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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...

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Autores principales: Filippone, Alessia, Mannino, Deborah, Cucinotta, Laura, Paterniti, Irene, Esposito, Emanuela, Campolo, Michela
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
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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.
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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
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