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Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model

Calpain activation has been implicated in various pathologies, including neurodegeneration. Thus, calpain inhibition could effectively prevent spinal cord injury (SCI) associated with neurodegeneration. In the current study, a dog SCI model was used to evaluate the therapeutic potential of a selecti...

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Autores principales: Metwally, Elsayed, Al-Abbadi, Hatim A., Hashem, Mohamed A., Mahmoud, Yasmina K., Ahmed, Eman A., Maaty, Ahmed I., Helal, Ibrahim E., Ahmed, Mahmoud F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9570220/
https://www.ncbi.nlm.nih.gov/pubmed/36233068
http://dx.doi.org/10.3390/ijms231911772
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author Metwally, Elsayed
Al-Abbadi, Hatim A.
Hashem, Mohamed A.
Mahmoud, Yasmina K.
Ahmed, Eman A.
Maaty, Ahmed I.
Helal, Ibrahim E.
Ahmed, Mahmoud F.
author_facet Metwally, Elsayed
Al-Abbadi, Hatim A.
Hashem, Mohamed A.
Mahmoud, Yasmina K.
Ahmed, Eman A.
Maaty, Ahmed I.
Helal, Ibrahim E.
Ahmed, Mahmoud F.
author_sort Metwally, Elsayed
collection PubMed
description Calpain activation has been implicated in various pathologies, including neurodegeneration. Thus, calpain inhibition could effectively prevent spinal cord injury (SCI) associated with neurodegeneration. In the current study, a dog SCI model was used to evaluate the therapeutic potential of a selective calpain inhibitor (PD150606) in combination with methylprednisolone sodium succinate (MPSS) as an anti-inflammatory drug. SCI was experimentally induced in sixteen mongrel dogs through an epidural balloon compression technique. The dogs were allocated randomly into four groups: control, MPSS, PD150606, and MPSS+PD150606. Clinical evaluation, serum biochemical, somatosensory evoked potentials, histopathological, and immunoblotting analyses were performed to assess treated dogs during the study. The current findings revealed that the combined administration of MPSS+PD150606 demonstrated considerably lower neuronal loss and microglial cell infiltration than the other groups, with a significant improvement in the locomotor score. The increased levels of inflammatory markers (GFAP and CD11) and calcium-binding proteins (Iba1 and S100) were significantly reduced in the combination group and to a lesser extent in MPSS or PD150606 treatment alone. Interestingly, the combined treatment effectively inhibited the calpain-induced cleavage of p35, limited cdk5 activation, and inhibited tau phosphorylation. These results suggest that early MPSS+PD150606 therapy after acute SCI may prevent subsequent neurodegeneration via calpain inhibition.
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spelling pubmed-95702202022-10-17 Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model Metwally, Elsayed Al-Abbadi, Hatim A. Hashem, Mohamed A. Mahmoud, Yasmina K. Ahmed, Eman A. Maaty, Ahmed I. Helal, Ibrahim E. Ahmed, Mahmoud F. Int J Mol Sci Article Calpain activation has been implicated in various pathologies, including neurodegeneration. Thus, calpain inhibition could effectively prevent spinal cord injury (SCI) associated with neurodegeneration. In the current study, a dog SCI model was used to evaluate the therapeutic potential of a selective calpain inhibitor (PD150606) in combination with methylprednisolone sodium succinate (MPSS) as an anti-inflammatory drug. SCI was experimentally induced in sixteen mongrel dogs through an epidural balloon compression technique. The dogs were allocated randomly into four groups: control, MPSS, PD150606, and MPSS+PD150606. Clinical evaluation, serum biochemical, somatosensory evoked potentials, histopathological, and immunoblotting analyses were performed to assess treated dogs during the study. The current findings revealed that the combined administration of MPSS+PD150606 demonstrated considerably lower neuronal loss and microglial cell infiltration than the other groups, with a significant improvement in the locomotor score. The increased levels of inflammatory markers (GFAP and CD11) and calcium-binding proteins (Iba1 and S100) were significantly reduced in the combination group and to a lesser extent in MPSS or PD150606 treatment alone. Interestingly, the combined treatment effectively inhibited the calpain-induced cleavage of p35, limited cdk5 activation, and inhibited tau phosphorylation. These results suggest that early MPSS+PD150606 therapy after acute SCI may prevent subsequent neurodegeneration via calpain inhibition. MDPI 2022-10-04 /pmc/articles/PMC9570220/ /pubmed/36233068 http://dx.doi.org/10.3390/ijms231911772 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
Metwally, Elsayed
Al-Abbadi, Hatim A.
Hashem, Mohamed A.
Mahmoud, Yasmina K.
Ahmed, Eman A.
Maaty, Ahmed I.
Helal, Ibrahim E.
Ahmed, Mahmoud F.
Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model
title Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model
title_full Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model
title_fullStr Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model
title_full_unstemmed Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model
title_short Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model
title_sort selective calpain inhibition improves functional and histopathological outcomes in a canine spinal cord injury model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9570220/
https://www.ncbi.nlm.nih.gov/pubmed/36233068
http://dx.doi.org/10.3390/ijms231911772
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