Inhibiting effect of minocycline on the regeneration of peripheral nerves.
The effect of minocycline on nerve regeneration was studied in a rat model of acute sciatic nerve injury, in which the injury was caused by resection and reimplantation of the right sciatic nerve. Immunohistochemical and molecular biological methods, as well as morphometric and electron microscopic techniques, were used. Compared with uninjured and PBS-treated injured nerves, the minocycline-treated injured nerve showed: (i) a decrease in macrophage recruitment and activation, probably resulting from inhibition of blood-brain-barrier break-down via reduced MMP2 and MMP9 induction, inhibition of revascularization via additional reduction of VEGF induction, and inhibition of inducible NO synthase (iNOS) induction; (ii) reduced activation of phagocytic Schwann cells, probably by inhibition of iNOS, MMP2 and MMP9 expression; (iii) a slowed Wallerian degeneration; and subsequently, (iv) a diminished nerve regeneration. Macrophages, especially their function in the removal of cellular debris and formation of a microenvironment beneficial for nerve regeneration, are strongly implicated in constructive events after nerve injuries. Therefore, we suggest that additional research into optimizing minocycline intervention for treatment of neurodegenerative diseases is needed before further clinical trials are performed.
Keilhoff
Gerburg
G
Institute of Medical Neurobiology, University of Magdeburg, D-39120 Magdeburg, Germany. gerbug.keilhoff@medizin.uni-magdeburg.de
Langnaese
Kristina
K
Wolf
Gerald
G
Fansa
Hisham
H
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020439:Growth Cones / Q000187:drug effects / Q000648:ultrastructure; D006131:Growth Inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008911:Minocycline / Q000494:pharmacology*; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D010525:Peripheral Nerves / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010587:Phagocytosis / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000378:metabolism / Q000503:physiopathology; D014855:Wallerian Degeneration / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control
D000893:Anti-Inflammatory Agents; D006131:Growth Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases; D008911:Minocycline