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A spatially specified systems pharmacology therapy for axonal recovery after injury

Affiliation
Department of Pharmacological Sciences ,Mount Sinai Institute for Systems Biomedicine ,Icahn School of Medicine at Mount Sinai ,New York ,NY ,United States
Siddiq, Mustafa M.;
Affiliation
Department of Pharmacological Sciences ,Mount Sinai Institute for Systems Biomedicine ,Icahn School of Medicine at Mount Sinai ,New York ,NY ,United States
Johnson, Nicholas P.;
Affiliation
Department of Pharmacological Sciences ,Mount Sinai Institute for Systems Biomedicine ,Icahn School of Medicine at Mount Sinai ,New York ,NY ,United States
Zorina, Yana;
Affiliation
Department of Pharmacological Sciences ,Mount Sinai Institute for Systems Biomedicine ,Icahn School of Medicine at Mount Sinai ,New York ,NY ,United States
Yadaw, Arjun Singh;
Affiliation
National Center for the Medical Consequences of Spinal Cord Injury ,James J. Peters VA Medical Center ,New York ,NY ,United States
Toro, Carlos A.;
Affiliation
Department of Pharmacological Sciences ,Mount Sinai Institute for Systems Biomedicine ,Icahn School of Medicine at Mount Sinai ,New York ,NY ,United States
Hansen, Jens;
Affiliation
Department of Pharmacological Sciences ,Mount Sinai Institute for Systems Biomedicine ,Icahn School of Medicine at Mount Sinai ,New York ,NY ,United States
Rabinovich, Vera;
Affiliation
Departments of Chemical and Biomedical Engineering ,University of South Florida ,Tampa ,FL ,United States
Gregorich, Sarah M.;
Affiliation
Department of Pharmacological Sciences ,Mount Sinai Institute for Systems Biomedicine ,Icahn School of Medicine at Mount Sinai ,New York ,NY ,United States
Xiong, Yuguang;
Affiliation
Department of Pharmacological Sciences ,Mount Sinai Institute for Systems Biomedicine ,Icahn School of Medicine at Mount Sinai ,New York ,NY ,United States
Tolentino, Rosa E.;
Affiliation
Department of Human Anatomy and Cell Science ,Basic Medical Sciences Building ,Winnipeg ,NM ,United States
Hannila, Sari S.;
Affiliation
Department of Pharmacological Sciences ,Mount Sinai Institute for Systems Biomedicine ,Icahn School of Medicine at Mount Sinai ,New York ,NY ,United States
Kaplan, Ehud;
Affiliation
Department of Pharmacological Sciences ,Mount Sinai Institute for Systems Biomedicine ,Icahn School of Medicine at Mount Sinai ,New York ,NY ,United States
Blitzer, Robert D.;
Affiliation
Department of Biological Sciences ,Hunter College ,City University of New York ,New York ,NY ,United States
Filbin, Marie T.;
Affiliation
National Center for the Medical Consequences of Spinal Cord Injury ,James J. Peters VA Medical Center ,New York ,NY ,United States
Cardozo, Christopher P.;
Affiliation
Departments of Chemical and Biomedical Engineering ,University of South Florida ,Tampa ,FL ,United States
Passaglia, Christopher L.;
Affiliation
Department of Pharmacological Sciences ,Mount Sinai Institute for Systems Biomedicine ,Icahn School of Medicine at Mount Sinai ,New York ,NY ,United States
Iyengar, Ravi

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.

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License Holder: Copyright © 2023 Siddiq, Johnson, Zorina, Yadaw, Toro, Hansen, Rabinovich, Gregorich, Xiong, Tolentino, Hannila, Kaplan, Blitzer, Filbin, Cardozo, Passaglia and Iyengar.

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