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 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.

Efficacy of some non-conventional herbal medications (sulforaphane, tanshinone IIA, and tetramethylpyrazine) in inducing neuroprotection in comparison with interleukin-10 after spinal cord injury: A meta-analysis

“…By considering the fact that the inhibition of inflammation results in preventing further neural damage, the administration of some conventional medications such as NSAIDs has been proposed so far. In this regard, Kopp et al 52 showed that ibuprofen which is a Food and Drug Administration-approved NSAID can enhance axonal regeneration by inhibiting the small GTPase RhoA molecule. Furthermore, Kwon et al 10 has expressed the efficacy of various medications including erythropoietin, NSAIDs, antiCD11d antibodies, minocycline, progesterone, estrogen, magnesium, riluzole, polyethylene glycol, atorvastatin, inosine, and pioglitazone as neuroprotective treatments for acute SCI in a systematic review on animal models.…”

Combination treatment with chondroitinase ABC in spinal cord injury—breaking the barrier

“…Myelin and myelin debris contain several myelin-associated molecules that inhibit regeneration [33][34][35] , among which the Nogo-A N-terminal region (amino-Nogo-A) is one of the most potent inhibitors. inhibition of Nogo-A increases axon plasticity and regeneration and improves functional recovery [36][37][38] .…”

Overcoming Drug Development Bottlenecks With Repurposing: Old drugs learn new tricks

“…For example, the widely used nonsteroidal anti-inflammatory drug ibuprofen was shown to possess a second molecular action: inhibiting the cytoskeletal regulating GTPase RhoA 7 . This led to preclinical use of ibuprofen in promoting axonal growth after spinal injury 8,9 , and a clinical trial has now started to assess its potential in traumatic spinal cord injury (ClinicalTrials.gov NCT02096913). However, in other cases, certain compounds never succeeded in their intended application and then are resurrected for new uses.…”