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Neuron Sep 2023Diabetes prevalence continues to climb with the aging population. Type 2 diabetes (T2D), which constitutes most cases, is metabolically acquired. Diabetic peripheral... (Review)
Review
Diabetes prevalence continues to climb with the aging population. Type 2 diabetes (T2D), which constitutes most cases, is metabolically acquired. Diabetic peripheral neuropathy (DPN), the most common microvascular complication, is length-dependent damage to peripheral nerves. DPN pathogenesis is complex, but, at its core, it can be viewed as a state of impaired metabolism and bioenergetics failure operating against the backdrop of long peripheral nerve axons supported by glia. This unique peripheral nerve anatomy and the injury consequent to T2D underpins the distal-to-proximal symptomatology of DPN. Earlier work focused on the impact of hyperglycemia on nerve damage and bioenergetics failure, but recent evidence additionally implicates contributions from obesity and dyslipidemia. This review will cover peripheral nerve anatomy, bioenergetics, and glia-axon interactions, building the framework for understanding how hyperglycemia and dyslipidemia induce bioenergetics failure in DPN. DPN and painful DPN still lack disease-modifying therapies, and research on novel mechanism-based approaches is also covered.
Topics: Humans; Aged; Diabetic Neuropathies; Diabetes Mellitus, Type 2; Peripheral Nerves; Hyperglycemia; Dyslipidemias
PubMed: 37263266
DOI: 10.1016/j.neuron.2023.05.003 -
Cell Metabolism Dec 2023The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on...
The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.
Topics: Peripheral Nerves; Myelin Sheath; Neuroglia; Schwann Cells; Nerve Regeneration
PubMed: 37989315
DOI: 10.1016/j.cmet.2023.10.017 -
Journal of the Peripheral Nervous... Jul 2023Autoimmune neuropathies are classified, on the basis of pathophysiology, as demyelinating or axonal. The term nodo-paranodopathy, introduced in 2013 to better categorize... (Review)
Review
BACKGROUND AND AIMS
Autoimmune neuropathies are classified, on the basis of pathophysiology, as demyelinating or axonal. The term nodo-paranodopathy, introduced in 2013 to better categorize the neuropathies with antiganglioside antibodies and later expanded to include neuropathies with antibodies to nodal and paranodal axoglial complexes, characterizes disorders in which the nodal region is critical in the pathogenesis. These neuropathies, although presenting electrophysiologic demyelinating features do not show pathologic evidence of segmental demyelination, or, although being classified as axonal, can show reversible nerve conduction failure and rapid recovery contrary with the communal concept of an axonal neuropathy.
METHODS
In this personal view is reported, with a splitting approach, an update on autoimmune nodo-paranodopathies, classified according to the domains of peripheral nerve fiber, the target antigens and the antibody class and subclass involved. The clinical features, the electrophysiologic findings, the results of the immunopathological and ultrastructural studies, the pathophysiology and treatment are also described.
RESULTS AND INTERPRETATION
The nodo-paranodopathy category integrates the clinical classification of autoimmune neuropathies and expands the traditional dichotomous demyelinating and axonal classification. It helps to a better systematization pointing to the domain and target antigens of the autoimmune process, it resolves conflicting pathologic and electrophysiologic findings, reconciles the contradiction that axonal neuropathies may be rapidly reversible, avoids taxonomical confusion and possible misdiagnoses. Finally this categorization, through the identification of the specific antibody and its prevalent class and subclass, clarifies the pathophysiological mechanisms and addresses to a more targeted therapeutic approach.
Topics: Humans; Peripheral Nervous System Diseases; Peripheral Nerves; Axons; Neural Conduction; Autoantibodies
PubMed: 37272673
DOI: 10.1111/jns.12569 -
ELife Aug 2023A key limiting factor of successful axon regeneration is the intrinsic regenerative ability in both the peripheral nervous system (PNS) and central nervous system (CNS)....
A key limiting factor of successful axon regeneration is the intrinsic regenerative ability in both the peripheral nervous system (PNS) and central nervous system (CNS). Previous studies have identified intrinsic regenerative ability regulators that act on gene expression in injured neurons. However, it is less known whether RNA modifications play a role in this process. Here, we systematically screened the functions of all common mA modification-related enzymes in axon regeneration and report ALKBH5, an evolutionarily conserved RNA mA demethylase, as a regulator of axonal regeneration in rodents. In PNS, knockdown of ALKBH5 enhanced sensory axonal regeneration, whereas overexpressing ALKBH5 impaired axonal regeneration in an mA-dependent manner. Mechanistically, ALKBH5 increased the stability of mRNA and thus limited regenerative growth associated lipid metabolism in dorsal root ganglion neurons. Moreover, in CNS, knockdown of ALKBH5 enhanced the survival and axonal regeneration of retinal ganglion cells after optic nerve injury. Together, our results suggest a novel mechanism regulating axon regeneration and point ALKBH5 as a potential target for promoting axon regeneration in both PNS and CNS.
Topics: Axons; Nerve Regeneration; AlkB Homolog 5, RNA Demethylase; Ganglia, Spinal; Retinal Ganglion Cells; RNA
PubMed: 37535403
DOI: 10.7554/eLife.85309 -
Handbook of Clinical Neurology 2024Median mononeuropathy is common, with carpal tunnel syndrome the most frequently encountered acquired mononeuropathy in clinical practice. However, other disorders of... (Review)
Review
Median mononeuropathy is common, with carpal tunnel syndrome the most frequently encountered acquired mononeuropathy in clinical practice. However, other disorders of the median nerve and many known anatomical variants can lead to misdiagnosis and unexpected surgical complications if their presence is not correctly identified. A number of inherited and acquired disorders can affect the median nerve proximal to the wrist, alone or accompanied by other affected peripheral nerves. Recognizing other disorders that can masquerade as median mononeuropathies can avoid misdiagnosis and misguided management. This chapter explores median nerve anatomical variants, disorders, and lesions, emphasizing the need for careful examination and electrodiagnostic study in the localization of median neuropathy.
Topics: Humans; Median Neuropathy; Median Nerve; Electrodiagnosis; Carpal Tunnel Syndrome
PubMed: 38697748
DOI: 10.1016/B978-0-323-90108-6.00011-9 -
Anesthesiology Clinics Jun 2024Continuous peripheral nerve block catheters are simple in concept: percutaneously inserting a catheter adjacent to a peripheral nerve. This procedure is followed by...
Continuous peripheral nerve block catheters are simple in concept: percutaneously inserting a catheter adjacent to a peripheral nerve. This procedure is followed by local anesthetic infusion via the catheter that can be titrated to effect for extended anesthesia or analgesia in the perioperative period. The reported benefits of peripheral nerve catheters used in the surgical population include improved pain scores, decreased narcotic use, decreased nausea/vomiting, decreased pruritus, decreased sedation, improved sleep, and improved patient satisfaction.
Topics: Humans; Anesthetics, Local; Catheterization; Catheters; Nerve Block; Peripheral Nerves
PubMed: 38705679
DOI: 10.1016/j.anclin.2023.11.012 -
Handbook of Clinical Neurology 2024Peripheral nerves are functional networks in the body. Disruption of these networks induces varied functional consequences depending on the types of nerves and organs...
Peripheral nerves are functional networks in the body. Disruption of these networks induces varied functional consequences depending on the types of nerves and organs affected. Despite the advances in microsurgical repair and understanding of nerve regeneration biology, restoring full functions after severe traumatic nerve injuries is still far from achieved. While a blunted growth response from axons and errors in axon guidance due to physical barriers may surface as the major hurdles in repairing nerves, critical additional cellular and molecular aspects challenge the orderly healing of injured nerves. Understanding the systematic reprogramming of injured nerves at the cellular and molecular levels, referred to here as "hallmarks of nerve injury regeneration," will offer better ideas. This chapter discusses the hallmarks of nerve injury and regeneration and critical points of failures in the natural healing process. Potential pharmacological and nonpharmacological intervention points for repairing nerves are also discussed.
Topics: Animals; Humans; Axons; Nerve Regeneration; Peripheral Nerve Injuries; Peripheral Nerves
PubMed: 38697733
DOI: 10.1016/B978-0-323-90108-6.00014-4 -
Hand Clinics Aug 2023Peripheral nerve injuries may substantially impair a patient's function and quality of life. Despite appropriate treatment, outcomes often remain poor. Direct repair... (Review)
Review
Peripheral nerve injuries may substantially impair a patient's function and quality of life. Despite appropriate treatment, outcomes often remain poor. Direct repair remains the standard of care when repair is possible without excessive tension. For larger nerve defects, nerve autografting is the gold standard. However, a considerable challenge is donor site morbidity. Processed nerve allografts and conduits are other options, but evidence supporting their use is limited to smaller nerves and shorter gaps. Nerve transfer is another technique that has seen increasing popularity. The future of care may include novel biologics and pharmacologic therapy to enhance regeneration.
Topics: Humans; Peripheral Nerves; Quality of Life; Peripheral Nerve Injuries; Plastic Surgery Procedures; Transplantation, Autologous; Nerve Regeneration
PubMed: 37453767
DOI: 10.1016/j.hcl.2023.05.001 -
Annals of Plastic Surgery Aug 2023Peripheral nerve injury is a common injury disease. Understanding of the mechanisms of periphery nerve repair and regeneration after injury is an essential prerequisite...
Peripheral nerve injury is a common injury disease. Understanding of the mechanisms of periphery nerve repair and regeneration after injury is an essential prerequisite for treating related diseases. Although the biological mechanisms of peripheral nerve injury and regeneration have been studied comprehensively, the clinical treatment methods are still limited. The bottlenecks of the treatments are the shortage of donor nerves and the limited surgical precision. Apart from the knowledge regarding the fundamental characteristics and physical processes of peripheral nerve injury, numerous studies have found that Schwann cells, growth factors, and extracellular matrix are main factors affecting the repair and regeneration process of injured nerves. At present, the therapeutical methods of the disease include microsurgery, autologous nerve transplantation, allograft nerve transplantation and tissue engineering technology. Tissue engineering technology, which combines seed cells, neurotrophic factors, and scaffold materials together, is promising for treating the patients with long-gapped and large nerve damage. With the development of neuron science and technology, the treatment of peripheral nerve injury diseases will continue being improved.
Topics: Humans; Peripheral Nerve Injuries; Schwann Cells; Tissue Engineering; Nerve Growth Factors; Transplantation, Autologous; Nerve Regeneration; Peripheral Nerves
PubMed: 36880740
DOI: 10.1097/SAP.0000000000003480 -
Handbook of Clinical Neurology 2024Peripheral neuropathy is a common referral for patients to the neurologic clinics. Paraneoplastic neuropathies account for a small but high morbidity and mortality... (Review)
Review
Peripheral neuropathy is a common referral for patients to the neurologic clinics. Paraneoplastic neuropathies account for a small but high morbidity and mortality subgroup. Symptoms include weakness, sensory loss, sweating irregularity, blood pressure instability, severe constipation, and neuropathic pain. Neuropathy is the first presenting symptom of malignancy among many patients. The molecular and cellular oncogenic immune targets reside within cell bodies, axons, cytoplasms, or surface membranes of neural tissues. A more favorable immune treatment outcome occurs in those where the targets reside on the cell surface. Patients with antibodies binding cell surface antigens commonly have neural hyperexcitability with pain, cramps, fasciculations, and hyperhidrotic attacks (CASPR2, LGI1, and others). The antigenic targets are also commonly expressed in the central nervous system, with presenting symptoms being myelopathy, encephalopathy, and seizures with neuropathy, often masked. Pain and autonomic components typically relate to small nerve fiber involvement (nociceptive, adrenergic, enteric, and sudomotor), sometimes without nerve fiber loss but rather hyperexcitability. The specific antibodies discovered help direct cancer investigations. Among the primary axonal paraneoplastic neuropathies, pathognomonic clinical features do not exist, and testing for multiple antibodies simultaneously provides the best sensitivity in testing (AGNA1-SOX1; amphiphysin; ANNA-1-HU; ANNA-3-DACH1; CASPR2; CRMP5; LGI1; PCA2-MAP1B, and others). Performing confirmatory antibody testing using adjunct methods improves specificity. Antibody-mediated demyelinating paraneoplastic neuropathies are limited to MAG-IgM (IgM-MGUS, Waldenström's, and myeloma), with the others associated with cytokine elevations (VEGF, IL6) caused by osteosclerotic myeloma, plasmacytoma (POEMS), and rarely angiofollicular lymphoma (Castleman's). Paraneoplastic disorders have clinical overlap with other idiopathic antibody disorders, including IgG4 demyelinating nodopathies (NF155 and Contactin-1). This review summarizes the paraneoplastic neuropathies, including those with peripheral nerve hyperexcitability.
Topics: Humans; Paraneoplastic Polyneuropathy; Multiple Myeloma; Peripheral Nervous System Diseases; Isaacs Syndrome; Autoantibodies; Peripheral Nerves; Immunoglobulin M; Pain
PubMed: 38494281
DOI: 10.1016/B978-0-12-823912-4.00020-7