Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy
Autor: | Mariam Sobhy Atalla, Reine-Solange Sauer, Robert Blum, Anna-Lena Bettenhausen, Alexander Brack, Heike L. Rittner, Maria Popp, Adel Ben-Kraiem, Kathrin Doppler, Carla Norwig |
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Rok vydání: | 2021 |
Předmět: |
Male
Pain Threshold Barrier Pathology medicine.medical_specialty Down-Regulation Pain Motor Activity Streptozocin Tight Junctions Capillary Permeability 03 medical and health sciences 0302 clinical medicine Diabetic Neuropathies Diabetes mellitus Claudin-1 Drug Discovery medicine Animals ddc:610 Rats Wistar Claudin Genetics (clinical) 030304 developmental biology 0303 health sciences Blood-Nerve Barrier Behavior Animal Tight junction business.industry Macrophages Nerve injury medicine.disease Pathophysiology Neuropathy Disease Models Animal medicine.anatomical_structure Hyperalgesia Molecular Medicine Original Article medicine.symptom business Perineurium 030217 neurology & neurosurgery |
Zdroj: | Journal of Molecular Medicine (Berlin, Germany) |
ISSN: | 1432-1440 0946-2716 |
Popis: | Abstract Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage. Key messages • In diabetic painful neuropathy in rats: • Blood nerve barrier and blood DRG barrier are leaky for micromolecules. • Perineurial Cldn1 sealing the blood nerve barrier is specifically downregulated. • Endoneurial vessel-associated macrophages are also decreased. • These changes occur after onset of hyperalgesia thereby maintaining rather than inducing pain. Graphical abstract |
Databáze: | OpenAIRE |
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