Neural Regeneration Research ›› 2016, Vol. 11 ›› Issue (1): 71-72.doi: 10.4103/1673-5374.169614

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Exploiting kinase polypharmacology for nerve regeneration

Hassan Al-Ali*, John L. Bixby, Vance P. Lemmon   

  1. Miami Project to Cure Paralysis, University of Miami, Miami, FL, USA(Al-Ali H, Bixby JL, Lemmon VP)
    Center for Computational Science, University of Miami, Miami, FL, USA (Bixby JL, Lemmon VP)
    Department of Neurological Surgery, University of Miami, Miami, FL, USA (Bixby JL, Lemmon VP)
    Department of Molecular & Cellular Pharmacology, University of Miami, Miami, FL, USA (Bixby JL)
  • Received:2015-08-19 Online:2016-01-15 Published:2016-01-15
  • Contact: Hassan Al-Ali, Ph.D., HAIALI@miami.edu.

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Abstract:

The humancentral nervous system (CNS) has a markedly poor capacity for regenerating its axons following injury. This appears to be due to two main causes: 1) a developmentally regulated decline in regenerative capacity within mature CNS neurons, and 2) the presence of biological components that constitute barriers to axon regeneration (e.g., growth-inhibitory molecules). Intrinsic alterations have been elucidated by studies that show causative links between developmental changes in gene expression programs and growth-signaling states on one hand, and changes in regenerative capacity on the other. In addition to these neuron-intrinsic factors, several molecular species that are native to the CNS microenvironment, such as myelin associated proteins, and others that are secreted by injury-activated astrocytes, such as chondroitin sulfate proteoglycans (CSPGs), exert extrinsic inhibitory influences on growing axons.

Given the various factors that negatively influence axon regrowth in the adult CNS, achieving clinically relevant regeneration to promote recovery from traumatic injury has been difficult. Experimental manipulation of individual inhibitory factors, or their mediators, has resulted in some improvement of regeneration/sprouting. However, manipulations that simultaneously target intrinsic growth capacity while also blocking inhibition from extrinsic factors appear to produce the most pronounced effects in vivo. Development of effective therapies thus requires agents that simultaneously modulate multiple sources of regeneration failure. This could be achieved with drugs that engage multiple targets (polypharmacology) within various relevant signaling networks. The use of multi-target drugs to treat complex polygenic disorders is not a new concept; however,the lack of appropriate methodologies have hindered systematic exploitation of polypharmacology. Interestingly though, it appears that polypharmacologyis important for the therapeutic efficacy of many approved drugs.