Cargando…

Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion

BACKGROUND: Traumatic spinal cord injury (SCI) induces secondary tissue damage that is associated with astrogliosis and inflammation. We previously reported that acute upregulation of a cluster of cell-cycle-related genes contributes to post-mitotic cell death and secondary damage after SCI. However...

Descripción completa

Detalles Bibliográficos
Autores principales: Wu, Junfang, Pajoohesh-Ganji, Ahdeah, Stoica, Bogdan A, Dinizo, Michael, Guanciale, Kelsey, Faden, Alan I
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410790/
https://www.ncbi.nlm.nih.gov/pubmed/22784881
http://dx.doi.org/10.1186/1742-2094-9-169
_version_ 1782239762702139392
author Wu, Junfang
Pajoohesh-Ganji, Ahdeah
Stoica, Bogdan A
Dinizo, Michael
Guanciale, Kelsey
Faden, Alan I
author_facet Wu, Junfang
Pajoohesh-Ganji, Ahdeah
Stoica, Bogdan A
Dinizo, Michael
Guanciale, Kelsey
Faden, Alan I
author_sort Wu, Junfang
collection PubMed
description BACKGROUND: Traumatic spinal cord injury (SCI) induces secondary tissue damage that is associated with astrogliosis and inflammation. We previously reported that acute upregulation of a cluster of cell-cycle-related genes contributes to post-mitotic cell death and secondary damage after SCI. However, it remains unclear whether cell cycle activation continues more chronically and contributes to more delayed glial change. Here we examined expression of cell cycle-related proteins up to 4 months following SCI, as well as the effects of the selective cyclin-dependent kinase (CDKs) inhibitor CR8, on astrogliosis and microglial activation in a rat SCI contusion model. METHODS: Adult male rats were subjected to moderate spinal cord contusion injury at T8 using a well-characterized weight-drop model. Tissue from the lesion epicenter was obtained 4 weeks or 4 months post-injury, and processed for protein expression and lesion volume. Functional recovery was assessed over the 4 months after injury. RESULTS: Immunoblot analysis demonstrated a marked continued upregulation of cell cycle-related proteins − including cyclin D1 and E, CDK4, E2F5 and PCNA − for 4 months post-injury that were highly expressed by GFAP(+) astrocytes and microglia, and co-localized with inflammatory-related proteins. CR8 administrated systemically 3 h post-injury and continued for 7 days limited the sustained elevation of cell cycle proteins and immunoreactivity of GFAP, Iba-1 and p22(PHOX) − a key component of NADPH oxidase − up to 4 months after SCI. CR8 treatment significantly reduced lesion volume, which typically progressed in untreated animals between 1 and 4 months after trauma. Functional recovery was also significantly improved by CR8 treatment after SCI from week 2 through week 16. CONCLUSIONS: These data demonstrate that cell cycle-related proteins are chronically upregulated after SCI and may contribute to astroglial scar formation, chronic inflammation and further tissue loss.
format Online
Article
Text
id pubmed-3410790
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-34107902012-08-03 Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion Wu, Junfang Pajoohesh-Ganji, Ahdeah Stoica, Bogdan A Dinizo, Michael Guanciale, Kelsey Faden, Alan I J Neuroinflammation Research BACKGROUND: Traumatic spinal cord injury (SCI) induces secondary tissue damage that is associated with astrogliosis and inflammation. We previously reported that acute upregulation of a cluster of cell-cycle-related genes contributes to post-mitotic cell death and secondary damage after SCI. However, it remains unclear whether cell cycle activation continues more chronically and contributes to more delayed glial change. Here we examined expression of cell cycle-related proteins up to 4 months following SCI, as well as the effects of the selective cyclin-dependent kinase (CDKs) inhibitor CR8, on astrogliosis and microglial activation in a rat SCI contusion model. METHODS: Adult male rats were subjected to moderate spinal cord contusion injury at T8 using a well-characterized weight-drop model. Tissue from the lesion epicenter was obtained 4 weeks or 4 months post-injury, and processed for protein expression and lesion volume. Functional recovery was assessed over the 4 months after injury. RESULTS: Immunoblot analysis demonstrated a marked continued upregulation of cell cycle-related proteins − including cyclin D1 and E, CDK4, E2F5 and PCNA − for 4 months post-injury that were highly expressed by GFAP(+) astrocytes and microglia, and co-localized with inflammatory-related proteins. CR8 administrated systemically 3 h post-injury and continued for 7 days limited the sustained elevation of cell cycle proteins and immunoreactivity of GFAP, Iba-1 and p22(PHOX) − a key component of NADPH oxidase − up to 4 months after SCI. CR8 treatment significantly reduced lesion volume, which typically progressed in untreated animals between 1 and 4 months after trauma. Functional recovery was also significantly improved by CR8 treatment after SCI from week 2 through week 16. CONCLUSIONS: These data demonstrate that cell cycle-related proteins are chronically upregulated after SCI and may contribute to astroglial scar formation, chronic inflammation and further tissue loss. BioMed Central 2012-07-11 /pmc/articles/PMC3410790/ /pubmed/22784881 http://dx.doi.org/10.1186/1742-2094-9-169 Text en Copyright ©2012 Wu et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Wu, Junfang
Pajoohesh-Ganji, Ahdeah
Stoica, Bogdan A
Dinizo, Michael
Guanciale, Kelsey
Faden, Alan I
Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion
title Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion
title_full Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion
title_fullStr Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion
title_full_unstemmed Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion
title_short Delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion
title_sort delayed expression of cell cycle proteins contributes to astroglial scar formation and chronic inflammation after rat spinal cord contusion
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410790/
https://www.ncbi.nlm.nih.gov/pubmed/22784881
http://dx.doi.org/10.1186/1742-2094-9-169
work_keys_str_mv AT wujunfang delayedexpressionofcellcycleproteinscontributestoastroglialscarformationandchronicinflammationafterratspinalcordcontusion
AT pajooheshganjiahdeah delayedexpressionofcellcycleproteinscontributestoastroglialscarformationandchronicinflammationafterratspinalcordcontusion
AT stoicabogdana delayedexpressionofcellcycleproteinscontributestoastroglialscarformationandchronicinflammationafterratspinalcordcontusion
AT dinizomichael delayedexpressionofcellcycleproteinscontributestoastroglialscarformationandchronicinflammationafterratspinalcordcontusion
AT guancialekelsey delayedexpressionofcellcycleproteinscontributestoastroglialscarformationandchronicinflammationafterratspinalcordcontusion
AT fadenalani delayedexpressionofcellcycleproteinscontributestoastroglialscarformationandchronicinflammationafterratspinalcordcontusion