Tags

Type your tag names separated by a space and hit enter

CR8, a novel inhibitor of CDK, limits microglial activation, astrocytosis, neuronal loss, and neurologic dysfunction after experimental traumatic brain injury.
J Cereb Blood Flow Metab. 2014 Mar; 34(3):502-13.JC

Abstract

Central nervous system injury causes a marked increase in the expression of cell cycle-related proteins. In this study, we show that cell cycle activation (CCA) is detected in mature neurons at 24 hours after rat lateral fluid percussion (LFP)-induced traumatic brain injury (TBI), as reflected by increased expression of cyclin G1, phosphorylated retinoblastoma (phospho-Rb), E2F1 and proliferating cell nuclear antigen (PCNA). These changes were associated with progressive cortical, hippocampal, and thalamic neuronal loss and microglial and astrocyte activation. Notably, we detected 5-bromo-2'-deoxyuridine (BrdU)-positive neurons, microglia, and astrocytes at 7 days, but not at 24 hours, suggesting that cell cycle reaches the S phase in these cell types at the latter time point. A delayed systemic post-LFP administration at 3 hours of CR8--a potent second-generation cyclin-dependent kinase (CDK) inhibitor--reduced CCA; cortical, hippocampal, and thalamic neuronal loss; and cortical microglial and astrocyte activation. Furthermore, CR8 treatment attenuated sensorimotor and cognitive deficits, alleviated depressive-like symptoms, and decreased lesion volume. These findings underscore the contribution of CCA to progressive neurodegeneration and chronic neuroinflammation following TBI, and demonstrate the neuroprotective potential of cell cycle inhibition in a clinically relevant experimental TBI model.

Authors+Show Affiliations

Department of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR-ORC), National Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, Maryland, USA.Department of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR-ORC), National Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, Maryland, USA.Department of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR-ORC), National Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, Maryland, USA.Department of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR-ORC), National Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, Maryland, USA.Department of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR-ORC), National Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Pub Type(s)

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

Language

eng

PubMed ID

24398934

Citation

Kabadi, Shruti V., et al. "CR8, a Novel Inhibitor of CDK, Limits Microglial Activation, Astrocytosis, Neuronal Loss, and Neurologic Dysfunction After Experimental Traumatic Brain Injury." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 34, no. 3, 2014, pp. 502-13.
Kabadi SV, Stoica BA, Loane DJ, et al. CR8, a novel inhibitor of CDK, limits microglial activation, astrocytosis, neuronal loss, and neurologic dysfunction after experimental traumatic brain injury. J Cereb Blood Flow Metab. 2014;34(3):502-13.
Kabadi, S. V., Stoica, B. A., Loane, D. J., Luo, T., & Faden, A. I. (2014). CR8, a novel inhibitor of CDK, limits microglial activation, astrocytosis, neuronal loss, and neurologic dysfunction after experimental traumatic brain injury. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 34(3), 502-13. https://doi.org/10.1038/jcbfm.2013.228
Kabadi SV, et al. CR8, a Novel Inhibitor of CDK, Limits Microglial Activation, Astrocytosis, Neuronal Loss, and Neurologic Dysfunction After Experimental Traumatic Brain Injury. J Cereb Blood Flow Metab. 2014;34(3):502-13. PubMed PMID: 24398934.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CR8, a novel inhibitor of CDK, limits microglial activation, astrocytosis, neuronal loss, and neurologic dysfunction after experimental traumatic brain injury. AU - Kabadi,Shruti V, AU - Stoica,Bogdan A, AU - Loane,David J, AU - Luo,Tao, AU - Faden,Alan I, Y1 - 2014/01/08/ PY - 2013/09/03/received PY - 2013/11/08/revised PY - 2013/12/02/accepted PY - 2014/1/9/entrez PY - 2014/1/9/pubmed PY - 2014/4/29/medline SP - 502 EP - 13 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 - 34 IS - 3 N2 - Central nervous system injury causes a marked increase in the expression of cell cycle-related proteins. In this study, we show that cell cycle activation (CCA) is detected in mature neurons at 24 hours after rat lateral fluid percussion (LFP)-induced traumatic brain injury (TBI), as reflected by increased expression of cyclin G1, phosphorylated retinoblastoma (phospho-Rb), E2F1 and proliferating cell nuclear antigen (PCNA). These changes were associated with progressive cortical, hippocampal, and thalamic neuronal loss and microglial and astrocyte activation. Notably, we detected 5-bromo-2'-deoxyuridine (BrdU)-positive neurons, microglia, and astrocytes at 7 days, but not at 24 hours, suggesting that cell cycle reaches the S phase in these cell types at the latter time point. A delayed systemic post-LFP administration at 3 hours of CR8--a potent second-generation cyclin-dependent kinase (CDK) inhibitor--reduced CCA; cortical, hippocampal, and thalamic neuronal loss; and cortical microglial and astrocyte activation. Furthermore, CR8 treatment attenuated sensorimotor and cognitive deficits, alleviated depressive-like symptoms, and decreased lesion volume. These findings underscore the contribution of CCA to progressive neurodegeneration and chronic neuroinflammation following TBI, and demonstrate the neuroprotective potential of cell cycle inhibition in a clinically relevant experimental TBI model. SN - 1559-7016 UR - https://www.unboundmedicine.com/medline/citation/24398934/CR8_a_novel_inhibitor_of_CDK_limits_microglial_activation_astrocytosis_neuronal_loss_and_neurologic_dysfunction_after_experimental_traumatic_brain_injury_ L2 - http://journals.sagepub.com/doi/full/10.1038/jcbfm.2013.228?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -