Novel neuroprotective therapy with NeuroHeal by autophagy induction for damaged neonatal motoneurons
| Autor: | David Romeo-Guitart, Sara Marmolejo-Martínez-Artesero, Xavier Navarro, César Marcos-DeJuana, Caty Casas |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Neonatal motoneurons Akt/PKB signaling pathway business.industry medicine.medical_treatment Autophagy Medicine (miscellaneous) Neuroprotection Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine PARP1 Medicine NeuroHeal SIRT1/AKT/FOXO3a Axotomy business Pharmacology Toxicology and Pharmaceutics (miscellaneous) Protein kinase B Transcription factor 030217 neurology & neurosurgery PI3K/AKT/mTOR pathway |
| Zdroj: | Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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