دورية أكاديمية
أعرض في EDS

Compounds co-targeting kinases in axon regulatory pathways promote regeneration and behavioral recovery after spinal cord injury in mice.

التفاصيل البيبلوغرافية
العنوان: Compounds co-targeting kinases in axon regulatory pathways promote regeneration and behavioral recovery after spinal cord injury in mice.
المؤلفون: Mah KM; The Miami Project to Cure Paralysis, Dept of Neurological Surgery, University of Miami, Miami, FL, USA., Wu W; Department of Neurological Surgery, and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Al-Ali H; The Miami Project to Cure Paralysis, Dept of Neurological Surgery, University of Miami, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, Dept of Medicine, University of Miami, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA., Sun Y; Department of Neurological Surgery, and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China., Han Q; Department of Neurological Surgery, and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Ding Y; Department of Neurological Surgery, and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Muñoz M; The Miami Project to Cure Paralysis, Dept of Neurological Surgery, University of Miami, Miami, FL, USA., Xu XM; Department of Neurological Surgery, and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Lemmon VP; The Miami Project to Cure Paralysis, Dept of Neurological Surgery, University of Miami, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA; Institute for Data Science and Computing, University of Miami, Miami, FL, USA. Electronic address: vlemmon@med.miami.edu., Bixby JL; The Miami Project to Cure Paralysis, Dept of Neurological Surgery, University of Miami, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA; Dept of Molecular and Cellular Pharmacology, University of Miami, Miami, FL, USA. Electronic address: jbixby@med.miami.edu.
المصدر: Experimental neurology [Exp Neurol] 2022 Sep; Vol. 355, pp. 114117. Date of Electronic Publication: 2022 May 16.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Academic Press Country of Publication: United States NLM ID: 0370712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2430 (Electronic) Linking ISSN: 00144886 NLM ISO Abbreviation: Exp Neurol Subsets: MEDLINE
أسماء مطبوعة: Publication: Orlando Fl : Academic Press
Original Publication: New York.
مواضيع طبية MeSH: Axons*/pathology , Spinal Cord Injuries*/pathology, Animals ; Disease Models, Animal ; Mice ; Nerve Regeneration/physiology ; Neurons/metabolism ; Pyramidal Tracts/pathology ; Recovery of Function/physiology ; Spinal Cord/pathology
مستخلص: Recovery from spinal cord injury (SCI) and other central nervous system (CNS) trauma is hampered by limits on axonal regeneration in the CNS. Regeneration is restricted by the lack of neuron-intrinsic regenerative capacity and by the repressive microenvironment confronting damaged axons. To address this challenge, we have developed a therapeutic strategy that co-targets kinases involved in both extrinsic and intrinsic regulatory pathways. Prior work identified a kinase inhibitor (RO48) with advantageous polypharmacology (co-inhibition of targets including ROCK2 and S6K1), which promoted CNS axon growth in vitro and corticospinal tract (CST) sprouting in a mouse pyramidotomy model. We now show that RO48 promotes neurite growth from sensory neurons and a variety of CNS neurons in vitro, and promotes CST sprouting and/or regeneration in multiple mouse models of spinal cord injury. Notably, these in vivo effects of RO48 were seen in several independent experimental series performed in distinct laboratories at different times. Finally, in a cervical dorsal hemisection model, RO48 not only promoted growth of CST axons beyond the lesion, but also improved behavioral recovery in the rotarod, gridwalk, and pellet retrieval tasks. Our results provide strong evidence for RO48 as an effective compound to promote axon growth and regeneration. Further, they point to strategies for increasing robustness of interventions in pre-clinical models.
(Copyright © 2021. Published by Elsevier Inc.)
التعليقات: Erratum in: Exp Neurol. 2023 Dec 26;:114669. (PMID: 38151457)
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معلومات مُعتمدة: P30 EY014801 United States EY NEI NIH HHS; R01 NS100531 United States NS NINDS NIH HHS; R01 NS111776 United States NS NINDS NIH HHS; R41 TR002293 United States TR NCATS NIH HHS; R01 NS103481 United States NS NINDS NIH HHS
فهرسة مساهمة: Keywords: Axon growth; Axon sprouting; Kinase inhibitors; Pellet retrieval; Polypharmacology; Pyramidotomy; Reproducibility
تواريخ الأحداث: Date Created: 20220519 Date Completed: 20220711 Latest Revision: 20231227
رمز التحديث: 20231228
مُعرف محوري في PubMed: PMC9443329
DOI: 10.1016/j.expneurol.2022.114117
PMID: 35588791
قاعدة البيانات: MEDLINE
الوصف
تدمد:1090-2430
DOI:10.1016/j.expneurol.2022.114117