title: Selective CDK inhibitor limits neuroinflammation and progressive neurodegeneration after brain trauma.
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.affiliation: Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Shruti V
authors.initials: SV
authors.lastname: Kabadi
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Stoica
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Byrnes
authors.forename: Marie
authors.initials: M
authors.lastname: Hanscom
authors.forename: David J
authors.initials: DJ
authors.lastname: Loane
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001930:Brain Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D002352:Carrier Proteins / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D019925:Cyclin A / Q000096:biosynthesis; D019938:Cyclin D1 / Q000096:biosynthesis; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000096:biosynthesis; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011687:Purines / Q000008:administration & dosage / Q000627:therapeutic use*; D000077546:Roscovitine; D013997:Time Factors; D013049:Spectrin
chemical_list: D002352:Carrier Proteins; D019925:Cyclin A; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D011687:Purines; D000077546:Roscovitine; D013049:Spectrin