Systems Therapeutics for Axonal Regeneration in the Central Nervous System
There are no known drugs or drug combinations that promote substantial central nervous system axonal regeneration after injury. We used systems pharmacology approaches to model pathways underlying axonal growth and identify a four-drug combination that regulates multiple subcellular processes in the cell body and axon using the optic nerve crush model in rats. We intravitreally injected agonists HU-210 (cannabinoid receptor-1) and IL-6 (interleukin 6 receptor) to stimulate retinal ganglion cells for axonal growth. We applied, in gel foam at the site of nerve injury, Taxol to stabilize growing microtubules, and activated protein C to clear the debris field since computational models predicted that this drug combination regulating two subcellular processes at the growth cone produces synergistic growth. Morphology experiments show that the four-drug combination promotes axonal regrowth to the optic chiasm and beyond. Physiologically, drug treatment restored pattern electroretinograms and some of the animals had detectable visual evoked potentials in the brain and behavioral optokinetic responses. We conclude that spatially targeted drug treatment can promote robust axonal regeneration and can restore limited functional recovery.