Original Article

Neurotherapeutics

, Volume 9, Issue 2, pp 405-421

CR8, a Selective and Potent CDK Inhibitor, Provides Neuroprotection in Experimental Traumatic Brain Injury

  • Shruti V. KabadiAffiliated withDepartment of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine
  • , Bogdan A. StoicaAffiliated withDepartment of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine Email author 
  • , Marie HanscomAffiliated withDepartment of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine
  • , David J. LoaneAffiliated withDepartment of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine
  • , Giorgi KharebavaAffiliated withDepartment of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine
  • , Michael G. Murray IIAffiliated withDepartment of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine
  • , Rainier M. CabatbatAffiliated withDepartment of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine
  • , Alan I. FadenAffiliated withDepartment of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine

Abstract

Traumatic brain injury (TBI) induces secondary injury mechanisms, including cell cycle activation (CCA), that leads to neuronal death and neurological dysfunction. We recently reported that delayed administration of roscovitine, a relatively selective cyclin-dependent kinase (CDK) inhibitor, inhibits CCA and attenuates neurodegeneration and functional deficits following controlled cortical impact (CCI) injury in mice. Here we evaluated the neuroprotective potential of CR8, a more potent second-generation roscovitine analog, using the mouse CCI model. Key CCA markers (cyclin A and B1) were significantly up-regulated in the injured cortex following TBI, and phosphorylation of CDK substrates was increased. Central administration of CR8 after TBI, at a dose 20 times less than previously required for roscovitine, attenuated CCA pathways and reduced post-traumatic apoptotic cell death at 24 h post-TBI. Central administration of CR8, at 3 h after TBI, significantly attenuated sensorimotor and cognitive deficits, decreased lesion volume, and improved neuronal survival in the cortex and dentate gyrus. Moreover, unlike roscovitine treatment in the same model, CR8 also attenuated post-traumatic neurodegeneration in the CA3 region of the hippocampus and thalamus at 21 days. Furthermore, delayed systemic administration of CR8, at a dose 10 times less than previously required for roscovitine, significantly improved cognitive performance after CCI. These findings further demonstrate the neuroprotective potential of cell cycle inhibitors following experimental TBI. Given the increased potency and efficacy of CR8 as compared to earlier purine analog types of CDK inhibitors, this drug should be considered as a candidate for future clinical trials of TBI.

Keywords

Cell cycle Traumatic brain injury Cyclin-dependent kinases Neurodegeneration Neuroprotection CR8