دورية أكاديمية
أعرض في EDS

PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.

التفاصيل البيبلوغرافية
العنوان: PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury.
المؤلفون: Michel-Flutot P; Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA., Cheng L; Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA., Thomas SJ; Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA., Lisi B; Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA., Schwartz H; Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA., Lam S; Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA., Lyttle M; Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA., Jaffe DA; Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA., Smith G; Department of Neuroscience, Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 191405104, USA., Li S; Department of Neuroscience, Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 191405104, USA., Wright MC; Department of Biology, Arcadia University, Glenside, PA 19038, USA., Lepore AC; Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: angelo.lepore@jefferson.edu.
المصدر: Experimental neurology [Exp Neurol] 2024 Aug; Vol. 378, pp. 114816. Date of Electronic Publication: 2024 May 22.
نوع المنشور: Journal Article
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*/drug effects , Diaphragm*/innervation , PTEN Phosphohydrolase*/antagonists & inhibitors , PTEN Phosphohydrolase*/metabolism , Recovery of Function*/physiology , Recovery of Function*/drug effects , Spinal Cord Injuries*/physiopathology , Spinal Cord Injuries*/pathology, Animals ; Female ; Rats ; Cervical Cord/injuries ; Chronic Disease ; Disease Models, Animal ; Rats, Sprague-Dawley ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/antagonists & inhibitors ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism
مستخلص: High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury (though this effect depended on the anesthetic regimen used during recording), while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function.
Competing Interests: Declaration of competing interest The authors report no declarations of interest.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
التعليقات: Update of: bioRxiv. 2024 Jan 11:2024.01.10.575021. doi: 10.1101/2024.01.10.575021. (PMID: 38260313)
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معلومات مُعتمدة: R01 NS079702 United States NS NINDS NIH HHS; R01 NS110385 United States NS NINDS NIH HHS
فهرسة مساهمة: Keywords: Axon; Breathing; Cervical; Chronic; Circuit; Contusion; Diaphragm; PTEN; PTPsigma; Regeneration; Respiratory; SCI; Spinal cord injury; Sprouting
المشرفين على المادة: EC 3.1.3.67 (PTEN Phosphohydrolase)
EC 3.1.3.67 (Pten protein, rat)
EC 3.1.3.48 (Receptor-Like Protein Tyrosine Phosphatases, Class 2)
تواريخ الأحداث: Date Created: 20240524 Date Completed: 20240614 Latest Revision: 20240627
رمز التحديث: 20240627
مُعرف محوري في PubMed: PMC11200215
DOI: 10.1016/j.expneurol.2024.114816
PMID: 38789023
قاعدة البيانات: MEDLINE
الوصف
تدمد:1090-2430
DOI:10.1016/j.expneurol.2024.114816