Materiały źródłowe

• #1 Neuropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK542220/

  Peripheral neuropathies encompass disorders of peripheral nerve cells and fibers, manifesting secondary to a wide range of pathologies. These include cranial nerves, spinal nerve roots and ganglia, nerve trunks and division, and autonomic nervous system nerves. […] Several methods classify peripheral neuropathies, including mononeuropathies, multifocal neuropathies, and polyneuropathies. Further subclassifications can be made by separating peripheral neuropathies as axonal, demyelinating, or mixed, essential for treatment and management. […] The exact pathophysiology of peripheral neuropathy depends on the underlying disease. Although a wide assortment of distinct diseases can ultimately lead to peripheral neuropathies, the mechanisms by which peripheral nerves suffer injury exhibit similar patterns.

• #2 Peripheral neuropathy – Wikipedia

  https://en.wikipedia.org/wiki/Peripheral_neuropathy

  Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropathies affecting motor, sensory, or autonomic nerve fibers result in different symptoms. More than one type of fiber may be affected simultaneously. Peripheral neuropathy may be acute (with sudden onset, rapid progress) or chronic (symptoms begin subtly and progress slowly), and may be reversible or permanent. […] Common causes include systemic diseases (such as diabetes or leprosy), hyperglycemia-induced glycation, vitamin deficiency, medication (e.g., chemotherapy, or commonly prescribed antibiotics including metronidazole and the fluoroquinolone class of antibiotics (such as ciprofloxacin, levofloxacin, moxifloxacin)), traumatic injury, ischemia, radiation therapy, excessive alcohol consumption, immune system disease, celiac disease, non-celiac gluten sensitivity, or viral infection. It can also be genetic (present from birth) or idiopathic (no known cause).

• #3 Peripheral neuropathy pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Peripheral_neuropathy_pathophysiology

  The pathophysiologic processes that can adversely affect peripheral nerves is very extensive. […] Processes which can damage the peripheral nerves at multiple levels via many molecular pathways include: Immunologic, metabolic, genetic, infectious, toxic and traumatic processes. […] Any pathologic process affecting the cell body will result in downstream degeneration of the cell’s axon. Primary motor neuron diseases, such as ALS or SMA, demonstrate axonal pathology peripherally when central neurons degenerate. Similarly, metabolic conditions, such as diabetes, the metabolic syndrome, nutritional deficiencies, or chronic renal failure, affect DRG cell bodies by mechanisms involving insulin resistance, oxidative stress, and apoptosis. Pathologic damage may also be considered to take place directly at the axon, independent of the cell body.

• #4 Neuropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK542220/

  Segmental demyelination refers to the degeneration of the myelin sheath, with sparing of the nerve axon. This type of reaction can present in mononeuropathies, sensorimotor, or, principally, motor neuropathies. These are often inflammatory and sometimes immune-mediated. About 20% of symmetrical peripheral neuropathies result from damage to the myelin. […] Wallerian degeneration occurs after a nerve axon degenerates due to a lesion or physical compression; the portion distal to the axon passively wastes away, likely due to a lack of nutrients from the cell body. […] Axonal degeneration, also known as the dying-back phenomenon: This type of degeneration usually manifests as symmetrical polyneuropathy (around 80%) and tends to cause weakness, most notably weakness in dorsiflexion of the ankles and foot, with accompanied trophic changes to muscle. The axon degenerates in a pattern that starts distal and progresses proximally; this is thought to be because the most distal portion of the axon is particularly vulnerable due to its distance from the cell body, which provides metabolic support. A proposed mechanism is that insult to the nerve causes impaired delivery of local axonal survival factors, resulting in an increased level of calcium intra-axonal, leading to a calcium-dependent cytoskeletal breakdown.

• #5 Peripheral Neuropathy

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/peripheral-neuropathy/

  Despite the diverse array of medical disorders that cause peripheral neuropathies, peripheral nerves exhibit only a few distinct pathologic reactions to an insult or disease: wallerian degeneration, axonal degeneration, and segmental demyelination. The specific mechanisms by which the various disorders affecting peripheral nerves induce these pathologic changes are largely unknown. […] In wallerian degeneration, the axon degenerates distal to a focal lesion that interrupts the continuity of the axon. This reaction often occurs in focal mononeuropathies that result from trauma or nerve infarction. […] Axonal degeneration, sometimes referred to as the dying-back phenomenon, results in axonal degeneration at the most distal extent of the axon. Axonal degenerative polyneuropathies are usually symmetrical, and as the disorder progresses, the axons typically degenerate in a distal-to-proximal gradient. Axonal degeneration is the most common type of pathologic reaction in generalized polyneuropathies, and it is often attributed to a metabolic cause.

• #6 Peripheral Neuropathy

  https://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/peripheral-neuropathy/

  Segmental demyelination refers to focal degeneration of the myelin sheath with sparing of the axon. This reaction can be seen in focal mononeuropathies and in generalized sensorimotor or predominantly motor neuropathies. Acquired segmental demyelinating polyneuropathies are often immune-mediated or inflammatory in origin. However, segmental demyelination can also occur in some hereditary polyneuropathies. […] In peripheral nerve disorders that are characterized by either wallerian degeneration or axonal degeneration, prognosis is less favorable because the axon must regenerate and reinnervate muscle, the sensory organ, blood vessels, and other structures before clinical recovery is noted. Recovery may be more rapid with segmental demyelination because remyelination is accomplished more quickly, thereby re-establishing normal conductivity of the axon and return of function.

• #7 Neuropathy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK542220/

  In those diseases where peripheral nerves suffer damage through Wallerian or axonal degeneration, the prognosis is poorer, as the recovery of the nerve is more challenging. The axon must regenerate itself and reinnervate the affected muscle or organ for clinical improvement. The prognosis of diseases that occur secondary to segmental demyelination is more favorable because remyelination is achieved more quickly, allowing the return of function of the axon.

• #8 Mechanisms of Chemotherapy-Induced Peripheral Neuropathy

  https://www.mdpi.com/1422-0067/20/6/1451

  Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. […] The pathomechanism by which chemotherapeutics damage the nervous system structures and cause CIPN is multifactorial and involves microtubule disruption, oxidative stress and mitochondrial damage, altered ion channel activity, myelin sheath damage, DNA damage, immunological processes and neuroinflammation. […] The exact mechanism of peripheral neuropathy induced by platinum-based chemotherapeutics is not yet fully understood; however, it seems that their antitumor mechanisms are responsible for the neurotoxic effect, since chemotherapeutics induce numerous changes either in the structure or functioning of neuronal and glial cells.

• #9 Mechanisms of Chemotherapy-Induced Peripheral Neuropathy

  https://www.mdpi.com/1422-0067/20/6/1451

  Mitochondrial dysfunction and oxidative stress have been highlighted as key players in the pathophysiology of platinum-induced neuropathy. […] Impairment in the physiological function of mitochondria may influence calcium signaling pathways and promote further pathological functional and structural changes in neuronal and glial cells. […] Disturbances in the neuronal and glial functioning (membrane excitability and release of neurotransmitters), resulting clinically in the development of peripheral neuropathy, may be partially induced by the altered action of sodium channels (NaV), potassium channels (KV) and transient receptor potential (TRP) channels. […] Recent studies indicate that glial cells may also contribute to peripheral neuropathy induced by platinum-based agents in animal models; however, it is not clear whether this mechanism may also be involved in chemotherapy-induced neuropathy in cancer patients.

• #10 Mechanisms of Chemotherapy-Induced Peripheral Neuropathy

  https://www.mdpi.com/1422-0067/20/6/1451

  The results from studies in human neuropathic pain and experimental animal models clearly show that the activation of glial cells and the subsequent release and elevation of pro-inflammatory cytokines (PIC): The IL-1b, IL-6 and TNF-a levels are common mechanisms of neuropathic pain induced by chemotherapeutics. […] The dysregulation of Ca2+ hemostasis has been shown to play a role in the pathogenesis of CIPN. […] The activation of microglia and astrocytes by taxanes also leads to the activation of attraction and activation of immune cells and to the release and elevation of pro-inflammatory cytokines (interleukins and chemokines), which results in the nociceptor sensitization and the development of neuroinflammation.

• #11 Peripheral Neuropathy in Diabetes Mellitus: Pathogenetic Mechanisms and Diagnostic Options

  https://www.mdpi.com/1422-0067/24/4/3554

  Diabetic neuropathy (DN) is one of the main microvascular complications of both type 1 and type 2 diabetes mellitus. […] The pathophysiological aspects underlying the onset and progression of DN are not entirely clear. […] The pathophysiology is characterized by predominantly metabolic/inflammatory damage that affects the peripheral nerves responsible for conducting the motor and sensory impulse. […] This microvascular complication is defined as “length-dependent” neuropathy since it affects the longest nerve fibers more frequently. […] The pathophysiological mechanisms through which diabetes causes neuropathic damage are many and involve various metabolic and intracellular signaling processes, still today not fully understood. […] Axonal degeneration, with both primary and secondary demyelination, has been documented in nerve biopsies from both animal models and individuals with diabetic polyneuropathy.

• #12 Peripheral Neuropathy in Diabetes Mellitus: Pathogenetic Mechanisms and Diagnostic Options

  https://www.mdpi.com/1422-0067/24/4/3554

  In particular, impairment of the myelin sheath and Schwann cells has been shown. […] Consequently, axonal impulse conduction and signaling are disrupted, together with a reduction of neurotrophic factors, thus resulting in centripetal degeneration and distal axonal loss that progresses length-dependently. […] Among the postulated mechanisms, an inflammatory process seems to induce nerve damage through metabolic and cellular pathways. […] The increased permeability of the damaged barrier facilitates the passage of high-molecular-weight proteins, such as albumin and immunoglobulin G (IgG), into the endoneurium. […] The hyperglycemia-induced flux, through the polyol pathway, promotes disrupted membrane permeability. […] The persistence of diabetes for 6 months in diabetic mouse models with active COX-2 gene resulted in increased oxidative and inflammatory stress, reduction of nerve conduction velocities, and intraepidermal fiber density, compared to mice with inactive COX-2 gene.

• #13 Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy | Nature Reviews Endocrinology

  https://www.nature.com/articles/s41574-021-00496-z

  Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). […] Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. […] The mechanisms of DSPN are not fully understood but involve downstream injurious pathways associated with hyperglycaemia, dyslipidaemia and microvascular disease leading to neuronal inflammation, oxidative stress, mitochondrial dysfunction and cell death. […] New compounds for the treatment of painful DSPN are being developed and the concept of stratifying patients according to various pain characteristics to improve analgesic response is being explored. […] Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.

• #14 The primary biochemical mechanisms of Diabetic Peripheral Neuropathy (DPN)

  https://www.pulsus.com/scholarly-articles/the-primary-biochemical-mechanisms-of-diabetic-peripheral-neuropathy-dpn-3753.html

  In general, the activation of polyol pathway is the reduction of glucose to sorbitol. […] Under hyperglycemia state, excessive glucose in cells is metabolized through the polyol pathway, which may induce the increased concentrations of sorbitol and fructose and decreased expression and uptake of inositol. As a result, the activity of Na+/K+-ATPase decreases and nerve conduction velocity slows down. Finally, peripheral nerve is damaged. […] Advanced Glycation End-Products (AGEs) are a binding product of excessive glucose and protein. […] Current researches show that AGEs can accelerate the aging of human body and induce a lot of chronic degenerative diseases by attacking the tissue cells. There are three mechanisms through which AGEs damage the cells. The first is to promote cell apoptosis by modifying the biochemical function of intracellular proteins. […] The combination of AGE and RAGE will increase the production of ROS and the activation of NF-B, resulting in multiple changes in gene expression and inducing the enhancement of endothelial permeability, proliferation of smooth muscle cells and fibroblasts, and degradation of extracellular matrix.

• #15 The primary biochemical mechanisms of Diabetic Peripheral Neuropathy (DPN)

  https://www.pulsus.com/scholarly-articles/the-primary-biochemical-mechanisms-of-diabetic-peripheral-neuropathy-dpn-3753.html

  The PKC family consists of many enzymes that can phosphorylate target proteins, and the activities of most members are determined by Ca2+, serine phosphate and diacylglycerol. […] The long-term hyperglycemia may increase the levels of diacylglycerol and activate the PKC pathway, and then induce inflammation and lead to the development of DPN. […] Polymerase (PARP) is a common nuclear DNA repair enzyme that generates protein-binding ADP-Ribose by splicing NAD+. […] The activity enhancement of PARP will excessively consume NAD+, which causes energy insufficiency and induces oxidative stress. […] The hexosamine pathway is also a pathway for glucose metabolism. […] Increased protein modification caused by O-glucosamine transferase may induce diabetic vascular complications via inhibiting transcription factor Sp1.

• #16 Metabolic Neuropathy: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1171051-overview

  Sural nerve biopsies from patients with diabetes have demonstrated changes suggestive of microvascular insufficiency, including membrane basement thickening, endothelial cell proliferation, and vessel occlusions. […] Ischemia from vascular disease induces oxidative stress and injury to nerves via an increase in the production of reactive oxygen species. Some studies have suggested that antioxidant therapy may improve NCVs in diabetic neuropathy. These findings suggest that the metabolic and vascular hypotheses may be linked mechanistically. […] Another mechanism in diabetic neuropathy is impaired neurotrophic support. Nerve growth factor (NGF) and other growth factors, such as neurotrophin-3 (NT-3), insulin-like growth factor-I (IGF-I), and IGF-II, may be decreased in tissues affected by diabetic neuropathy. Other factors such as abnormalities in vasoactive substances and nonenzymatic glycation have demonstrated possible involvement in diabetic neuropathy development.

• #17

  https://journals.lww.com/md-journal/fulltext/2023/01060/mechanism_of_schwann_cells_in_diabetic_peripheral.30.aspx

  Diabetic peripheral neuropathy (DPN) is the most common neuropathy in the world, mainly manifested as bilateral symmetry numbness, pain or paresthesia, with a high rate of disability and mortality. Schwann cells (SCs), derived from neural ridge cells, are the largest number of glial cells in the peripheral nervous system, and play an important role in DPN. Studies have found that SCs are closely related to the pathogenesis of DPN, such as oxidative stress, endoplasmic reticulum stress, inflammation, impaired neurotrophic support and dyslipidemia. This article reviews the mechanism of SCs in DPN. […] Schwann cells (SCs) are the most abundant cells in peripheral nerve tissue and play an important role in the pathogenesis of DPN. […] Recent studies have found that SCs are involved in multiple pathways of DPN development. During DPN, some key signaling pathways in SCs are activated, such as high polyalcohol pathway flux driven by hyperglycemia, oxidative stress, mitochondrial dysfunction, dyslipidemia, and inflammation. Activation of these pathways and subsequent transcriptional changes lead to sustained increases in glycolysis, reactive oxygen species (ROS) formation, cellular nicotinamide adenine dinucleotide consumption, and deoxyribonucleic acid (DNA) methylation alterations that induce diabetic neuropathy, ultimately leading to myelin destruction, demyelination, axonal conduction abnormalities, and impaired neuronal regeneration.

• #18

  https://journals.lww.com/md-journal/fulltext/2023/01060/mechanism_of_schwann_cells_in_diabetic_peripheral.30.aspx

  The injury of SCs is an important factor in the development of DPN, and taking SCs as a research target can provide a new idea for the treatment of DPN. […] Oxidative stress is caused by an imbalance between the production of ROS and the antioxidant system. In the state of diabetes, hyperglycemia stimulates SCs mitochondria to produce a large number of ROS, resulting in mitochondrial DNA damage and mitochondrial gene mutation, eventually leading to the death of SCs and axonal degeneration. […] SCs must produce abundant myelin proteins through the ER to assemble and maintain the myelin structure. ERS impairs the synthesis of SCs myelin, and actively myelinated SCs are more susceptible to ERS than mature SCs. […] SCs are closely related to the inflammatory reaction. Under the condition of high GLU, the levels of tumor necrosis factor- (TNF-), interleukin (IL)-6, IL-1, nuclear factor-B (NF-B) and Toll-like receptors in SCs were significantly increased.

• #19 Pathophysiology and Therapeutic Perspectives for Chemotherapy-induced Peripheral Neuropathy | Anticancer Research

  https://ar.iiarjournals.org/content/42/10/4667

  Chemotherapy-induced peripheral neuropathy (CIPN) develops as a challenging nerve-damaging adverse effect of anticancer drugs used in chemotherapy. […] The pathophysiology of CIPN is very complex and relies on several processes depending on the type of chemotherapy used, although the underlying molecular mechanisms are still unknown. […] Many chemotherapy agents are associated with indirect or direct neurotoxicity and CIPN, including platinum derivates, taxanes, vinca alkaloids, proteasome inhibitors, Bortezomib, immunomodulatory agents and several classes of biological agents such as targeted therapies, multikinase inhibitors, immunotherapy, and antibody-drug conjugates. […] The mechanisms of chemotherapeutic agent-induced chemotherapy-induced peripheral neuropathy (CIPN) involve mitochondrial damage and oxidative stress, microtubule disruption, impaired ion channel activity, myelin sheath damage, DNA damage, neuroinflammation, and immunological processes.

• #20 Peripheral Neuropathies Associated with Drugs and Toxins | PM&R KnowledgeNow

  https://now.aapmr.org/peripheral-neuropathies-associated-with-drugs-and-toxins/

  It can be difficult to show a causal relationship between an agent and a resultant neuropathy. […] The precise mechanism for the development of the neuropathy is often unclear. There are different proposed neurotoxicity mechanisms depending on the drug. […] Peripheral axons are susceptible to agents that interfere with axonal transport or energy metabolism. Toxic exposure causes axonal degeneration, which primarily affects distal nerve segments. However, certain agents primarily affect the proximal nerve segment. […] Dorsal root ganglion toxicity […] Microtubular axon transport function abnormalities […] Voltage gated […] Sodium channel abnormalities […] Demyelination […] In CIPN, most symptoms plateau and show gradual improvement, especially after discontinuation, such as with paclitaxel.

• #21 Pathophysiology and Therapeutic Perspectives for Chemotherapy-induced Peripheral Neuropathy | Anticancer Research

  https://ar.iiarjournals.org/content/42/10/4667

  Accumulated pre-clinical and clinical studies demonstrated that platinum-based chemotherapeutic drugs (cisplatin, oxaliplatin, and carboplatin) mainly used for the treatment of various types of solid tumors, induce CIPN by neuro-inflammation resulting from glia cell activation or by alteration of excitability of trigeminal ganglion (TG) and dorsal root ganglion (DRG) neurons, due to the change of voltage-gated channels. […] The neurotoxic effect induced by platinum-based chemotherapeutic agents is strictly associated with their different anticancer mechanisms (affecting mainly mitochondria), which impair the functions and the structure of glial and neuronal cells. […] A significant role of neuroinflammation, blood-brain barrier disruption, defective neurogenesis, and oxidative stress has been postulated in causing cognitive deficits.

• #22 Scientist identifies mechanism underlying peripheral neuropathy | ScienceDaily

  https://www.sciencedaily.com/releases/2016/04/160414114253.htm

  Rieger’s research showed that paclitaxel induces the degeneration of sensory nerve endings by damaging the outer layer of the skin, or epidermis. […] The increase in MMP-13 activity could be triggered by oxidative stress, which is also a hallmark of diabetic peripheral neuropathy. […] Rieger treated the zebrafish with pharmacological agents that reduce MMP-13 activity, with the result that skin defects were improved and chemotherapy-induced nerve damage was reversed. […] MMP-13 over-activation has also been linked to various other disease conditions, such as tendon injury, intestinal inflammatory and cancer, raising the possibility that drugs developed to treat peripheral neuropathy could yield other health benefits as well. […] The next step is to study the effect of MMP-13 on peripheral neuropathy in mammalian models.

• #23 Peripheral Neuropathy | National Institute of Neurological Disorders and Stroke

  https://www.ninds.nih.gov/health-information/disorders/peripheral-neuropathy

  Peripheral neuropathy refers to the many conditions that involve damage to the peripheral nervous system. […] When peripheral nerves cant send and receive signals like they should, it can have serious consequences for the body. […] In peripheral neuropathy, nerve signaling is disrupted in three ways: Signals that should be sent, arent; Signals that are sent when they shouldnt be; Errors that change the messages being sent. […] Most neuropathies are length-dependent, meaning the farthest nerve endings from the brain (those in the feet) are where the symptoms develop first or are worse. […] In severe cases, these neuropathies can spread upward toward the central parts of the body. […] Inflammatory peripheral neuropathies such as Guillain-Barr syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP), the body’s immune system mistakenly attacks peripheral nerves, damaging myelin and weakening signaling along affected nerves.

• #24 Peripheral neuropathy pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Peripheral_neuropathy_pathophysiology

  Schwann cells and the myelin sheath are often selectively targeted in immune-mediated processes such as GBS, CIDP, paraproteinemias, and their variants. It is theorized that a phenomenon of molecular mimicry occurs in these diseases, wherein glycoprotein epitopes found in myelin bear structural similarity to those found in other infectious agents. Immune recognition of these pathogens then spreads to include normal epitopes on the myelin sheath. Pathologic studies reveal both humoral and cellular immune activation and lymphocytic infiltration with patchy demyelination and remyelination. A number of GBS variants which are more prevalent in Asia and Central/South America also damage axons along with myelin, and are commonly associated with Campylobacter jejuni infection. […] Hereditary neuropathies can also affect both axons and/or their myelin sheaths. The most common type, hereditary motor sensory neuropathy (HMSN or Charcot-Marie-Tooth disease), is classified into many clinical subtypes. Many other genetic syndromes also produce varying disruption of Schwann cell, axon and/or neuronal function. Both the Schwann cells and axons of the peripheral nerve depend upon delicate vasa nervorum for perfusion and metabolic support. Many metabolic and inflammatory processes, while directly affecting peripheral nerves and neuronal cell bodies, can also result in damage to nerve vasculature and indirectly produce ischemic damage, particularly to axons. Primary vasculitides as well as other rheumatologic disorders (systemic lupus erythematosus, Sjgren’s syndrome, nonsystemic vasculitis of the peripheral nerves, etc.)

• #25

  https://link.springer.com/article/10.1007/s13311-021-01080-z

  Nerve development requires a coordinated sequence of events and steps to be accomplished for the generation of functional peripheral nerves to convey sensory and motor signals. […] Any abnormality during development may result in pathological structure and function of the nerve, which evolves in peripheral neuropathy. […] Finally, we will describe how disruption of these pathways may result in human neuropathies. […] When radial sorting is impaired, both myelination and peripheral nerve maturation are delayed or stopped resulting in peripheral neuropathy. […] Many genes and pathways are involved, and their role is emerging in recent years characterizing different form of inherited neuropathies, including Charcot-Marie-Tooth (CMT). […] Defective radial sorting of axons characterizes a condition in which axons with diameter larger than 1 m are not sorted, ensheathed, and eventually myelinated by SCs, but lie in bundles with other axons of variable diameter.

• #26

  https://link.springer.com/article/10.1007/s13311-021-01080-z

  The prototype of defective axonal sorting is the neuropathy due to recessive mutations in LAMA2 gene, encoding for the 2 chain of laminin-211 that is therefore not assembled in the SC basal lamina. […] However, many other genes have been described so far in molecular pathways associated to axonal sorting defects. […] While nerve development is therefore a complex and tightly regulated integration of several events, we will concentrate in this review on one essential step: the radial sorting of axons. […] It is interesting how many molecules have been recognized in regulating these events in the SC-ECM pole, while many others (probably) are still to be identified on the other pole, connecting SC to axon. […] This suggests that defective radial sorting may participate in the pathogenesis of many peripheral neuropathies, even if we do not find direct pathological evidence of this defect and might also interfere with nerve regeneration, another context where SCs and axons have to carefully interact.

• #27 Paraesthesia and peripheral neuropathy

  https://www.racgp.org.au/afp/2015/march/paraesthesia-and-peripheral-neuropathy

  Clinicians will often overlook the potential for iatrogenically induced peripheral neuropathy, as may occur with frequently used medications, including amiodarone, statins, antiretrovirals, tacrolimus or even agents not often considered to be associated with peripheral neuropathy, such as levodopa, which is commonly used to treat Parkinson’s disease. […] It is widely accepted that various chemotherapies for malignancy can cause peripheral neuropathy, including taxanes, platinum compounds, vinca alkaloids, proteasome inhibitors and antiangiogenic/immunomodulatory agents. […] Deficiencies of vitamins, such as B6 or B12, may evoke peripheral neuropathies and may be associated with therapies, including levodopa. […] Proper physical examination should have defined the distribution of the dysaesthesia reflective of the paraesthesia, which was the presenting symptom.

• #28 Peripheral Neuropathy | National Institute of Neurological Disorders and Stroke

  https://www.ninds.nih.gov/health-information/disorders/peripheral-neuropathy

  NINDS-supported researchers hope to better understand how auto-antibodies cause peripheral nerve damage and how the effects of these antibodies can be blocked. […] Rapid communication between the peripheral nervous system and the central nervous system depends on myelination, a process through which special cells called Schwann cells create an insulating coating around axons (called myelin). […] Schwann cells play a critical role in the regeneration of nerve cell axons in the peripheral nervous system. […] By better understanding myelination and Schwann cell function, researchers hope to find targets for new therapies to treat or prevent nerve damage associated with neuropathy.

• #29

  https://journals.lww.com/md-journal/fulltext/2023/01060/mechanism_of_schwann_cells_in_diabetic_peripheral.30.aspx

  Insufficient secretion of neurotrophic factors in SCs is a very important reason for diabetic neuropathy. […] A high rate of GLU metabolism through the polyol pathway leads to dysregulation of lipid metabolism in SCs, and it is not fully understood that the accumulation of triglycerides, cholesterol, and free fatty acids in the plasma of diabetic patients appears to drive lipid-mediated neuropathology through mechanisms of oxidative and inflammatory pathways in SCs. […] The pathogenesis of DPN is complex. As the most important myelin cells in the peripheral nervous system, SCs can maintain the structure and function of neurons, nourish axons, and promote survival and growth after injury. As shown in Figure 1, SCs are closely related to the pathogenesis of DPN. The apoptosis of SCs induced by hyperglycemia is involved in the pathogenesis of DPN, including oxidative stress, inflammatory response, autophagy dysfunction, ERS and other pathological processes.

• #30 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20231128/Salk-scientists-uncover-mechanism-for-repairing-damaged-nerves-during-peripheral-neuropathy.aspx

  Each year in the United States there are more than 3 million cases of peripheral neuropathy, wherein nerves outside of the brain and spinal cord are damaged and cause pain and loss of feeling in the affected areas. […] Salk scientists have now uncovered in mice a mechanism for repairing damaged nerves during peripheral neuropathy. […] They discovered that the protein Mitf helps turn on the repair function of specialized nervous system Schwann cells. […] We wanted to know what mechanisms control damage response in peripheral nerves under varying conditions – like acute trauma, genetic disorders, or degenerative diseases. […] We found that Schwann cells, which are special cells in nerves that protect and support neurons’ axons, enter their repair state because of a pathway mediated by the protein Mitf.

• #31 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20231128/Salk-scientists-uncover-mechanism-for-repairing-damaged-nerves-during-peripheral-neuropathy.aspx

  The mechanisms that orchestrate this feat have remained poorly understood. […] To unravel how Schwann cells differentiate to begin repairing peripheral nerve damage, the researchers looked at mouse models of Charcot Marie Tooth disease (CMT), a type of hereditary neuropathy. […] But our findings show that there are gene programs turned on by Mitf that repair some of the damage done in those chronic disease scenarios, and when you turn those programs off, disease symptoms get worse. […] In mice with CMT, the researchers noticed that the Schwann cells completing the repairs had high levels of Mitf in their nuclei – where the genetic instructions for how to be a Schwann cell and how to conduct repairs are stored. […] Damage then prompted Mitf to relocate from the cytoplasm of the cell to the nucleus, where it would direct the Schwann cell to make repairs.

• #32 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20231128/Salk-scientists-uncover-mechanism-for-repairing-damaged-nerves-during-peripheral-neuropathy.aspx

  In cases of both trauma and CMT, nerve repair was arrested in the absence of Mitf – demonstrating that Mitf is required for peripheral nerve repair and regeneration. […] According to Daboussi, Mitf acts like a fire extinguisher. […] Most surprising, noted Pfaff, was that Mitf was orchestrating these repairs during a chronic disease like CMT. […] Harnessing Schwann cell repair programs has great potential in treating chronic diseases. […] It’s possible that with targeted therapeutics, we can prompt more Schwann cells to repair peripheral nerve damage and push those repairs to completion in chronic cases. […] Furthermore, now that we have a better grasp on the repair mechanisms, we can see if it’s possible to initiate repairs in the brain stem and spinal cord, too.

• #33 Scientist identifies mechanism underlying peripheral neuropathy | ScienceDaily

  https://www.sciencedaily.com/releases/2016/04/160414114253.htm

  Recent research identifying the underlying mechanisms of peripheral neuropathy, or nerve damage, has raised the prospect that drug therapies can be developed for the treatment of this condition, which causes pain, numbness and/or tingling in the hands and feet. […] A lack of understanding of the underlying mechanisms has held back the development of treatments. […] Sandra Rieger’s research has advanced that mission by elucidating a mechanism underlying peripheral neuropathy, opening the door to the development of therapeutic agents that can reverse nerve damage linked to chemotherapy, and possibly diabetes and other conditions. […] Our research indicates that there may potentially be a common underlying mechanism for some neuropathies affecting the sensory nervous system that could be manipulated with drugs targeting a single enzyme.

• #34 Peripheral Neuropathy and Our Drug | What is Peripheral Neuropathy?

  http://winsantor.com/peripheral-neuropathy-and-our-drug/

  While peripheral neuropathies can be initiated by diverse events (diabetes, HIV, chemotherapy, etc.), it is believed that most display some degree of mitochondrial dysfunction. Disruption to normal mitochondrial activity results in a chronic axonal energy deficit that is the proximate cause of the damage to peripheral nerves, one of the highest users of cellular energy, and subsequently to the symptoms of neuropathy. […] Our team discovered this dysfunction can be disrupted and normal cell function (homeostasis) can be reestablished through inhibition of a GPCR (G-protein coupled receptor) found on the membranes of axon terminals of peripheral nerves. This inhibition can occur through the introduction of antagonists to this GPCR system. Homeostasis in sensory neurons stimulates nerve growth and proper functioning through the formation of new neural connections between damaged and undamaged neurons, i.e., plasticity.

• #35 Peripheral Neuropathy and Our Drug | What is Peripheral Neuropathy?

  http://winsantor.com/peripheral-neuropathy-and-our-drug/

  WST-057 is a topical reformulation of one of these antagonists. This antagonist is the active ingredient in WST-057, and a specific GPCR antagonist that has been in use in Asia and Europe for nearly 40 years in an oral (systemic) pill to treat peptic ulcers. It was selected by our team because of its historical systemic safety (ingested) in large populations for decades. WST-057 takes this same active ingredient which is applied topically once a day to the skin to treat the nerve damage locally. This localizes the active ingredient to target the GPCR receptors found on the ends of the peripheral nerves found in the extremities of patients. Binding the receptor activates a cascade of protein, including AMP-activated protein kinase (AMPK), that then drives mitochondrial function. The new proteins increase the activity and/or number of mitochondria which leads to an increase of available ATP (energy). […] The ATP molecules provide the energy necessary for nerve growth. The nerve growth can be seen in two ways: the extension in axon length and the formation of new axons in a process known as branching.

• #36 Diagnosis of peripheral neuropathy | Neurological Research and Practice | Full Text

  https://neurolrespract.biomedcentral.com/articles/10.1186/s42466-020-00064-2

  Peripheral neuropathy represents a spectrum of diseases with different etiologies. The most common causes are diabetes, exposure to toxic substances including alcohol and chemotherapeutics, immune-mediated conditions, and gene mutations. […] The diagnosis of peripheral neuropathy necessitates a thorough workup of possible etiologies in order to identify treatable causes of this disease spectrum as early as possible. […] A demyelinating neuropathy in patients who present with symptoms summarized in clinical pattern #3 or #4 is highly suggestive for an immune-mediated neuropathy. These acquired demyelinating neuropathies often have a patchy distribution of demyelinating features with different nerve conduction velocities. In contrast, uniform demyelination is more suggestive of an inherited neuropathy, i.e., Charcot-Marie-Tooth (CMT) type 1(A).

• #37 Peripheral Neuropathy: Differential Diagnosis and Management | AAFP

  https://www.aafp.org/pubs/afp/issues/2010/0401/p887.html

  The presence of neuropathic symptoms, decreased ankle reflexes, and decreased distal sensations, regardless of distal muscle weakness and atrophy, makes the diagnosis of peripheral neuropathy likely. […] Electrodiagnostic studies can help determine whether the neuropathy is the result of damage to the axons (axonal neuropathy) or the myelin (demyelinating neuropathy), or both (mixed). […] Nerve biopsy should be considered when the diagnosis remains uncertain after laboratory and electrodiagnostic testing, or when confirmation of the diagnosis is needed before initiating aggressive treatment. […] Treatment of peripheral neuropathy has two goals: controlling the underlying disease process and treating troublesome symptoms.

• #38 Diagnosis of peripheral neuropathy | Neurological Research and Practice | Full Text

  https://neurolrespract.biomedcentral.com/articles/10.1186/s42466-020-00064-2

  Genetic testing should be considered when clinical history or examination suggests a hereditary origin of the peripheral neuropathy (i.e., clinical pattern #2, #4, occasionally #5). Positive family history is the most apparent hint but may be absent in the case of de novo mutations, adopted individuals, or small families. […] Nerve biopsy as an invasive procedure should be considered in patients presenting with symptoms and signs suggestive of an inflammatory neuropathy. Mainly when a non-systemic vasculitic neuropathy is suspected, nerve biopsy is mandatory to confirm the diagnosis.

• #39 Peripheral Neuropathies Associated with Drugs and Toxins | PM&R KnowledgeNow

  https://now.aapmr.org/peripheral-neuropathies-associated-with-drugs-and-toxins/

  In contrast, oxaliplatin neuropathy may worsen for up to three months after discontinuation. […] Drugs and toxins should always be considered in evaluation of peripheral neuropathy, and particularly in cases where there is no obvious explanation. These neuropathies can significantly affect quality of life. […] Researchers continue to identify new biomarkers of CIPN and related proteins to better understand the pathogenesis and inform strategies for future CIPN treatment.

• #40 Collagen turnover is associated with cardiovascular autonomic and peripheral neuropathy in type 1 diabetes: novel pathophysiological mechanism? | Cardiovascular Diabetology | Full Text

  https://cardiab.biomedcentral.com/articles/10.1186/s12933-023-01891-8

  Diabetic cardiovascular autonomic neuropathy (CAN) and distal symmetrical polyneuropathy (DSPN) are severe diabetic complications. […] Higher levels of markers of collagen turnover such as serum PRO-C6 (marker of collagen type VI (COL6) formation) and C3M (marker of collagen type III (COL3) degradation) have been associated with diabetic complications, such as diabetic nephropathy and mortality. […] The association between markers of collagen turnover and neuropathy may reflect an increased accumulation of extracellular matrix around the nerves and possibly the pro-inflammatory and pro-fibrotic effect that some by-product of collagens acquire as seen for the COL6-derived bioactive fragment endotrophin. […] Our data demonstrate that COL6 turnover assessed by sPRO-C6 concentrations is associated with presence of CAN in T1D.

• #41 Pharmacological and Nonpharmacological Treatments for Painful Diabetic Peripheral Neuropathy

  https://e-dmj.org/journal/view.php?doi=10.4093/dmj.2023.0018

  Diabetic peripheral neuropathy (DPN) is one of the most prevalent chronic complications of diabetes. […] DPN is one of the microvascular complications of diabetes and shares pathophysiologic mechanisms of glucose-mediated vascular damage with other complications. […] However, glycemic control per se cannot fully prevent or improve DPN, especially in patients with type 2 diabetes mellitus (T2DM). […] Metabolic abnormalities other than hyperglycemia such as obesity, dyslipidemia, and hypertension were found to be important risk factors of DPN. […] More specifically, in the neurologic system, insulin resistance could lead to impaired glucose uptake by Schwann cell, which in turn can cause axonal energy deficit. […] However, it is unclear whether the pathophysiology and risk factors differ between painful and painless DPN. […] From a treatment perspective, there is no promising disease-modifying medication for DPN. […] Given the lack of drugs that target the pathophysiology of DPN, new drugs are needed for the treatment of pain associated with DPN.

• #42 Pathogenesis of diabetic polyneuropathy – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-diabetic-polyneuropathy

  Involvement of the peripheral and autonomic nervous systems is the most common complication of diabetes. The duration and severity of hyperglycemia and the metabolic syndrome are the two important risk factors for the development of diabetic neuropathy in patients with type 1 or type 2 diabetes. […] This topic will address the pathogenesis of diabetic polyneuropathy. […] Distal symmetric polyneuropathy is the most common form of diabetic neuropathy. The cause is a length-dependent „dying back” axonopathy, primarily involving the distal portions of the longest myelinated and unmyelinated sensory axons, with relative sparing of motor axons. […] Thus, the morphologic characteristics of diabetic neuropathy support a vascular component, although most damage is likely secondary to metabolic impairment and loss of required energy in the distal sensory axons.

• #43 Diabetic Neuropathy: Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1170337-overview

  The nonenzymatic reaction of excess glucose with proteins, nucleotides, and lipids results in advanced glycation end products (AGEs) that may have a role in disrupting neuronal integrity and repair mechanisms through interference with nerve cell metabolism and axonal transport. […] The increased production of free radicals in diabetes may be detrimental via several mechanisms that are not fully understood. These include direct damage to blood vessels leading to nerve ischemia and facilitation of AGE reactions. Despite the incomplete understanding of these processes, use of the antioxidant alpha-lipoic acid may hold promise for improving neuropathic symptoms. […] Problems that are a consequence of or co-contributors to these disturbed biochemical processes include altered gene expression with altered cellular phenotypes, changes in cell physiology relating to endoskeletal structure or cellular transport, reduction in neurotrophins, and nerve ischemia. Clinical trials of the best-studied neurotrophin, human recombinant nerve growth factor, were disappointing. With future refinements, however, pharmacologic intervention targeting one or more of these mechanisms may prove successful. […] In the case of focal or asymmetrical diabetic neuropathy syndromes, vascular injury or autoimmunity may play more important roles.

• #44 The primary biochemical mechanisms of Diabetic Peripheral Neuropathy (DPN)

  https://www.pulsus.com/scholarly-articles/the-primary-biochemical-mechanisms-of-diabetic-peripheral-neuropathy-dpn-3753.html

  Oxidative stress is the common basis of insulin resistance, diabetes and cardiovascular diseases. […] It decreases the electron transfer rates and increases the superoxide produced by complex I and complex III. […] Diabetic neuropathy presents chronic subclinical signs of inflammation, and proinflammatory factors contribute to the occurrence and maintenance of neuropathic pain. […] Proinflammatory factors, like TNF-, IL-1, IL-6, IL-8, MCP-1 and C-RP, play key roles in amplifying inflammatory reactions. […] Recent studies on patients with T1DM have found that controlling blood glucose is significant in preventing neuropathy, but that does not work in patients with T2DM. […] It is noted that the incidence of dyslipidemia in T2DM is high and lipid homeostasis has been found to be associated with diabetic neuropathy.

• #45 Hemodynamic Considerations in the Pathophysiology of Peripheral Neuropathy | IntechOpen

  https://www.intechopen.com/chapters/63580

  Peripheral neuropathic pain presents one of the greatest ongoing challenges to both acute and chronic pain management yet our understanding of the origins and pathogenesis of this complex disease state are severely lacking. […] Because of the varied origins of neuropathy, this cannot be discussed as a single entity but we can seek to identify a final common pathway. […] We will for this reason examine each known pathogenetic category of neuropathy separately then discuss the effect of hemodynamic alterations through changes in blood pressure to determine any correlations between these alterations and specific effects upon neural structure and function. […] The vascular supply to peripheral nerves is often overlooked both in the natural history of common, well-understood diseases as well as in the management of acute and chronic pain syndromes.

• #46 Hemodynamic Considerations in the Pathophysiology of Peripheral Neuropathy | IntechOpen

  https://www.intechopen.com/chapters/63580

  When chronic peripheral neuropathic pain develops the results can be devastating with significant impairment in quality of functioning in the activities of daily living and cause significant loss of income as well as lost productivity in the workplace. […] Emphasis will be placed upon the second crush theory as a mechanism of vasculopathic contribution to decreases in axonal transport mechanisms, as well as specific diseases and drug interactions that result in perfusion dependent mechanisms of neural injury. […] It should be noted that peripheral neural blood flow has been thought to present as a double edged sword in the development of certain neuropathies. […] The role of oxidative stress in the pathogenesis of diabetic peripheral neuropathy as it was related to obstructive sleep apnea was studied.

• #47 Hemodynamic Considerations in the Pathophysiology of Peripheral Neuropathy | IntechOpen

  https://www.intechopen.com/chapters/63580

  The findings iterate the significance of nitrosative stress in the development of neuropathy as well as vasculopathy and suggest that further studies of PDCs in the treatment of experimental diabetes are needed. […] The role of endothelium-dependent and endothelium-independent microvasodilation and their relationships to neural microcirculatory control was examined in type I and type II diabetic patients. […] The study led to the conclusion that endothelial function and nitric oxide play a significant role in the pathogenesis of peripheral neuropathy in type II diabetic patients and that this disease process is the result in part of significant C-fiber impairment. […] The relationship between endothelial and neutral control of skin blood flow in patients with diabetic peripheral neuropathy was studied.

• #48 Hemodynamic Considerations in the Pathophysiology of Peripheral Neuropathy | IntechOpen

  https://www.intechopen.com/chapters/63580

  The relationship between hypertension and diabetic peripheral neuropathy remains unclear and a consistent correlation (either positive or negative) between the two entities is yet to be found in the literature. […] The possible direct causes of neurodegeneration have been mentioned previously. […] It is at this level that we believe extensive research must be performed both at the bench as well as at the bedside in order to find possible correlation with any basic science breakthroughs.

• #49 Hemodynamic Considerations in the Pathophysiology of Peripheral Neuropathy | IntechOpen

  https://www.intechopen.com/chapters/63580

  These findings contribute to the argument that hypertension and poor vascular compliance are risk factors for peripheral neuropathy in clinical diabetes. […] The mechanism of these disorders, they assert, is neural ischemia caused by a venous microangiopathy and increased endoneurial pressure. […] The study implicates a perfusion dependent neuropathic pathogenesis exist in this syndrome. […] The role of hypertension in the development of peripheral neuropathy was studied by Gregory et al. in 2012. […] The group also noted reduced levels of myelin basic protein. […] Hence in the murine model, at least in the presence of diabetes, hypertension is not associated with a protective effect against the development of peripheral neuropathy seen in at least one human study. […] The relationship between hypotension and sensory motor peripheral diabetic neuropathy was further studied in a 2007 work by this same group.

• #50 Peripheral Neuropathy – A New Insight into the Mechanism, Evaluation and Management of a Complex Disorder | IntechOpen

  https://www.intechopen.com/books/3464

  Understanding the rapid changes in the evaluation and management of peripheral neuropathies, as well as the complexity of their mechanism, is a mandatory requirement for the practitioner to optimize patient’s care. […] The objective of this book is to update health care professionals on recent advances in the pathogenesis, diagnosis and treatment of peripheral neuropathy.

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