title: CR8, a novel inhibitor of CDK, limits microglial activation, astrocytosis, neuronal loss, and neurologic dysfunction after experimental traumatic brain injury.
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.affiliation: 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.
authors.forename: Shruti V
authors.initials: SV
authors.lastname: Kabadi
authors.affiliation: 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.
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Stoica
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Loane
authors.affiliation: 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.
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.affiliation: 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.
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C532131:CR8 compound; D018696:Neuroprotective Agents; D011687:Purines; D011725:Pyridines; D018844:Cyclin-Dependent Kinases