Cargando…
LRRK2 Inhibition by PF06447475 Antagonist Modulates Early Neuronal Damage after Spinal Cord Trauma
Spinal cord injury (SCI) is a devastating event followed by neurodegeneration, activation of the inflammatory cascade, and immune system. The leucine-rich-repeat kinase 2 (LRRK2) is a gene associated with Parkinson’s disease (PD), moreover, its kinase activity was found to be upregulated after insti...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9495377/ https://www.ncbi.nlm.nih.gov/pubmed/36139708 http://dx.doi.org/10.3390/antiox11091634 |
_version_ | 1784794003028312064 |
---|---|
author | Filippone, Alessia Mannino, Deborah Cucinotta, Laura Paterniti, Irene Esposito, Emanuela Campolo, Michela |
author_facet | Filippone, Alessia Mannino, Deborah Cucinotta, Laura Paterniti, Irene Esposito, Emanuela Campolo, Michela |
author_sort | Filippone, Alessia |
collection | PubMed |
description | Spinal cord injury (SCI) is a devastating event followed by neurodegeneration, activation of the inflammatory cascade, and immune system. The leucine-rich-repeat kinase 2 (LRRK2) is a gene associated with Parkinson’s disease (PD), moreover, its kinase activity was found to be upregulated after instigated inflammation of the central nervous system (CNS). Here, we aimed to investigate the PF06447475 (abbreviated as PF-475) role as a pharmacological LRRK2 antagonist by counteracting pathological consequences of spinal cord trauma. The in vivo model of SCI was induced by extradural compression of the spinal cord, then mice were treated with PF0-475 (2.5–5 and 10 mg/kg i.p) 1 and 6 h after SCI. We found that PF-475 treatments at the higher doses (5 and 10 mg/kg) showed a great ability to significantly reduce the degree of spinal cord tissue injury, glycogen accumulation, and demyelination of neurons associated with trauma. Furthermore, oxidative stress and cytokines expression levels, including interleukins (IL-1, IL-6, IL-10, and 12), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), secreted and released after trauma were decreased by LRRK2 antagonist treatments. Our results suggest that the correlations between LRRK2 and inflammation of the CNS exist and that LRRK2 activity targeting could have direct effects on the intervention of neuroinflammatory disorders. |
format | Online Article Text |
id | pubmed-9495377 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94953772022-09-23 LRRK2 Inhibition by PF06447475 Antagonist Modulates Early Neuronal Damage after Spinal Cord Trauma Filippone, Alessia Mannino, Deborah Cucinotta, Laura Paterniti, Irene Esposito, Emanuela Campolo, Michela Antioxidants (Basel) Article Spinal cord injury (SCI) is a devastating event followed by neurodegeneration, activation of the inflammatory cascade, and immune system. The leucine-rich-repeat kinase 2 (LRRK2) is a gene associated with Parkinson’s disease (PD), moreover, its kinase activity was found to be upregulated after instigated inflammation of the central nervous system (CNS). Here, we aimed to investigate the PF06447475 (abbreviated as PF-475) role as a pharmacological LRRK2 antagonist by counteracting pathological consequences of spinal cord trauma. The in vivo model of SCI was induced by extradural compression of the spinal cord, then mice were treated with PF0-475 (2.5–5 and 10 mg/kg i.p) 1 and 6 h after SCI. We found that PF-475 treatments at the higher doses (5 and 10 mg/kg) showed a great ability to significantly reduce the degree of spinal cord tissue injury, glycogen accumulation, and demyelination of neurons associated with trauma. Furthermore, oxidative stress and cytokines expression levels, including interleukins (IL-1, IL-6, IL-10, and 12), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), secreted and released after trauma were decreased by LRRK2 antagonist treatments. Our results suggest that the correlations between LRRK2 and inflammation of the CNS exist and that LRRK2 activity targeting could have direct effects on the intervention of neuroinflammatory disorders. MDPI 2022-08-23 /pmc/articles/PMC9495377/ /pubmed/36139708 http://dx.doi.org/10.3390/antiox11091634 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Filippone, Alessia Mannino, Deborah Cucinotta, Laura Paterniti, Irene Esposito, Emanuela Campolo, Michela LRRK2 Inhibition by PF06447475 Antagonist Modulates Early Neuronal Damage after Spinal Cord Trauma |
title | LRRK2 Inhibition by PF06447475 Antagonist Modulates Early Neuronal Damage after Spinal Cord Trauma |
title_full | LRRK2 Inhibition by PF06447475 Antagonist Modulates Early Neuronal Damage after Spinal Cord Trauma |
title_fullStr | LRRK2 Inhibition by PF06447475 Antagonist Modulates Early Neuronal Damage after Spinal Cord Trauma |
title_full_unstemmed | LRRK2 Inhibition by PF06447475 Antagonist Modulates Early Neuronal Damage after Spinal Cord Trauma |
title_short | LRRK2 Inhibition by PF06447475 Antagonist Modulates Early Neuronal Damage after Spinal Cord Trauma |
title_sort | lrrk2 inhibition by pf06447475 antagonist modulates early neuronal damage after spinal cord trauma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9495377/ https://www.ncbi.nlm.nih.gov/pubmed/36139708 http://dx.doi.org/10.3390/antiox11091634 |
work_keys_str_mv | AT filipponealessia lrrk2inhibitionbypf06447475antagonistmodulatesearlyneuronaldamageafterspinalcordtrauma AT manninodeborah lrrk2inhibitionbypf06447475antagonistmodulatesearlyneuronaldamageafterspinalcordtrauma AT cucinottalaura lrrk2inhibitionbypf06447475antagonistmodulatesearlyneuronaldamageafterspinalcordtrauma AT paternitiirene lrrk2inhibitionbypf06447475antagonistmodulatesearlyneuronaldamageafterspinalcordtrauma AT espositoemanuela lrrk2inhibitionbypf06447475antagonistmodulatesearlyneuronaldamageafterspinalcordtrauma AT campolomichela lrrk2inhibitionbypf06447475antagonistmodulatesearlyneuronaldamageafterspinalcordtrauma |