TY - JOUR T1 - Systems Therapeutics for Axonal Regeneration in the Central Nervous System JF - bioRxiv DO - 10.1101/157099 SP - 157099 AU - Mustafa M. Siddiq AU - Yana Zorina AU - Jens Hansen AU - Arjun S. Yadaw AU - Vera Rabinovich AU - Sarah M. Gregorich AU - Yuguang Xiong AU - Ehud Kaplan AU - Robert D. Blitzer AU - Marie T. Filbin AU - Christopher L. Passaglia AU - Ravi Iyengar Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/28/157099.abstract N2 - Injured central nervous system (CNS) axons do not regenerate, due to lack of 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 with the potential to increase neuronal capacity by regulating multiple subcellular processes at the cell body to trigger long neurites in inhibitory environments. Dynamical computational models of neurite outgrowth showed that the transcriptional effects of drugs applied at the cell body when combined with drugs that work locally near the site of the injured axons could produce extensive synergistic growth. We used the optic nerve crush in rats to test the drug combinations. We intravitreally injected two drugs, HU-210 (cannabinoid receptor-1 agonist) and IL-6 (interleukin 6 receptor agonist) to stimulate retinal ganglion cells (RGCs) whose axons had been crushed, and applied two drugs in gel foam, taxol to stabilize microtubules and activated protein C (APC) to potentially clear the injury site debris field. Morphology experiments using the injured optic nerve show that the four-drug combination promotes robust axonal regeneration from the RGC to the chiasm. Electrophysiologically the four-drug treatment restored pattern electroretinograms (pERG), and about 25% of the animals had detectable visual evoked potentials (VEP) in the brain. We conclude that systems pharmacology-based drug treatment can promote functional axonal regeneration after nerve injury. ER -