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Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury

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Abstract

Limited axonal plasticity within the central nervous system (CNS) is a major restriction for functional recovery after CNS injury. The small GTPase RhoA is a key molecule of the converging downstream cascade that leads to the inhibition of axonal re-growth. The Rho-pathway integrates growth inhibitory signals derived from extracellular cues, such as chondroitin sulfate proteoglycans, Nogo-A, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein, Ephrins and repulsive guidance molecule-A, into the damaged axon. Consequently, the activation of RhoA results in growth cone collapse and finally outgrowth failure. In turn, the inhibition of RhoA-activation blinds the injured axon to its growth inhibitory environment resulting in enhanced axonal sprouting and plasticity. This has been demonstrated in various CNS-injury models for direct RhoA-inhibition and for downstream/upstream blockade of the RhoA-associated pathway. In addition, RhoA-inhibition reduces apoptotic cell death and secondary damage and improves locomotor recovery in clinically relevant models after experimental spinal cord injury (SCI). Unexpectedly, a subset of “small molecules” from the group of non-steroid anti-inflammatory drugs, particularly the FDA-approved ibuprofen, has recently been identified as (1) inhibiting RhoA-activation, (2) enhancing axonal sprouting/regeneration, (3) protecting “tissue at risk” (neuroprotection) and (4) improving motor recovery confined to realistic therapeutical time-frames in clinically relevant SCI models. Here, we survey the effect of small-molecule-induced RhoA-inhibition on axonal plasticity and neurofunctional outcome in CNS injury paradigms. Furthermore, we discuss the body of preclinical evidence for a possible clinical translation with a focus on ibuprofen and illustrate putative risks and benefits for the treatment of acute SCI.

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Authors and Affiliations

  1. Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité—Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany

    M. A. Kopp, B. Brommer & J. M. Schwab

  2. Trauma Hospital Berlin, Treatment Centre for Spinal Cord Injuries, Berlin, Germany

    T. Liebscher & A. Niedeggen

  3. Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University Tübingen, Tübingen, Germany

    S. Laufer

  4. Department of Neurology and Experimental Neurology, Center for Stroke Research Berlin, Charité—Universitätsmedizin Berlin, Berlin, Germany

    G. J. Jungehulsing & U. Dirnagl

  5. Program in Cellular Neuroscience, Neurodegeneration and Repair, and Department of Neurology, Yale University School of Medicine, New Haven, USA

    S. M. Strittmatter

Authors
  1. M. A. Kopp
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  2. T. Liebscher
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  3. A. Niedeggen
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  4. S. Laufer
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  5. B. Brommer
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  6. G. J. Jungehulsing
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  7. S. M. Strittmatter
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  8. U. Dirnagl
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  9. J. M. Schwab
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Corresponding author

Correspondence to J. M. Schwab.

Additional information

This work is funded by the German Research Council (DFG, Research Training School, Neuroinflammation No. 1258 & Exc 247), German Ministry of Science and Education, the Berlin-Brandenburg Center for Regenerative Therapies (BCRT, No. 81717034), the International Foundation for Research in Paraplegia, Switzerland (IFP, no. P102) and Wings for Life Spinal Cord Research Foundation, Austria (no. 89830429). Spinal cord injury Reaserch, Department of Experimental Neurology, Charité is Associated Member of the European Multi-center Study about Spinal Cord Injury

Author disclosure statement

S.M.S. is a co-founder of Axerion Therapeutics seeking to develop NgR- and PrP-based therapies.

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Kopp, M.A., Liebscher, T., Niedeggen, A. et al. Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury. Cell Tissue Res 349, 119–132 (2012). https://doi.org/10.1007/s00441-012-1334-7

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  • DOI: https://doi.org/10.1007/s00441-012-1334-7

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