcome measures. The certainty of evidence ranged from low to very low. Conclusions: Current evidence suggests that NMES may serve as a potential adjunct to conventional rehabilitation in children with BPBI. However, given the low to very low certainty of the evidence, high risk of bias, and substantial clinical and methodological heterogeneity among the included studies, definitive clinical recommendations cannot currently be made. Future well-designed randomized controlled trials using standardized protocols, consistent outcome measures, and longer follow-up periods are warranted. Full article

Sports injuries, especially musculoskeletal and neurological types from strenuous exercise, are a global public health challenge. Characterized by a high incidence and slow recovery, these injuries differ from typical trauma, often resulting in severe mechanical transmission loss and an imbalanced immune microenvironment. Consequently, standard interventions struggle to achieve true tissue regeneration. Gelatin, a collagen-derived biomaterial, offers RGD-mediated cell adhesion, MMP-responsive degradation, and high modifiability. These qualities make it an excellent foundation for biomimetic repair scaffolds. This paper reviews the design principles and recent advances in gelatin-based multifunctional hydrogels in sports medicine. First, we analyse their structure and engineering advantages. Next, we summarise strategies and mechanisms for modules like conductivity, antibacterial activity, self-healing, stimulus responsiveness, and tissue adhesion. The review links these modules to types of injuries: bone or cartilage, tendon or ligament, skeletal muscle, spinal cord, and peripheral nerve. It clarifies their clinical and translational value in remodelling immune microenvironments, regulating electrophysiology, promoting interfacial regeneration, and restoring motor function. This review provides focused insights from materials science and sports rehabilitation to advance precision treatments for sports injuries. Full article

Glaucoma is a chronic progressive optic neuropathy and one of the leading causes of irreversible blindness worldwide. Although elevated intraocular pressure remains the most important modifiable risk factor, increasing evidence suggests that immune dysregulation and autoimmune responses also contribute substantially to disease onset and progression. Clinical studies across different glaucoma subtypes have identified subtype-dependent immune abnormalities, including altered serum autoantibody profiles, dysregulated cytokine and chemokine expression, and changes in peripheral immune cell subsets. Experimental and translational studies further indicate that multiple immunopathogenic mechanisms are involved in glaucomatous neurodegeneration, including glial cell-mediated immune responses, activation of pattern recognition receptor signalling pathways, adaptive immune responses, and complement cascade dysregulation. These processes may interact to sustain chronic neuroinflammation, promote retinal ganglion cell injury, and accelerate optic nerve degeneration. Importantly, a better understanding of immune involvement in glaucoma has generated growing interest in immunomodulatory therapy as a potential strategy beyond intraocular pressure lowering. Targeting microglial activation, inflammatory signalling pathways, adaptive immune imbalance, and complement-mediated injury has shown neuroprotective potential in animal or in vitro models, whereas clinical evidence in glaucoma patients remains limited. These findings may provide preliminary directions for future therapeutic development. In this review, we summarise the current clinical evidence linking glaucoma with autoimmunity, discuss the major immune mechanisms implicated in disease pathogenesis, and highlight recent advances in immunomodulatory therapeutic strategies. Elucidating the immune basis of glaucoma may help pave the way for more precise and effective treatments for this complex optic neuropathy. We believe that immune dysregulation in glaucoma functions as a context-dependent amplifier of retinal ganglion cell injury rather than a uniform primary driver, with innate (microglia/astrocytes), adaptive (T/B cells, HSP-specific immunity), and complement pathways interacting to sustain neuroinflammation and neurodegeneration. This integrated immune response contributes to subtype- and stage-specific vulnerability, and targeting these maladaptive immune mechanisms represents a promising, precision-guided strategy for neuroprotection beyond intraocular pressure lowering. Full article

Background/Objectives: Trigeminal neuralgia (TN) is a debilitating neurological condition characterized by recurrent, severe pain linked to peripheral and central sensitization within trigeminal pathways. Current pharmacologic treatments are limited by inadequate efficacy or dose-limiting side effects, and botulinum neurotoxin type A (BoNT/A) has emerged as a viable option. However, its potential use in the management of TN is hampered by methodological limitations in existing studies and a lack of pivotal clinical trials. This study investigated the efficacy, optimal treatment site, preventive utility, and duration of effect of incobotulinumtoxinA (Inco/A), a BoNT/A, in a model of TN. Methods: An infraorbital nerve chronic constriction injury model was used to induce mechanical allodynia in male Sprague–Dawley rats, reproducing the trigeminal sensitization seen in TN. The effects of subcutaneous Inco/A (1, 2, and 4 U) were measured using the mechanical sensitivity (von Frey) test to evaluate the dose response, effect of injection location, potential preventive nature of treatment, and duration of benefit. Results: Inco/A produced a robust, dose-dependent reduction in mechanical allodynia, predominantly via a local mechanism of action. Both preventive and therapeutic administration of Inco/A was efficacious, with significant reduction in allodynia even when administered up to 28 days before nerve injury. The anti-allodynic effect persisted up to 56 days post-injection. Conclusions: Inco/A is highly effective in alleviating mechanical allodynia in a validated rat model of TN. The findings highlight Inco/A as a promising candidate for clinical translation in TN and related neuropathic pain syndromes and support systematic investigation in well-controlled human trials. Full article

Background: Carpal tunnel syndrome (CTS) is the most prevalent peripheral nerve entrapment neuropathy, with rising incidence in aging populations. Uncertainty persists regarding the efficacy and safety of carpal tunnel release (CTR) in patients aged ≥ 70 years. Objectives: To systematically evaluate the indications, clinical outcomes, and utility of CTR in elderly patients (≥70 years), with comparison to younger cohorts. Methods: Following PRISMA 2020 guidelines, PubMed/MEDLINE, Scopus, CENTRAL, Embase, Web of Science, and grey literature sources were searched from inception through September 2025. Two independent reviewers extracted data; inter-rater agreement was strong (κ = 0.81–0.86). The primary outcome was the Boston Carpal Tunnel Questionnaire (BCTQ). Weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated using DerSimonian–Laird random-effects models. Certainty of evidence was assessed using the GRADE framework. Results: A total of 20 studies encompassing 3841 operated hands, including 1139 hands in elderly patients and 2702 hands in younger comparators across comparative studies, were analyzed. Mean SS-BCTQ improvement was 1.8 points (95%CI: 1.6–2.0; exceeding the established MCID of 1.04–1.05 points). FS-BCTQ improvement was 1.1 points (95%CI: 0.9–1.3; marginally below the pooled MCID of 1.13 points). Elderly patients demonstrated SS-BCTQ improvement of 1.7 points and satisfaction rates of 72–94%, comparable to younger cohorts (75–95%; p = 0.38). Grip strength improved 15–25% in younger patients but remained unchanged in elderly patients (p < 0.001). Sensory recovery reached 42% in elderly versus 58% in younger patients (p < 0.01). Complication rates were low and age-independent (3.1%; RR 1.08; 95%CI: 0.86–1.35; p = 0.52). GRADE certainty was as follows: low for symptom and functional improvement; very low for surgery versus conservative management. Conclusions: CTR is associated with significant symptomatic benefit in elderly patients when conservative treatment fails, with complication rates comparable to younger populations. Age alone should not constitute a surgical contraindication. Preoperative counseling must establish realistic expectations regarding grip strength and functional recovery. High-quality randomized trials in elderly populations remain an urgent research priority. Full article

Artificial nerve guidance conduits (NGCs) have gained significant attention in the field of peripheral nerve regeneration for the treatment of critically sized nerve defects. Nanotechnology-based NGCs are being explored as potential solutions for repairing and reconstructing peripheral nerve injuries due to their unique structure and topography. In this study, we present a novel core–sheath GelMA/PCL nanofiber construct fabricated through electrospinning and phase separation methods. The core–sheath GelMA/PCL nanofibers replicate the topological morphology of the native extracellular matrix (ECM). The outer layer, composed of GelMA, serves as an “adhesion domain” facilitating direct interaction with surrounding cells and tissues while improving wettability, integrin-mediated cell adhesion/attachment, and degradation. PCL, acting as the “elastic domain” within the nanofibers, enhances mechanical properties, maintains long-term stability of the NGCs, and enables controlled release of GelMA. Histomorphometric analysis along with electrophysiological and behavioral assessments demonstrate that these core–sheath GelMA/PCL nanofiber-based NGCs can activate endogenous mechanisms for peripheral nerve repair while promoting sensory/motor nerve regeneration and functional recovery. Overall, our findings demonstrate that GelMA/PCL nanofibers within the nuclear sheath can effectively remodel the nerve regeneration microenvironment by integrating “mechanical- biochemical” signals, thereby offering a novel strategy for addressing critical-size nerve defects. Full article

Recent advancements in biology and medicine have facilitated the progress of nerve regeneration that markedly improves the treatment of peripheral nerve injuries, enhancing outcomes and recovery rates. It has been reported that erythropoietin (EPO) is currently being studied as a potential agent for neural repair. However, much evidence has confirmed that EPO treatment can induce systemic adverse effects in the clinical fields, including coronary stent thrombosis and deep vein thrombosis. Herein, a derivative of EPO without any hematopoietic activities, which is named carbamylated erythropoietin (CEPO), has been synthesized and investigated for its effects on peripheral neural repair both in vitro and in vivo. The in vitro experimental results demonstrated that CEPO enhanced Schwann cell viability, proliferation, migration, and nerve growth factor (NGF) expression, while the optimal concentration of CEPO was found to be 25 μg/mL. The in vivo observations at 21 days post-injection indicated that the CEPO group exhibited a significant functional improvement in the sciatic nerve injury model, guiding regrowing axons across the injury site. Thus, CEPO serves as a promising candidate or adjunctive strategy for peripheral nerve injuries, demonstrating promising clinical applications and potential for enhancing Schwann cell viability, proliferation, and migration, as well as anticipated nerve axon development. Full article

Background/Objectives: Vagus nerve stimulation (VNS) has evolved from a laboratory experiment to a standard of care in several neurological disorders like epilepsy, depression and stroke rehabilitation at present. Methods: We reviewed the published literature relevant to its origins in animal models leading to various clinical applications. Results: Bailey and Bremer published their observations following VNS in animals while further studies established its utility in some forms of epilepsy. Subsequent observations in epilepsy patients treated with VNS revealed the unequivocal improvement in psychological and behavioral disorders. Consequently, VNS received approval for its application in resistant depression disorders. Multiple studies revealed changes due to neuronal plasticity following VNS that could result in the significant clinical recovery of motor function in chronic ischemic stroke patients. Chronic incomplete cervical spinal cord injury, head injury and peripheral nerve injury deficits are also being studied for recovery patterns. Transcutaneous approaches and closed-loop stimulation are showing encouraging results that may facilitate the extension of the application of neuromodulation using VNS. Conclusions: For the recovery of motor function following paralysis in stroke patients or cervical spinal cord injuries, the timing of the stimulation after physical activity during rehabilitation has been identified as a key factor. In addition to the timing of the stimulation, the titration of the parameters is also being studied to obtain optimized recovery in cases of motor, sensory, or sphincter deficits. Full article

Peripheral nerve blocks can effectively reduce the use of general anesthesia and opioids in situations where robust pain management is critical, such as severe extremity trauma and hip, femur, and knee surgeries. Despite these benefits, nerve blocks are underutilized due to the high skill required to accurately insert a needle and safely deliver local anesthetic. To overcome this challenge, ultrasound image guidance enabled by artificial intelligence (AI) offers a semi-automated solution for regional anesthesia delivery by non-specialists. As a first step towards realizing an integrated platform for AI-guided nerve blocks, the main objective of this study is to develop and characterize deep learning algorithms to interpret anatomical landmarks on ultrasound images in real time and identify aimpoints for needle placement. Our AI system was trained on over 55,000 images from 20 porcine models and demonstrated an average area under the precision–recall curve of 0.92 (SD = 0.03) for in vivo landmark detection in the femoral nerve region. In prospective live animal testing, aimpoint identification had a 98.3% success rate with an average time of 40.5 s (SD = 33.5). Future work will focus on integrated testing with handheld robotics towards a more accessible method for delivering regional anesthesia in settings from point of injury to medical transport to hospitals. Full article

Background/Objectives: While the functions of angiotensin-converting enzyme (ACE) 1 and 2 are well established in peripheral tissues, the role of the spinal ACE1 and ACE2 pathways in the development of neuropathic pain remains unclear. This study examined the role of the spinal ACE1 and ACE2 pathways in trigeminal neuropathic pain produced by inferior alveolar nerve (IAN) injury. Methods: The experiments were conducted using male Sprague-Dawley rats (6–8 weeks old, weighing 220–250 g). The left mandibular second molar was extracted, and a dental mini-implant was placed to induce IAN injury. IAN injury produced robust and long-lasting mechanical allodynia and markedly increased angiotensinogen (AGT) expression within the ipsilateral trigeminal subnucleus caudalis (iTSC). Results: Neuropathic mechanical allodynia was inhibited by intracisternally administered losartan (an angiotensin II type-1 receptor antagonist), but not by an angiotensin II type-2 receptor antagonist. Intracisternal treatment with captopril (an ACE1 inhibitor) and diminazene aceturate (an ACE2 activator) produced significant anti-allodynic effects. Intracisternally injected angiotensin-(1-7) reduced neuropathic mechanical allodynia, and this anti-allodynic effect was blocked by pretreatment with A779, a Mas receptor inhibitor. In naïve rats, the intracisternal administration of DX600 (an ACE2 inhibitor) resulted in mechanical allodynia, which was inhibited by intracisternal pretreatment with losartan. IAN injury led to upregulated ACE1 expression and downregulated ACE2 expression in the iTSC. Conclusions: Our findings indicate that IAN injury induces a polarized shift in the ACEs within the iTSC, characterized by increased ACE1 and decreased ACE2 expression. Their modulation may therefore offer a promising strategy for developing effective treatments for chronic pain. Full article

Peripheral nerve ischemia–reperfusion injury is considered to contribute to sensory disturbances that impair quality of life in patients with diabetic neuropathy and chemotherapy-induced neuropathy. However, the spinal mechanisms underlying these disturbances remain unclear, partly due to the lack of established animal models and evaluation systems. In the present study, we used a rat hindlimb ischemia–reperfusion model and in vivo extracellular recording to examine bidirectional changes in neuronal activity in the spinal dorsal horn. Ischemia was induced by tightly binding the rat ankle with a rubber band, followed by reperfusion. Behavioral analysis showed a significant increase in hindlimb licking behavior after reperfusion, indicating the development of sensory disturbance-like responses. Extracellular recordings from superficial dorsal horn neurons showed diverse patterns of spontaneous firing and responses to mechanical stimulation, with both hypersensitive and desensitized responses. Furthermore, mRNA expression levels of immediate early genes (Egr1, Egr3, and Fos) were upregulated in the spinal cord after reperfusion. These results suggest that this ischemia–reperfusion model reproduces complex neuronal responses relevant to peripheral neuropathy and provides a useful evaluation system for evaluating both increased and decreased neural activity. This approach may contribute to elucidating the mechanisms of sensory disturbances and to the development of new treatments for neuropathic conditions. Full article

Peripheral nerve injuries cause profound medical and socioeconomic consequences. Despite substantial microsurgical advances, including nerve autografting, nerve transfers, and the commercial availability of effective conduits, functional recovery remains incomplete for most patients. Current outcomes underscore the need for novel adjunctive therapies capable of enhancing axonal regeneration, accelerating reinnervation, and mitigating denervation-induced target atrophy. Tacrolimus, a calcineurin inhibitor widely used in organ transplantation, has emerged as a potent immunomodulatory and neuroregenerative agent. However, its systemic use is constrained by severe dose-limiting toxicities and metabolic derangements. This limitation has driven a paradigm shift toward localized tacrolimus delivery, leveraging biomaterials to achieve therapeutic drug concentrations at the repair site while minimizing systemic toxicity. This review synthesizes the state-of-the-art advances in biomaterial-based tacrolimus local delivery systems. We highlight biological mechanisms underlying tacrolimus-mediated neuroregeneration and immunomodulation. Engineering strategies including nerve conduits, wraps, injectable hydrogels, electrospun scaffolds, and stimuli-responsive carriers are discussed, with attention to polymeric composition, fabrication technologies, degradation kinetics, and pharmacological performance. We also explored the regulatory, manufacturing, and scalability challenges inherent to drug–device combination products. Finally, we identify emerging directions including multimodal biomaterials that integrate tacrolimus with trophic factors, extracellular vesicles, or bioelectrical stimulation. Collectively, biomaterial-enabled tacrolimus delivery represents a transformative strategy to bridge traditional nerve surgical repair and functional recovery. This review provides a roadmap for future interdisciplinary innovation at the interface of biomaterials science, neurobiology, pharmacology, and surgery. Full article

Spinal cord stimulation (SCS) has expanded beyond pain treatment, becoming a neuromodulatory method capable of recruiting spinal and supraspinal circuits involved in motor recovery. This review summarises mechanistic knowledge, supports engineering developments, and describes the changing clinical translation of SCS in rehabilitation. Mounting scientific data shows that SCS’s effects go beyond dorsal column modulation and may involve segmental networks that promote activity-dependent plasticity and sensorimotor pathway restoration, probably due to a combination of Hebbian and non-Hebbian mechanisms (synaptic potentiation, interneuronal reorganisation, and altered afferent–efferent coupling). More recent advances, such as bursts and the high-frequency paradigm, closed-loop control, and data-driven parameter optimisation methods, improve the precision, stability, and calibration of stimulation for each individual. By combining SCS with non-invasive forms of neuromodulation (TMS, tDCS, and peripheral nerve stimulation), one can potentially further intensify corticospinal plasticity and maintain improvements in functions. Spinal cord stimulation remains an established treatment for chronic neuropathic pain, including failed back surgery syndrome and complex regional pain syndrome. In recent years, however, increasing attention has been directed toward its potential role in motor recovery after spinal cord injury and stroke. Progress in this area is limited by patient heterogeneity, variability in outcome measures, the complexity of multimodal rehabilitation protocols, and regulatory and logistical constraints—particularly when adaptive or closed-loop systems are used. Current evidence suggests that motor-restorative applications of SCS should be interpreted cautiously and integrated within carefully designed rehabilitation programmes, with attention to patient selection and realistic expectations regarding the durability of the benefit. Full article