title: Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury.
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.
authors.affiliation: Department of Neurology and Experimental Neurology, Spinal Cord Injury Research, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Kopp
authors.forename: T
authors.initials: T
authors.lastname: Liebscher
authors.forename: A
authors.initials: A
authors.lastname: Niedeggen
authors.forename: S
authors.initials: S
authors.lastname: Laufer
authors.forename: B
authors.initials: B
authors.lastname: Brommer
authors.forename: G J
authors.initials: GJ
authors.lastname: Jungehulsing
authors.forename: S M
authors.initials: SM
authors.lastname: Strittmatter
authors.forename: U
authors.initials: U
authors.lastname: Dirnagl
authors.forename: J M
authors.initials: JM
authors.lastname: Schwab
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009473:Neuronal Plasticity / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D054852:Small Molecule Libraries; D020741:rho GTP-Binding Proteins