Tissue plasminogen activator and neuropathy open the blood-nerve barrier with upregulation of microRNA-155-5p in male rats
| Autor: | Liu Hu, Reine-Solange Sauer, Ann-Kristin Reinhold, Egle M. Mambretti, Susanne M. Krug, Michael Fromm, Alexander Brack, Shaobing Yang, Jeremy Tsung-Chieh Chen, Heike L. Rittner |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Inflammation Constriction Pathologic Tissue plasminogen activator Adherens junction 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Internal medicine medicine Animals Rats Wistar Molecular Biology Blood-Nerve Barrier Tight Junction Proteins Tight junction Chemistry Peripheral Nervous System Diseases Recombinant Proteins Up-Regulation MicroRNAs 030104 developmental biology Endocrinology Allodynia Hyperalgesia Tissue Plasminogen Activator Chronic Disease Molecular Medicine Neuralgia medicine.symptom 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Biochimica et biophysica acta. Molecular basis of disease. 1865(6) |
| ISSN: | 1879-260X |
| Popis: | The blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels is sealed by tight junction proteins. BNB alterations are a crucial factor in the pathogenesis of peripheral neuropathies. However, barrier opening, e.g. by tissue plasminogen activator (tPA), can also facilitate topical application of analgesics. Here, we examined tPA both in the pathophysiology of neuropathy-induced BNB opening or via exogenous application and its effect on the cytoplasmatic tight junction protein anchoring protein, zona occludens-1 (ZO-1), the adherens molecule JAM-C and microRNA(miR)-155-5p. Specifically, we investigated whether tPA alone and barrier opening lead to pain behavioral changes, i.e. hyperalgesia, or whether these effects require further factors. Male Wistar rats underwent chronic constriction injury (CCI) or were treated by a single perisciatic application of recombinant (r)tPA. CCI elicited mechanical allodynia, tPA mRNA upregulation, macrophage invasion, BNB leakage for large molecule tracers, downregulation of ZO-1 and JAM-C mRNA/protein, and a loss of immunoreactivity of both in perineurium and endoneurial cells. Similarly, after perisciatic rtPA injection, ZO-1 and JAM-C mRNA as well as cytosolic/membrane protein and ZO-1 immunoreactivity were downregulated, and the BNB was opened. Neither mechanical hypersensitivity nor macrophage infiltration was observed after rtPA in contrast to CCI. Mechanistically, miR-155-5p, which is known to destabilize barriers and tight junction proteins like claudin-1 and ZO-1, was increased in CCI and to lesser extent after rtPA application. In summary, tPA transiently opens the BNB possibly via miR-155-5p. However, tPA does not provoke allodynia in the absence of a neuropathic stimulus like a ligation or inflammation. |
| Databáze: | OpenAIRE |
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