AUTHOR=Siddiq Mustafa M. , Johnson Nicholas P. , Zorina Yana , Yadaw Arjun Singh , Toro Carlos A. , Hansen Jens , Rabinovich Vera , Gregorich Sarah M. , Xiong Yuguang , Tolentino Rosa E. , Hannila Sari S. , Kaplan Ehud , Blitzer Robert D. , Filbin Marie T. , Cardozo Christopher P. , Passaglia Christopher L. , Iyengar Ravi TITLE=A spatially specified systems pharmacology therapy for axonal recovery after injury JOURNAL=Frontiers in Pharmacology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1225759 DOI=10.3389/fphar.2023.1225759 ISSN=1663-9812 ABSTRACT=

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 axons 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. Physiologically, drug treatment restored or preserved pattern electroretinograms and some of the animals had detectable visual evoked potentials in the brain and behavioral optokinetic responses. Morphology experiments show that the four-drug combination protects axons or promotes axonal regrowth to the optic chiasm and beyond. We conclude that spatially targeted drug treatment is therapeutically relevant and can restore limited functional recovery.