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Published online before print March 18, 2008
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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070660

Accepted for publication December 27, 2007.

Article

Soluble Complement Receptor 1 Protects the Peripheral Nerve from Early Axon Loss after Injury

Valeria Ramaglia*, Ruud Wolterman*, Maryla de Kok*, Miriam Ann Vigar{dagger}, Ineke Wagenaar-Bos{ddagger}, Rosalind Helen Mary King{sect}, Brian Paul Morgan{dagger}, and Frank Baas*¶@

From the Neurogenetics Laboratory* and the Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; the Department of Immunopathology,{ddagger} Sanquin-AMC Landsteiner Laboratory, Amsterdam, The Netherlands; the Department of Medical Biochemistry and Immunology,{dagger} School of Medicine, Cardiff University, Cardiff, United Kingdom; and the Royal Free and University College Medical School,{sect} London, United Kingdom

@ To whom correspondence should be addressed. E-mail: f.baas{at}amc.uva.nl.


  Abstract

Complement activation is a crucial early event in Wallerian degeneration. In this study we show that treatment of rats with soluble complement receptor 1 (sCR1), an inhibitor of all complement pathways, blocked both systemic and local complement activation after crush injury of the sciatic nerve. Deposition of membrane attack complex (MAC) in the nerve was inhibited, the nerve was protected from axonal and myelin breakdown at 3 days after injury, and macrophage infiltration and activation was strongly reduced. We show that both classical and alternative complement pathways are activated after acute nerve trauma. Inhibition of the classical pathway by C1 inhibitor (Cetor) diminished, but did not completely block, MAC deposition in the injured nerve, blocked myelin breakdown, inhibited macrophage infiltration, and prevented macrophage activation at 3 days after injury. However, in contrast to sCR1 treatment, early signs of axonal degradation were visible in the nerve, linking MAC deposition to axonal damage. We conclude that sCR1 protects the nerve from early axon loss after injury and propose complement inhibition as a potential therapy for the treatment of diseases in which axon loss is the main cause of disabilities.




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