Unknown

Dataset Information

0

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.

SUBMITTER: Kopp MA 

PROVIDER: S-EPMC3744771 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Kopp M A MA   Liebscher T T   Niedeggen A A   Laufer S S   Brommer B B   Jungehulsing G J GJ   Strittmatter S M SM   Dirnagl U U   Schwab J M JM  

Cell and tissue research 20120221 1


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 molec  ...[more]

Similar Datasets

| S-EPMC4964175 | biostudies-literature
| S-EPMC5908415 | biostudies-literature
| S-EPMC8367350 | biostudies-literature
| S-EPMC1299028 | biostudies-literature
| S-EPMC5561061 | biostudies-literature
| PRJNA532533 | ENA
| S-EPMC7287126 | biostudies-literature
| S-EPMC4465862 | biostudies-literature
| S-EPMC4586490 | biostudies-literature
| S-EPMC8021110 | biostudies-literature