myelin-basic-protein and Neuralgia

In the peripheral nerve, mechanosensitive axons are insulated by myelin, a multilamellar membrane formed by Schwann cells. Here, we offer first evidence that a myelin degradation product induces mechanical hypersensitivity and global transcriptomics changes in a sex-specific manner. Focusing on downstream signaling events of the functionally active 84-104 myelin basic protein (MBP(84-104)) fragment released after nerve injury, we demonstrate that exposing the sciatic nerve to MBP(84-104) via endoneurial injection produces robust mechanical hypersensitivity in female, but not in male, mice. RNA-seq and systems biology analysis revealed a striking sexual dimorphism in molecular signatures of the dorsal root ganglia (DRG) and spinal cord response, not observed at the nerve injection site. Mechanistically, intra-sciatic MBP(84-104) induced phospholipase C (PLC)-driven (females) and phosphoinositide 3-kinase-driven (males) phospholipid metabolism (tier 1). PLC/inositol trisphosphate receptor (IP3R) and estrogen receptor co-regulation in spinal cord yielded Ca

Topics: Animals; Calcium Signaling; Female; Ganglia, Spinal; Inositol 1,4,5-Trisphosphate Receptors; Male; Mice; Myelin Basic Protein; Neuralgia; Peptide Fragments; RNA-Seq; Sciatic Nerve; Sex Characteristics; Transcriptome; Type C Phospholipases

Neuropathic pain is characterized by an uncertain etiology and by a poor response to common therapies. The ineffectiveness and the frequent side effects of the drugs used to counteract neuropathic pain call for the discovery of new therapeutic strategies. Laser therapy proved to be effective for reducing pain sensitivity thus improving the quality of life. However, its application parameters and efficacy in chronic pain must be further analyzed. We investigated the pain relieving and protective effect of Photobiomodulation Therapy in a rat model of compressive mononeuropathy induced by Chronic Constriction Injury of the sciatic nerve (CCI). Laser (MLS-MiS) applications started 7 days after surgery and were performed ten times over a three week period showing a reduction in mechanical hypersensitivity and spontaneous pain that started from the first laser treatment until the end of the experiment. The ex vivo analysis highlighted the protective role of laser through the myelin sheath recovery in the sciatic nerve, inhibition of iNOS expression and enhancement of EAAT-2 levels in the spinal cord. In conclusion, this study supports laser treatment as a future therapeutic strategy in patients suffering from neuropathic pain induced by trauma.

Topics: Animals; Behavior, Animal; Excitatory Amino Acid Transporter 2; Hyperalgesia; Inflammation; Lasers; Low-Level Light Therapy; Male; Myelin Basic Protein; Myelin Sheath; Neuralgia; Nitric Oxide Synthase Type II; Pain Threshold; Pressure; Quality of Life; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Spinal Cord

To investigate the effects of genistein in a rat model of sciatic nerve crush injury and complete sciatic nerve transection. The effects of genistein were compared with those of gabapentin, which is widely used in clinical practice for peripheral nerve injury.. Forty-eight rats were randomly divided into six groups (8 rats in each group): group 1 (sham); group 2, sciatic nerve crush injury (control); group 3, sciatic nerve crush injury+genistein 20 mg/kg; group 4, sciatic nerve crush injury+gabapentin 90 mg/kg; group 5, sciatic nerve transection+genistein 20 mg/kg; group 6, sciatic nerve transection+gabapentin 90 mg/kg. The effects of genistein and gabapentin were assessed with immunohistochemical staining for growth associated protein-43 (GAP-43) and myelin basic protein (MBP). Interleukin-1β and tumor necrosis factor α levels in the injured nerve specimens were assessed as a measure of inflammatory response; walking track analysis and sciatic function index for neurological recovery and the paw mechanical withdrawal threshold were examined for neuropathic pain.. On histopathological examination, genistein use was associated with a greater immunoreactivity for GAP-43 and MBP compared with that associated with gabapentin. Genistein and gabapentin had similar effects on anti-inflammatory activity, functional recovery, and neuropathic pain.. Genistein and gabapentin exhibit positive effects on histopathology, inflammation, and clinical findings of peripheral nerve injury. When the systemic side effects of gabapentin are considered, genistein (a basic soy isoflavone that has no side effects) can be used as an alternative to medical treatment in peripheral nerve injury.

Topics: Amines; Animals; Anti-Inflammatory Agents; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; GAP-43 Protein; Genistein; Interleukin-1beta; Male; Myelin Basic Protein; Nerve Crush; Neuralgia; Neuroprotective Agents; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; Recovery of Function; Sciatic Nerve; Sciatic Neuropathy; Treatment Outcome; Tumor Necrosis Factor-alpha

Myelin basic protein (MBP) is an auto-antigen able to induce intractable pain from innocuous mechanical stimulation (mechanical allodynia). The mechanisms provoking this algesic MBP activity remain obscure. Our present study demonstrates that membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) releases the algesic MBP peptides from the damaged myelin, which then reciprocally enhance the expression of MT1-MMP in nerve to sustain a state of allodynia. Specifically, MT1-MMP expression and activity in rat sciatic nerve gradually increased starting at day 3 after chronic constriction injury (CCI). Inhibition of the MT1-MMP activity by intraneural injection of the function-blocking human DX2400 monoclonal antibody at day 3 post-CCI reduced mechanical allodynia and neuropathological signs of Wallerian degeneration, including axon demyelination, degeneration, edema and formation of myelin ovoids. Consistent with its role in allodynia, the MT1-MMP proteolysis of MBP generated the MBP69-86-containing epitope sequences in vitro. In agreement, the DX2400 therapy reduced the release of the MBP69-86 epitope in CCI nerve. Finally, intraneural injection of the algesic MBP69-86 and control MBP2-18 peptides differentially induced MT1-MMP and MMP-2 expression in the nerve. With these data we offer a novel, self-sustaining mechanism of persistent allodynia via the positive feedback loop between MT1-MMP and the algesic MBP peptides. Accordingly, short-term inhibition of MT1-MMP activity presents a feasible pharmacological approach to intervene in this molecular circuit and the development of neuropathic pain.

Topics: Animals; Female; Hyperalgesia; Matrix Metalloproteinase 1; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Myelin Basic Protein; Myelin Sheath; Neuralgia; Peptides; Rats, Sprague-Dawley; Sciatic Nerve

Peripheral nerve block guidance with a nerve stimulator or echo may not prevent intrafascicular injury. This study investigated whether intrafascicular lidocaine induces peripheral neuropathic pain and whether this pain can be alleviated by minocycline administration.. A total of 168 male Sprague-Dawley rats were included. In experiment 1, 2% lidocaine (0.1 mL) was injected into the left sciatic nerve. Hindpaw responses to thermal and mechanical stimuli, and sodium channel and activating transcription factor (ATF-3) expression in dorsal root ganglion (DRG) and glial cells in the spinal dorsal horn (SDH), were measured on days 4, 7, 14, 21, and 28. On the basis of the results in experiment 1, rats in experiment 2 were divided into sham, extraneural, intrafascicular, peri-injury minocycline, and postinjury minocycline groups. Behavioral responses, macrophage recruitment, expression changes of myelin basic protein and Schwann cells in the sciatic nerve, dysregulated expression of ATF-3 in the DRG, and activated glial cells in L5 SDH were assessed on days 7 and 14.. Intrafascicular lidocaine induced mechanical allodynia, downregulated Nav1.8, increased ATF-3 expression in the DRG, and activated glial cells in the SDH. Increased expression of macrophages, Schwann cells, and myelin basic protein was found in the sciatic nerve. Minocycline attenuated intrafascicular lidocaine-induced neuropathic pain and nerve damage significantly. Peri-injury minocycline was better than postinjury minocycline administration in alleviating mechanical behaviors, mitigating macrophage recruitment into the sciatic nerve, and suppressing activated microglial cells in the spinal cord.. Systemic minocycline administration alleviates intrafascicular lidocaine injection-induced peripheral nerve damage.

Topics: Activating Transcription Factor 3; Analysis of Variance; Anesthetics, Local; Animals; Anti-Bacterial Agents; CD11b Antigen; Disease Models, Animal; Ganglia, Spinal; Glial Fibrillary Acidic Protein; Lidocaine; Male; Minocycline; Myelin Basic Protein; Neuralgia; Neuroglia; Pain Measurement; Rats; Sciatic Nerve; Sodium Channels

Gabapentin (GBP) is an anti-convulsive drug often used as analgesic to control neuropathic pain. This study aimed at evaluating oral GBP treatment (30, 60, 120 mg/kg, 60 min prior to chronic constriction of the sciatic nerve (CCSN) along 15-day treatment post-injury, 12 h/12 h) by monitoring spontaneous and induced-pain behaviors in Wistar rats on 5th and 15th days post-injury during early neuropathic events. CCSN animals receiving saline were used as controls. Another aim of this study was to evaluate GBP effects on myelin basic protein (MBP) on the 5th and 15th days post-injury and nerve morphology by transmission electron microscopy to address nerve regeneration. On the 5th and 15th days, GBP (60 mg/kg) reduced neuropathic pain behaviors (scratching and biting) in the ipsilateral paw and alleviated mechanical allodynia in comparison with the neuropathic saline group. GBP significantly increased climbing and rearing behaviors in CCSN and CCSN-free animals suggesting increased motor activity rather than sedation. We found three-fold significant increase in MBP expression by western blots on the 15th day when compared to controls. In addition, GPB (60 mg/kg) improved nerve axonal, fiber and myelin area 15 days post-surgery. In conclusion, GBP alleviated mechanical and thermal allodynia and spontaneous pain-related behaviors and improved later nerve morphology. Our findings suggest that GBP improve nerve remyelination after chronic constriction of the sciatic nerve.

Topics: Amines; Animals; Anticonvulsants; Constriction, Pathologic; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; Male; Myelin Basic Protein; Nerve Regeneration; Neuralgia; Rats, Wistar; Sciatic Nerve

Current treatments used in Multiple Sclerosis (MS) are partly effective in the early stages of the disease but display very limited benefits in patients affected by progressive MS. One possible explanation is that these therapies are unable to target the inflammatory component most active during the progressive phase of the disease, and compartmentalized behind the blood-brain barrier. Our findings show that Rapamycin ameliorates clinical and histological signs of chronic EAE when administered during ongoing disease. Moreover, Rapamycin significantly reduced the hyperalgesia observed before clinical development of EAE which, in turn, is completely abolished by the administration of the drug.

Topics: Analysis of Variance; Animals; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Glycoproteins; Hyperalgesia; Immunosuppressive Agents; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Myelin Sheath; Myelin-Oligodendrocyte Glycoprotein; Neuralgia; Pain Threshold; Peptide Fragments; Pertussis Toxin; RNA, Messenger; Sirolimus; T-Lymphocytes; Time Factors

Immunohistochemistry was used to examine the expression of prostaglandin E(2) receptors EP1 and EP4 in sciatic nerves from the rat chronic constriction injury (CCI) model of neuropathic pain. At 21 days post-surgery the CCI rats had developed mechanical hyperalgesia on the operated side, and quantitative image analysis showed a highly significant doubling of the area occupied by EP1- and EP4-positive pixels in sections from CCI nerves when compared to sham-operated controls. Co-localisation studies with the marker ED1 revealed that 73% of the EP1-positive cells and 54% of the EP4-positive cells in the injured nerves represented infiltrating macrophages. Cells negative for ED1 and positive for either EP1 or EP4 were characterised as Schwann cells from their morphology and expression of myelin basic protein and S100 antigens. Similar EP1- and EP4-positive Schwann cell profiles were observed in sections of uninjured control nerves. Low levels of EP receptor expression were found in neurofilament-immunostained axons, but no consistent differences were observed in the levels of axonal EP staining between CCI and control tissue. These data provide further evidence of the importance of prostaglandins in the pathogenesis of neuropathic pain, and suggest that not only infiltrating macrophages but also Schwann cells may be involved in the modulation of these mediators in response to nerve injury.

Topics: Animals; Axons; Chemotaxis, Leukocyte; Chronic Disease; Disease Models, Animal; Immunohistochemistry; Inflammation; Ligation; Macrophages; Male; Myelin Basic Protein; Neuralgia; Peripheral Nervous System Diseases; Prostaglandins; Rats; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP4 Subtype; S100 Proteins; Schwann Cells; Sciatic Neuropathy; Up-Regulation

Rheumatoid arthritis (RA) is a diffuse connective tissue disease and a multi-system disorder with inflammatory process affecting joints in the first place. RA is found in 1 to 3% of population; the first signs of it are usually found in people aged 35 to 50. Neurological pathology in RA is manifested by cervicocranialgia, cervical myelopathy, pathological changes in the upper cervical spine, and cerebral disorders. However, exact mechanisms of the development of central nervous system (CNS) lesions in RA have not been presented. The aim of this study was to clarify the pathophysiological mechanisms and clinical peculiarities of cerebral disturbances in RA. The subjects were 42 female patients, who underwent clinical, neurological, clinicolaboratory, immunological, and clinicophysiological examination. Subjective and objective symptoms were studied; the following syndromes of CNS pathology were distinguished: initial manifestations of cerebral functional insufficiency; disseminated cerebral micro symptoms; focal cerebral lesion. These disorders were accompanied by changes in biochemical parameters which evidenced the presence of connective tissue destruction and immune inflammation. Immunological tests revealed elevation of the level of myelin basic protein antibodies, which correlated with the degree of neurological disturbances and the duration of the disease. The level of myeloperoxidase was elevated, but the degree of this elevation did not depend on the degree of the cerebral disorder and displayed a negative correlation with the duration of the disease. The results of the study demonstrate primary lesion of small vessels in RA--secondary vasculitis followed by demyelinization of CNS white substance. Thus, three forms of cerebrovascular pathology, caused by acute or chronic cerebral vascular insufficiency in RA can be distinguished: initial manifestations of cerebral circulation insufficiency; discirculatory encephalopathy; transient cerebral circulation disturbances and cerebral stroke.

Topics: Adult; Aged; Antibodies; Arthritis, Rheumatoid; Cerebrovascular Disorders; Cervical Vertebrae; Electroencephalography; Female; Humans; Male; Middle Aged; Myelin Basic Protein; Neuralgia; Peroxidase