Drug combinations targeting multiple cellular mechanisms enable axonal regeneration from crushed optic nerve into the brain

Abstract

Injured central nervous system axons do not regenerate, due to the limited intrinsic capacity of the neurons and the inhibitory environment at the injury site. Currently, there are no drugs or drug combinations to promote axonal regeneration in the injured spinal cord or optic nerve. We used a systems pharmacology approach to develop a four-drug combination, designed to regulate multiple subcellular processes at the cell body and the injured axon to promote regrowth of long projections through inhibitory environments. We tested this drug combination using the optic nerve crush model in rats. We intravitreally injected two drugs, HU-210 (cannabinoid receptor-1 agonist) and IL-6 (interleukin 6 receptor agonist) to stimulate retinal ganglion cell bodies (RGCs) whose axons had been crushed, and applied two other drugs in gel foam over the injury site: taxol to stabilize microtubules, and activated protein C (APC) to clear the injury site debris field. Dynamical computational models showed that the transcriptional effects of drugs applied at the cell body combined with drugs that work near the site of the injured axons could produce extensive synergistic growth by relief of inhibition at the growth cone. Morphology experiments show that the four-drug combination promotes axonal regeneration from the site of injury to the optic chiasm and the visual cortex. Electrophysiologically, the four-drug treatment restored pattern electroretinograms (pERG), and the animals had detectable visual evoked potentials (VEP) in the brain. We conclude that systems pharmacology-based drug treatment can promote functional axonal regeneration to the brain after nerve injury.