Novel neuroprotective therapy with NeuroHeal by autophagy induction for damaged neonatal motoneurons
Romeo-Guitart, David (Universitat Autònoma de Barcelona. Institut de Neurociències)
Marcos-DeJuana, César (Universitat Autònoma de Barcelona. Institut de Neurociències)
Marmolejo Martínez-Artesero, Sara (Universitat Autònoma de Barcelona. Institut de Neurociències)
Navarro, X. (Xavier) (Xavier) (Universitat Autònoma de Barcelona. Institut de Neurociències)
Casas Louzao, Caty (Universitat Autònoma de Barcelona. Institut de Neurociències)

Date:	2020
Abstract:	Rationale : Protective mechanisms allow healthy neurons to cope with diverse stresses. Excessive damage as well as aging can lead to defective functioning of these mechanisms. We recently designed NeuroHeal using artificial intelligence with the goal of bolstering endogenous neuroprotective mechanisms. Understanding the key nodes involved in neuroprotection will allow us to identify even more effective strategies for treatment of neurodegenerative diseases. Methods : We used a model of peripheral nerve axotomy in rat pups, that induces retrograde apoptotic death of motoneurons. Nourishing mothers received treatment with vehicle, NeuroHeal or NeuroHeal plus nicotinamide, an inhibitor of sirtuins, and analysis of the pups were performed by immunohistochemistry, electron microscopy, and immunoblotting. In vitro, the post-translational status of proteins of interest was detailed using organotypic spinal cord cultures and genetic modifications in cell lines to unravel the neuroprotective mechanisms involved. Results : We found that the concomitant activation of the NAD + -dependent deacetylase SIRT1 and the PI3K/AKT signaling pathway converge to increase the presence of deacetylated and phosphorylated FOXO3a, a transcription factor, in the nucleus. This favors the activation of autophagy, a pro-survival process, and prevents pro-apoptotic PARP1/2 cleavage. Major conclusion : NeuroHeal is a neuroprotective agent for neonatal motoneurons that fine-tunes autophagy on by converging SIRT1/AKT/FOXO3a axis. NeuroHeal is a combo of repurposed drugs that allow its readiness for prospective pediatric use.
Grants:	Ministerio de Economía y Competitividad SAF 2014-59701
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Neonatal motoneurons ; Neuroprotection ; Autophagy ; SIRT1/AKT/FOXO3a ; NeuroHeal
Published in:	Theranostics, Vol. 10 (april 2020) , p. 5154-5168, ISSN 1838-7640

DOI: 10.7150/thno.43765
PMID: 32308774

15 p, 2.3 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Neurociències (INc)
Articles > Research articles
Articles > Published articles