Search Results (94)

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

Sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD⁺) hydrolase involved in axonal degeneration and neuronal cell death. SARM1 plays a pivotal role in triggering the neurodegenerative processes that underlie peripheral neuropathies, traumatic brain injury, and neurodegenerative diseases. Importantly, SARM1 knockdown or knockout prevents the degeneration; as a result, SARM1 has been attracting attention as a potent therapeutic target. In recent years, the development of several SARM1 inhibitors derived from synthetic chemical compounds has been reported; however, no dietary ingredients with SARM1 inhibitory activity have been identified. Therefore, we here focused on dietary ingredients and found that carnosol, an antioxidant contained in rosemary, inhibits the NAD⁺-cleavage activity of SARM1. Purified carnosol inhibited the enzymatic activity of SARM1 and suppressed neurite degeneration and cell death induced by the anti-cancer medicine vincristine (VCR). Carnosol also inhibited VCR-induced hyperalgesia symptoms, suppressed the loss of intra-epidermal nerve fibers in vivo, and reduced the blood fluid level of phosphorylated neurofilament-H caused by an axonal degeneration event. These results indicate that carnosol has a neuroprotective effect via SARM1 inhibition in addition to its previously known antioxidant effect via NF-E2-related factor 2 and thus suppresses neurotoxin-induced peripheral neuropathy. Full article

Pericytes (PCs), a heterogeneous population of perivascular supporting cells, are critical regulators of vascular stability, angiogenesis, and blood–tissue barrier integrity. Increasing evidence highlights their active role in the pathophysiology of diabetic microangiopathies, including those affecting the retina, kidney, brain, heart, and peripheral nerves. In diabetes, hyperglycemia-induced PC dysfunction is a major contributor to vascular degeneration, impaired tissue repair, and disease progression across multiple organs. Pericytes also share many characteristics with mesenchymal stem cells (MSCs). They exhibit regenerative capacity, immunomodulatory activities, and multipotent capacities. This review explores the emerging role of PCs as tissue resident MSCs, emphasizing their pathophysiological involvement in diabetes complications, and their potential for utilization in regenerative medicine. We also discuss advances in PC-based therapies, tissue engineering strategies, and clinical applications. Thus, PCs are positioned as promising targets for therapeutic intervention and vascular tissue regeneration. Full article

Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders. Full article

Peripheral nervous system (PNS) neurons, including motor neurons (MNs), possess a remarkable ability to regenerate and reinnervate target muscles following nerve injury. This process is orchestrated by a combination of intrinsic neuronal properties and extrinsic factors, with Schwann cells (SCs) playing a central role. Upon injury, SCs transition into a repair phenotype that allows axonal regeneration through molecular signaling and structural guidance. However, the identity of the SCs’ reprogramming factors is only partially known. We previously identified hydrogen peroxide (H₂O₂) as an early and key driver of nerve repair, inducing gene expression rewiring in SCs to support nerve re-growth. In this study, we quantitatively assessed the role of H₂O₂ in the activation of key pro-regenerative signaling pathways in SCs following sciatic nerve compression, specifically the extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun, which are essential for functional nerve recovery. Notably, we found that H₂O₂ neutralization does not impact degeneration, but it significantly affects the regenerative response. Collectively, our findings establish H₂O₂ as a promising regulator of the Schwann cell injury response at the injury site, linking oxidative signaling to the molecular mechanisms governing nerve regeneration. Full article

Peripheral nerve injury disrupts the function of the peripheral nervous system, leading to sensory, motor, and autonomic deficits. While peripheral nerves possess an intrinsic regenerative capacity, complete sensory and motor recovery remains challenging due to the unpredictable nature of the healing process, which is influenced by the extent of the injury, age, and timely intervention. Recent advances in microsurgical techniques, imaging technologies, and a deeper understanding of nerve microanatomy have enhanced functional outcomes in nerve repair. Nerve injury initiates complex pathophysiological responses, including Wallerian degeneration, macrophage activation, Schwann cell dedifferentiation, and axonal sprouting. Complete nerve disruptions require surgical intervention to restore nerve continuity and function. Direct nerve repair is the gold standard for clean transections with minimal nerve gaps. However, in cases with larger nerve gaps or when direct repair is not feasible, alternatives such as autologous nerve grafting, vascularized nerve grafts, nerve conduits, allografts, and nerve transfers may be employed. Autologous nerve grafts provide excellent biocompatibility but are limited by donor site morbidity and availability. Vascularized grafts are used for large nerve gaps and poorly vascularized recipient beds, while nerve conduits serve as a promising solution for smaller gaps. Nerve transfers are utilized when neither direct repair nor grafting is possible, often involving re-routing intact regional nerves to restore function. Nerve conduits play a pivotal role in nerve regeneration by bridging nerve gaps, with significant advancements made in material composition and design. Emerging trends in nerve regeneration include the use of 3D bioprinting for personalized conduits, gene therapy for targeted growth factor delivery, and nanotechnology for nanofiber-based conduits and stem cell therapy. Advancements in molecular sciences have provided critical insights into the cellular and biochemical mechanisms underlying nerve repair, leading to targeted therapies that enhance axonal regeneration, remyelination, and functional recovery in peripheral nerve injuries. This review explores the current strategies for the therapeutic management of peripheral nerve injuries, highlighting their indications, benefits, and limitations, while emphasizing the need for tailored approaches based on injury severity and patient factors. Full article

Pathological changes and the cellular and molecular mechanisms underlying axonopathy and myelinopathy are key to understanding a wide range of inherited and acquired peripheral nerve disorders. While the clinical indications for nerve biopsy have diminished over time, its diagnostic value remains significant in select conditions, offering a unique window into the pathophysiological processes of peripheral neuropathies. Evidence highlights the symbiotic relationship between axons and myelinating Schwann cells, wherein disruptions in axo-glial interactions contribute to neuropathogenesis. This review synthesizes recent insights into the pathological and molecular underpinnings of axonopathy and myelinopathy. Axonopathy encompasses Wallerian degeneration, axonal atrophy, and dystrophy. Although extensively studied in traumatic nerve injury, the mechanisms of axonal degeneration and Schwann cell-mediated repair are increasingly recognized as pivotal in non-traumatic disorders, including dying-back neuropathies. We briefly outline key transcription factors, signaling pathways, and epigenetic changes driving axonal regeneration. For myelinopathy, we discuss primary segmental demyelination and dysmyelination, characterized by defective myelin development. We describe paranodal demyelination in light of recent findings in nodopathies, emphasizing that it is not an exclusive indicator of demyelinating disorders. This comprehensive review provides a framework to enhance our understanding of peripheral nerve pathology and its implications for developing targeted therapies. Full article

Background and Objectives: Peripheral nerve injuries often result in significant functional impairment, and complete recovery remains challenging despite surgical interventions. Polyethylene glycol (PEG) has shown promise in nerve repair by facilitating axonal fusion and inhibiting Wallerian degeneration. This study investigates the biochemical, histopathological, and electrophysiological effects of PEG 3350 in a sciatic nerve injury model. Materials and Methods: Thirty adult male Wistar rats were divided into three groups: a control group, a surgery and saline group, and a surgery and PEG 3350 treatment group. Sciatic nerve transection was performed, and PEG 3350 was administered intraperitoneally for 12 weeks. Electromyography (EMG) and the inclined plane test assessed functional recovery. Sciatic nerve tissues were analyzed histologically and biochemically, including nerve growth factor (NGF), heat shock protein 70 (HSP-70), and malondialdehyde (MDA) levels. Results: PEG 3350 significantly improved electrophysiological parameters, reducing compound muscle action potential (CMAP) latency and increasing CMAP amplitude compared to the saline group (p < 0.05). Functional recovery, assessed by the inclined plane test, showed a significant improvement in the PEG-treated group (p < 0.01). Biochemical analysis revealed increased NGF and HSP-70 levels, suggesting enhanced neuroprotection and regeneration. Histopathological analysis demonstrated reduced fibrosis and increased axonal density in the PEG group compared to controls. PEG 3350 enhances nerve regeneration by improving electrophysiological function, promoting axonal repair, and increasing neurotrophic factor expression. Conclusions: These findings suggest PEG as a potential adjunct therapy for peripheral nerve injuries. Future research should explore the optimal administration protocols and combined therapeutic strategies for maximizing recovery. Full article

Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes mellitus, characterized by progressive nerve damage driven by chronic hyperglycemia and systemic inflammation. The pathophysiology of DPN is significantly influenced by pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α. These cytokines promote oxidative stress, vascular dysfunction, and neuronal degeneration by activating important signaling pathways including NF-κB and MAPK. While IL-6 promotes a pro-inflammatory microenvironment, increasing neuronal damage and neuropathic pain, TNF-α and IL-1β worsen Schwann cell failure by compromising axonal support and causing demyelination. Immune cell infiltration and TLR activation increase the inflammatory cascade in DPN, resulting in a persistent neuroinflammatory state that sustains peripheral nerve injury. The main characteristics of DPN are axonal degeneration, decreased neurotrophic support, and Schwann cell dysfunction, which weaken nerve transmission and increase susceptibility to damage. Advanced glycation end-products, TNF-α, and CXCL10 are examples of biomarkers that may be used for early diagnosis and disease progression monitoring. Additionally, crucial molecular targets have been found using proteomic and transcriptome techniques, enabling precision medicine for the treatment of DPN. This review emphasizes the importance of cytokine signaling in the pathogenesis of DPN and how cytokine-targeted treatments might reduce inflammation, restore nerve function, and improve clinical outcomes for diabetic patients. Full article

Background: Charcot–Marie–Tooth (CMT) disease is an inherited peripheral neuropathy primarily involving motor and sensory neurons. Mutations in INF2, an actin assembly factor, cause two diseases: peripheral neuropathy CMT-DIE (MIM614455) and/or focal segmental glomerulosclerosis (FSGS). These two phenotypes arise from the progressive degeneration affecting podocytes and Schwann cells. In general, nerve enlargement has been reported in 25% of the demyelinating CMT subtype (CMT1), while little is known about the CMT-DIE caused by INF2 variants. Methods: To characterize the peripheral nerve phenotype of INF2-related CMT, we studied the clinical course, imaging, histology, and germline genetic variants in two unrelated CMT-DIE patients. Results: Patient 1 (INF2 p.Gly73Asp) and patient 2 (p.Val108Asp) first noticed walking difficulties at 10 to 12 years old. Both of them were electrophysiologically diagnosed with demyelinating neuropathy. In patient 2, the sural nerve biopsy revealed an onion bulb formation. Both patients developed nephrotic syndrome almost simultaneously with CMT and progressed into renal failure at the age of 16 to 17 years. Around the age of 30 years, both patients manifested multiple hypertrophy of the trunk, plexus, and root in the cervical, brachial, lumbosacral nerves, and cauda equina. The histology of the cervical mass in patient 2 revealed Schwannoma. Exome analysis showed that patient 2 harbors a germline LZTR1 p.Arg68Gly variant, while patient 1 has no schwannomatosis-related mutations. Conclusions: Peripheral neuropathy caused by INF2 variants may lead to the development of multifocal hypertrophy with age, likely due to the initial demyelination and subsequent Schwann cell proliferation. Schwannoma could co-occur when the tissues attain additional hits in schwannomatosis-related genes (e.g., LZTR1). Full article

Peripheral nerve injury has become an increasingly prevalent clinical concern, causing great morbidity in the community. Although there have been significant advancements in the treatment of peripheral nerve damage in recent years, the issue of long-term nerve regeneration remains. Furthermore, Wallerian degeneration has created an obstacle to long-term nerve regeneration. For this reason, there has been extensive research on the use of exogenous and endogenous stem cells as an adjunct or even primary treatment option for peripheral nerve injury. The plasticity and inducibility of stem cells make them an enticing option for initiating neuronal cell regrowth and optimal sensory and functional nerve regeneration. Peripheral nerve injury has a broad range of causative factors and etiologies. As such, unique stem cell-induced peripheral nerve treatments are being investigated to ameliorate the damage incited by all causes, including trauma, neuropathy, and systemic neurodegenerative diseases. This review is oriented to outline the potential role of stem cell therapies in peripheral nerve injury versus the current standards of care, compare the benefits and drawbacks of specific stem cell lines under investigation, and highlight the current models of stem cell therapy in the peripheral nervous system, with the ultimate goal of narrowing down and optimizing the role and scope of stem cell therapy in peripheral nerve injury. Full article

Over the past two decades, the development of nerve guide conduits (NGCs) has gained much attention due to the impellent need to find innovative strategies to take care of damaged or degenerated peripheral nerves in clinical surgery. In this view, significant effort has been spent on the development of high-performance NGCs by different materials and manufacturing approaches. Herein, a highly versatile and easy-to-handle route to process 3D porous tubes made of chitosan and gelatin to be used as a nerve guide conduit were investigated. This allowed us to fabricate highly porous substrates with a porosity that ranged from 94.07 ± 1.04% to 97.23 ± 1.15% and average pore sizes—estimated via X-ray computed tomography (XCT) reconstruction and image analysis—of hundreds of microns and an irregular shape with an aspect ratio that ranged from 0.70 ± 0.19 to 0.80 ± 0.15 as a function of the chitosan/gelatin ratio. More interestingly, the addition of gelatin allowed us to modulate the mechanical properties, which gradually reduced the stiffness—max strength from 0.634 ± 0.015 MPa to 0.367 ± 0.021 MPa—and scaffold toughness—from 46.2 kJ/m³ to 14.0 kJ/m³—as the gelatin content increased. All these data fall into the typical ranges of the morphological and mechanical parameters of currently commercialized NGC products. Preliminary in vitro studies proved the ability of 3D porous tubes to support neuroblastoma cell (SH-SY5Y) adhesion and proliferation. In perspective, the proposed approach could also be easily implemented with the integration of other processing techniques (e.g., electrospinning) for the design of innovative bi-layered systems with an improved cell interface and molecular transport abilities. Full article

Background: Sterile α and Toll/IL-1 receptor motif-containing 1 (SARM1) is a central regulator of programmed axon death and a crucial nicotinamide adenine dinucleotide (NAD+) hydrolase (NADase) in mammalian tissues, hydrolyzing NAD+ and playing an important role in cellular NAD+ recycling. Abnormal SARM1 expression is linked to axon degeneration, which causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Methods: In this study, we use PC6 assay of hydrolase activity, DRG axon regeneration and CIPN model to screen for potent SARM1 Inhibitors. Results: Two novel SARM1 inhibitors (compound 174 and 331P1) are charcterized for its high potency for SARM1 NADase. In a chemotherapy-induced peripheral neuropathy (CIPN) myopathy model, compound 331P1 treatment prevented the decline in neurofilament light chain (NfL) levels caused by axonal injury in a dose-dependent manner, associated with elevated intraepidermal nerve fiber (IENF) intensity in mouse foot paw tissue, suggesting its functionality in reversing axon degeneration. Conclusions: The newly designed SARM1 inhibitor 331P1 is a promising candidate due to its excellent in vivo efficacy, favorable CYP inhibition properties, and attractive safety profiles. The 331P1 compound possesses the potential to be developed as a novel neuroprotective therapy that can prevent or halt the neurodegenerative process in CIPN. Full article

Although several methods are being applied to treat peripheral nerve injury, a perfect treatment that leads to full functional recovery has not yet been developed. SMAD (Suppressor of Mothers Against Decapentaplegic Homolog) plays a crucial role in nerve regeneration by facilitating the survival and growth of nerve cells following peripheral nerve injury. We conducted a systematic literature review on the role of SMAD in this context. Following peripheral nerve injury, there was an increase in the expression of SMAD1, -2, -4, -5, and -8, while SMAD5, -6, and -7 showed no significant changes; SMAD8 expression was decreased. Specifically, SMAD1 and SMAD4 were found to promote nerve regeneration, whereas SMAD2 and SMAD6 inhibited it. SMAD exerts its effects by promoting neuronal survival and growth through BMP/SMAD1, BMP/SMAD4, and BMP/SMAD7 signaling pathways. Furthermore, it activates nerve regeneration programs via the PI3K/GSK3/SMAD1 pathway, facilitating active regeneration of nerve cells and subsequent functional recovery after peripheral nerve damage. By leveraging these mechanisms of SMAD, novel strategies for treating peripheral nerve damage could potentially be developed. We aim to further elucidate the precise mechanisms of nerve regeneration mediated by SMAD and explore the potential for developing targeted nerve treatments based on these findings. Full article

5q-Spinal muscular atrophy (5q-SMA) is one of the most common neuromuscular diseases due to homozygous mutations in the SMN1 gene. This leads to a loss of function of the SMN1 gene, which in the end determines lower motor neuron degeneration. Since the generation of the first mouse models of SMA neuropathology, a complex degenerative involvement of the neuromuscular junction and peripheral axons of motor nerves, alongside lower motor neurons, has been described. The involvement of the neuromuscular junction in determining disease symptoms offers a possible parallel therapeutic target. This narrative review aims at providing an overview of the current knowledge about the pathogenesis and significance of neuromuscular junction dysfunction in SMA, circulating biomarkers, outcome measures and available or developing therapeutic approaches. Full article