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International Journal of Molecular... Nov 2020Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries... (Review)
Review
Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons. The axons emerge from the stump of the viable nerve attached to the neuronal soma. The SCs downregulate myelin-associated genes and concurrently, upregulate growth-associated genes that include neurotrophic factors as do the injured neurons. However, the gene expression is transient and progressively fails to support axon regeneration within the SC-containing endoneurial tubes. Moreover, despite some preference of regenerating motor and sensory axons to "find" their appropriate pathways, the axons fail to enter their original endoneurial tubes and to reinnervate original target organs, obstacles to functional recovery that confront nerve surgeons. Several surgical manipulations in clinical use, including nerve and tendon transfers, the potential for brief low-frequency electrical stimulation proximal to nerve repair, and local FK506 application to accelerate axon outgrowth, are encouraging as is the continuing research to elucidate the molecular basis of nerve regeneration.
Topics: Animals; Axons; Humans; Muscle, Skeletal; Nerve Regeneration; Neurogenesis; Peripheral Nerve Injuries; Peripheral Nerves; Recovery of Function; Schwann Cells; Tacrolimus
PubMed: 33212795
DOI: 10.3390/ijms21228652 -
BioMed Research International 2021Damage and regeneration naturally occur in the peripheral nervous system. The neurotropic B vitamins thiamine (B1), pyridoxine (B6), and cobalamin (B12) are key players,... (Review)
Review
Damage and regeneration naturally occur in the peripheral nervous system. The neurotropic B vitamins thiamine (B1), pyridoxine (B6), and cobalamin (B12) are key players, which maintain the neuronal viability in different ways. Firstly, they constantly protect nerves against damaging environmental influences. While vitamin B1 acts as a site-directed antioxidant, vitamin B6 balances nerve metabolism, and vitamin B12 maintains myelin sheaths. However, nerve injury occurs at times, because of an imbalance between protective factors and accumulating stress and noxae. This will result in the so-called Wallerian degeneration process. The presence of vitamins B1, B6, and B12 paves the way out to the following important regeneration by supporting the development of new cell structures. Furthermore, vitamin B1 facilitates the usage of carbohydrates for energy production, whereas vitamin B12 promotes nerve cell survival and remyelination. Absence of these vitamins will favor permanent nerve degeneration and pain, eventually leading to peripheral neuropathy.
Topics: Animals; Humans; Nerve Growth Factors; Nerve Regeneration; Vitamin B Complex
PubMed: 34337067
DOI: 10.1155/2021/9968228 -
Neurology India 2019Peripheral nerve injuries are a heterogeneous and distinct group of disorders that are secondary to various causes commonly including motor vehicle accidents, falls,... (Review)
Review
Peripheral nerve injuries are a heterogeneous and distinct group of disorders that are secondary to various causes commonly including motor vehicle accidents, falls, industrial accidents, household accidents, and penetrating trauma. The earliest classification of nerve injuries was given by Seddon and Sunderland, which holds true till date and is commonly used. Neuropraxia, axonotmesis, and neurotmesis are the three main types of nerve injuries. The electrophysiological studies including nerve conduction studies (NCS) and electromyography (EMG) play a key role and are now considered an extension of the clinical examination in patients with peripheral nerve injuries. The electrophysiological results should be interpreted in the light of clinical examination. These studies help in localizing the site of lesion, determine the type and severity of lesion, and help in prognosticating. In neuropraxia, the compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) are elicitable on stimulating the nerve distal to the site of the lesion but demonstrate conduction block on proximal stimulation. The electrodiagnostic findings in axonotmesis and neurotmesis are similar. After few days of injury, Wallerian degeneration sets in with failure to record CMAP and SNAP. Intraoperative technique involves recording from the peripheral nerves during the intraoperative period and has proved useful in the surgical management of nerve injuries and helps in identifying the injured nerve, to determine whether the nerve is in continuity and in localizing the site of lesion. Intraoperative monitoring also helps in identifying the nerve close to an ongoing surgery so that surgical damage to the nerve can be prevented.
Topics: Action Potentials; Electrodiagnosis; Electromyography; Humans; Intraoperative Neurophysiological Monitoring; Neural Conduction; Neurosurgical Procedures; Peripheral Nerve Injuries; Peripheral Nerves; Prognosis
PubMed: 31857526
DOI: 10.4103/0028-3886.273626 -
Frontiers in Immunology 2022Traumatic optic neuropathy (TON) refers to a pathological condition caused by a direct or indirect insult to the optic nerves, which often leads to a partial or... (Review)
Review
Traumatic optic neuropathy (TON) refers to a pathological condition caused by a direct or indirect insult to the optic nerves, which often leads to a partial or permanent vision deficit due to the massive loss of retinal ganglion cells (RGCs) and their axonal fibers. Retinal microglia are immune-competent cells residing in the retina. In rodent models of optic nerve crush (ONC) injury, resident retinal microglia gradually become activated, form end-to-end alignments in the vicinity of degenerating RGC axons, and actively internalized them. Some activated microglia adopt an amoeboid morphology that engulf dying RGCs after ONC. In the injured optic nerve, the activated microglia contribute to the myelin debris clearance at the lesion site. However, phagocytic capacity of resident retinal microglia is extremely poor and therefore the clearance of cellular and myelin debris is largely ineffective. The presence of growth-inhibitory myelin debris and glial scar formed by reactive astrocytes inhibit the regeneration of RGC axons, which accounts for the poor visual function recovery in patients with TON. In this Review, we summarize the current understanding of resident retinal microglia in RGC survival and axon regeneration after ONC. Resident retinal microglia play a key role in facilitating Wallerian degeneration and the subsequent axon regeneration after ONC. However, they are also responsible for producing pro-inflammatory cytokines, chemokines, and reactive oxygen species that possess neurotoxic effects on RGCs. Intraocular inflammation triggers a massive influx of blood-borne myeloid cells which produce oncomodulin to promote RGC survival and axon regeneration. However, intraocular inflammation induces chronic neuroinflammation which exacerbates secondary tissue damages and limits visual function recovery after ONC. Activated retinal microglia is required for the proliferation of oligodendrocyte precursor cells (OPCs); however, sustained activation of retinal microglia suppress the differentiation of OPCs into mature oligodendrocytes for remyelination after injury. Collectively, controlled activation of retinal microglia and infiltrating myeloid cells facilitate axon regeneration and nerve repair. Recent advance in single-cell RNA-sequencing and identification of microglia-specific markers could improve our understanding on microglial biology and to facilitate the development of novel therapeutic strategies aiming to switch resident retinal microglia's phenotype to foster neuroprotection.
Topics: Axons; Humans; Microglia; Nerve Regeneration; Neuroinflammatory Diseases; Optic Nerve Injuries; Retinal Ganglion Cells
PubMed: 35309305
DOI: 10.3389/fimmu.2022.860070 -
Frontiers in Cellular Neuroscience 2019Traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality amongst civilians and military personnel globally. Despite advances in our... (Review)
Review
Traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality amongst civilians and military personnel globally. Despite advances in our knowledge of the complex pathophysiology of TBI, the underlying mechanisms are yet to be fully elucidated. While initial brain insult involves acute and irreversible primary damage to the parenchyma, the ensuing secondary brain injuries often progress slowly over months to years, hence providing a window for therapeutic interventions. To date, hallmark events during delayed secondary CNS damage include Wallerian degeneration of axons, mitochondrial dysfunction, excitotoxicity, oxidative stress and apoptotic cell death of neurons and glia. Extensive research has been directed to the identification of druggable targets associated with these processes. Furthermore, tremendous effort has been put forth to improve the bioavailability of therapeutics to CNS by devising strategies for efficient, specific and controlled delivery of bioactive agents to cellular targets. Here, we give an overview of the pathophysiology of TBI and the underlying molecular mechanisms, followed by an update on novel therapeutic targets and agents. Recent development of various approaches of drug delivery to the CNS is also discussed.
PubMed: 31827423
DOI: 10.3389/fncel.2019.00528 -
Seminars in Interventional Radiology Apr 2022Chest wall pain affects many patients following chest surgery, fractures, or malignancies, and can be very difficult to manage with normal pharmacologic agents.... (Review)
Review
Chest wall pain affects many patients following chest surgery, fractures, or malignancies, and can be very difficult to manage with normal pharmacologic agents. Intercostal ablation provides one alternative treatment modality for patients suffering from intercostal pain. Intercostal cryoneurolysis involves using extreme cold to cause Wallerian degeneration of the targeted intercostal nerve. This article reviews the patient selection, technique, and complications in the utilization of intercostal neurolysis in the treatment of intractable chest pain.
PubMed: 35781990
DOI: 10.1055/s-0042-1745763 -
The Journal of Clinical Investigation Nov 2021Peripheral nerves have the capacity for regeneration, but the rate of regeneration is so slow that many nerve injuries lead to incomplete recovery and permanent...
Peripheral nerves have the capacity for regeneration, but the rate of regeneration is so slow that many nerve injuries lead to incomplete recovery and permanent disability for patients. Macrophages play a critical role in the peripheral nerve response to injury, contributing to both Wallerian degeneration and nerve regeneration, and their function has recently been shown to be dependent on intracellular metabolism. To date, the impact of their intracellular metabolism on peripheral nerve regeneration has not been studied. We examined conditional transgenic mice with selective ablation in macrophages of solute carrier family 16, member 1 (Slc16a1), which encodes monocarboxylate transporter 1 (MCT1), and found that MCT1 contributed to macrophage metabolism, phenotype, and function, specifically in regard to phagocytosis and peripheral nerve regeneration. Adoptive cell transfer of wild-type macrophages ameliorated the impaired nerve regeneration in macrophage-selective MCT1-null mice. We also developed a mouse model that overexpressed MCT1 in macrophages and found that peripheral nerves in these mice regenerated more rapidly than in control mice. Our study provides further evidence that MCT1 has an important biological role in macrophages and that manipulations of macrophage metabolism can enhance recovery from peripheral nerve injuries, for which there are currently no approved medical therapies.
Topics: Animals; Female; Macrophages; Male; Mice; Mice, Transgenic; Monocarboxylic Acid Transporters; Nerve Regeneration; Peripheral Nerve Injuries; Sciatic Nerve; Symporters
PubMed: 34491913
DOI: 10.1172/JCI141964 -
Theranostics 2021Axonal degeneration is a common pathological feature in many acute and chronic neurological diseases such as spinal cord injury (SCI). SARM1 (sterile alpha and TIR...
Axonal degeneration is a common pathological feature in many acute and chronic neurological diseases such as spinal cord injury (SCI). SARM1 (sterile alpha and TIR motif-containing 1), the fifth TLR (Toll-like receptor) adaptor, has diverse functions in the immune and nervous systems, and recently has been identified as a key mediator of Wallerian degeneration (WD). However, the detailed functions of SARM1 after SCI still remain unclear. Modified Allen's method was used to establish a contusion model of SCI in mice. Furthermore, to address the function of SARM1 after SCI, conditional knockout (CKO) mice in the central nervous system (CNS), SARM1-CKO mice, and SARM1-CKO mice were successfully generated by Nestin-Cre and GFAP-Cre transgenic mice crossed with SARM1 mice, respectively. Immunostaining, Hematoxylin-Eosin (HE) staining, Nissl staining and behavioral test assays such as footprint and Basso Mouse Scale (BMS) scoring were used to examine the roles of SARM1 pathway in SCI based on these conditional knockout mice. Drugs such as FK866, an inhibitor of SARM1, and apoptozole, an inhibitor of heat shock protein 70 (HSP70), were used to further explore the molecular mechanism of SARM1 in neural regeneration after SCI. We found that SARM1 was upregulated in neurons and astrocytes at early stage after SCI. SARM1-CKO and SARM1-CKO mice displayed normal development of the spinal cords and motor function. Interestingly, conditional deletion of SARM1 in neurons and astrocytes promoted the functional recovery of behavior performance after SCI. Mechanistically, conditional deletion of SARM1 in neurons and astrocytes promoted neuronal regeneration at intermediate phase after SCI, and reduced neuroinflammation at SCI early phase through downregulation of NF-κB signaling after SCI, which may be due to upregulation of HSP70. Finally, FK866, an inhibitor of SARM1, reduced the neuroinflammation and promoted the neuronal regeneration after SCI. Our results indicate that SARM1-mediated prodegenerative pathway and neuroinflammation promotes the pathological progress of SCI and anti-SARM1 therapeutics are viable and promising approaches for preserving neuronal function after SCI.
Topics: Animals; Armadillo Domain Proteins; Astrocytes; Axons; Cytoskeletal Proteins; Down-Regulation; Inflammation; Male; Mice; Mice, Knockout; NF-kappa B; Nerve Regeneration; Neurons; Recovery of Function; Signal Transduction; Spinal Cord; Spinal Cord Injuries; Up-Regulation
PubMed: 33754056
DOI: 10.7150/thno.49054 -
Brain : a Journal of Neurology Nov 2021Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central...
Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by sterile alpha and TIR motif containing 1 (SARM1) is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved programme of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders. Using a biochemical assay for SARM1 NADase we identified a novel series of potent and selective irreversible isothiazole inhibitors of SARM1 enzymatic activity that protected rodent and human axons in vitro. In sciatic nerve axotomy, we observed that these irreversible SARM1 inhibitors decreased a rise in nerve cADPR and plasma neurofilament light chain released from injured sciatic nerves in vivo. In a mouse paclitaxel model of CIPN we determined that Sarm1 knockout mice prevented loss of axonal function, assessed by sensory nerve action potential amplitudes of the tail nerve, in a gene-dosage-dependent manner. In that CIPN model, the irreversible SARM1 inhibitors prevented loss of intraepidermal nerve fibres induced by paclitaxel and provided partial protection of axonal function assessed by sensory nerve action potential amplitude and mechanical allodynia.
Topics: Animals; Antineoplastic Agents, Phytogenic; Armadillo Domain Proteins; Axons; Cells, Cultured; Cytoskeletal Proteins; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Induced Pluripotent Stem Cells; Mice; Mice, Knockout; Paclitaxel; Peripheral Nervous System Diseases; Thiazoles
PubMed: 33964142
DOI: 10.1093/brain/awab184