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Selective CDK inhibitor limits neuroinflammation and progressive neurodegeneration after brain trauma.
J Cereb Blood Flow Metab. 2012 Jan; 32(1):137-49.JC

Abstract

Traumatic brain injury (TBI) induces secondary injury mechanisms, including cell-cycle activation (CCA), which lead to neuronal cell death, microglial activation, and neurologic dysfunction. Here, we show progressive neurodegeneration associated with microglial activation after TBI induced by controlled cortical impact (CCI), and also show that delayed treatment with the selective cyclin-dependent kinase inhibitor roscovitine attenuates posttraumatic neurodegeneration and neuroinflammation. CCI resulted in increased cyclin A and D1 expressions and fodrin cleavage in the injured cortex at 6 hours after injury and significant neurodegeneration by 24 hours after injury. Progressive neuronal loss occurred in the injured hippocampus through 21 days after injury and correlated with a decline in cognitive function. Microglial activation associated with a reactive microglial phenotype peaked at 7 days after injury with sustained increases at 21 days. Central administration of roscovitine at 3 hours after CCI reduced subsequent cyclin A and D1 expressions and fodrin cleavage, improved functional recovery, decreased lesion volume, and attenuated hippocampal and cortical neuronal cell loss and cortical microglial activation. Furthermore, delayed systemic administration of roscovitine improved motor recovery and attenuated microglial activation after CCI. These findings suggest that CCA contributes to progressive neurodegeneration and related neurologic dysfunction after TBI, likely in part related to its induction of microglial activation.

Authors+Show Affiliations

Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21829212

Citation

Kabadi, Shruti V., et al. "Selective CDK Inhibitor Limits Neuroinflammation and Progressive Neurodegeneration After Brain Trauma." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 32, no. 1, 2012, pp. 137-49.
Kabadi SV, Stoica BA, Byrnes KR, et al. Selective CDK inhibitor limits neuroinflammation and progressive neurodegeneration after brain trauma. J Cereb Blood Flow Metab. 2012;32(1):137-49.
Kabadi, S. V., Stoica, B. A., Byrnes, K. R., Hanscom, M., Loane, D. J., & Faden, A. I. (2012). Selective CDK inhibitor limits neuroinflammation and progressive neurodegeneration after brain trauma. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 32(1), 137-49. https://doi.org/10.1038/jcbfm.2011.117
Kabadi SV, et al. Selective CDK Inhibitor Limits Neuroinflammation and Progressive Neurodegeneration After Brain Trauma. J Cereb Blood Flow Metab. 2012;32(1):137-49. PubMed PMID: 21829212.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective CDK inhibitor limits neuroinflammation and progressive neurodegeneration after brain trauma. AU - Kabadi,Shruti V, AU - Stoica,Bogdan A, AU - Byrnes,Kimberly R, AU - Hanscom,Marie, AU - Loane,David J, AU - Faden,Alan I, Y1 - 2011/08/10/ PY - 2011/8/11/entrez PY - 2011/8/11/pubmed PY - 2012/3/1/medline SP - 137 EP - 49 JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JO - J. Cereb. Blood Flow Metab. VL - 32 IS - 1 N2 - Traumatic brain injury (TBI) induces secondary injury mechanisms, including cell-cycle activation (CCA), which lead to neuronal cell death, microglial activation, and neurologic dysfunction. Here, we show progressive neurodegeneration associated with microglial activation after TBI induced by controlled cortical impact (CCI), and also show that delayed treatment with the selective cyclin-dependent kinase inhibitor roscovitine attenuates posttraumatic neurodegeneration and neuroinflammation. CCI resulted in increased cyclin A and D1 expressions and fodrin cleavage in the injured cortex at 6 hours after injury and significant neurodegeneration by 24 hours after injury. Progressive neuronal loss occurred in the injured hippocampus through 21 days after injury and correlated with a decline in cognitive function. Microglial activation associated with a reactive microglial phenotype peaked at 7 days after injury with sustained increases at 21 days. Central administration of roscovitine at 3 hours after CCI reduced subsequent cyclin A and D1 expressions and fodrin cleavage, improved functional recovery, decreased lesion volume, and attenuated hippocampal and cortical neuronal cell loss and cortical microglial activation. Furthermore, delayed systemic administration of roscovitine improved motor recovery and attenuated microglial activation after CCI. These findings suggest that CCA contributes to progressive neurodegeneration and related neurologic dysfunction after TBI, likely in part related to its induction of microglial activation. SN - 1559-7016 UR - https://www.unboundmedicine.com/medline/citation/21829212/Selective_CDK_inhibitor_limits_neuroinflammation_and_progressive_neurodegeneration_after_brain_trauma_ L2 - http://journals.sagepub.com/doi/full/10.1038/jcbfm.2011.117?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -