A spatially specified systems pharmacology therapy for axonal recovery after injury

Frontiers in Pharmacology

Pharmacology

Marie T. Filbin¹  Sari S. Hannila²  Arjun Singh Yadaw³  Yana Zorina³  Robert D. Blitzer³  Vera Rabinovich³  Mustafa M. Siddiq³  Yuguang Xiong³  Jens Hansen³  Ravi Iyengar³  Rosa E. Tolentino³  Ehud Kaplan⁴  Nicholas P. Johnson⁵  Christopher L. Passaglia⁶  Sarah M. Gregorich⁶  Carlos A. Toro⁷  Christopher P. Cardozo⁸ 

[1] Department of Biological Sciences, Hunter College, City University of New York, New York, NY, United States;Department of Human Anatomy and Cell Science, Basic Medical Sciences Building, Winnipeg, NM, United States;Department of Pharmacological Sciences, Mount Sinai Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States;Department of Pharmacological Sciences, Mount Sinai Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States;Department of Philosophy of Science, Prague and the National Institute of Mental Health, Charles University, Prague, CZ, United States;Department of Pharmacological Sciences, Mount Sinai Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States;Departments of Chemical and Biomedical Engineering, University of South Florida, Tampa, FL, United States;National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, New York, NY, United States;Departments of Chemical and Biomedical Engineering, University of South Florida, Tampa, FL, United States;National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, New York, NY, United States;Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States;National Center for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, New York, NY, United States;Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States;Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States;

关键词: microfluidic chambers;    retinal ganglion cell;    iDISCO;    electrophysiology;    electroretinogram;   

DOI  :  10.3389/fphar.2023.1225759

 received in 2023-05-22, accepted in 2023-09-06,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

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