Neuropathic pain resolution by nerve barrier sealing and netrin-1

• Applicants: Privatdozentin Dr. Susanne Marlen Krug; Professorin Dr. Heike Rittner
• Subject Area: Anaesthesiology ; Anatomy and Physiology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 399489785

• Final Report Year: 2022

Final Report Abstract

Nerves are shielded by three barriers: the perineurium surrounding the nerves, the capillary barrier of vessels within the nerve, and Schwann cells covering neurons and forming the myelin barrier. After nerve trauma all three barriers break down resulting into altered nerve signal conduction. Symptoms include impaired sensation and pain. Netrin-1 is a protein known to regulate the guidance of neurons. Shortly after nerve injury, only low amounts of netrin-1 are produced in the injured nerve. In this project we discovered a new function of netrin-1 as a multitarget barrier stabilizer. If animals are treated with netrin-1 all three barriers can be reconstituted and pain and hypersensitivity resolve. A certain netrin-1 receptor, neogenin, is responsible for this effect. Thus, netrin-1 could be potentially used to foster recovery from nerve damage in patients. Patients with severe neuropathy of different origin indeed have less barrier proteins expressed when nerve biopsies were examined by immunohistochemistry. We think that barrier damage facilitates nerve damage resulting in neurodegeneration and pain. In this context, claudin-12 seems to be a game changer because its presence distinguishes painful from painless neuropathy. We initially hypothesized that netrin-1 fragments promoted barrier opening and full netrin-1 would seal barriers. However, we did not find increased levels of netrin-1 fragments – so this pathway does not seem to be of relevance in nerve barrier breakdown.

Publications

• Regional Differences in Tight Junction Protein Expression in the Blood–DRG Barrier and Their Alterations after Nerve Traumatic Injury in Rats. International Journal of Molecular Sciences, 21(1), 270.
  Lux, Thomas J.; Hu, Xiawei; Ben-Kraiem, Adel; Blum, Robert; Chen, Jeremy Tsung-Chieh & Rittner, Heike L.
  
• Tissue plasminogen activator and neuropathy open the blood-nerve barrier with upregulation of microRNA-155-5p in male rats. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1865(6), 1160-1169.
  Reinhold, Ann-Kristin; Yang, Shaobing; Chen, Jeremy Tsung-Chieh; Hu, Liu; Sauer, Reine-Solange; Krug, Susanne M.; Mambretti, Egle M.; Fromm, Michael; Brack, Alexander & Rittner, Heike L.
  
• Characteristics of the nerve barrier and the blood dorsal root ganglion barrier in health and disease. Experimental Neurology, 327, 113244.
  Reinhold, A.K. & Rittner, H.L.
  
• Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury. International Journal of Molecular Sciences, 22(18), 10090.
  Chen, Jeremy Tsung-Chieh; Schmidt, Lea; Schürger, Christina; Hankir, Mohammed K.; Krug, Susanne M. & Rittner, Heike L.