title: Cyclin D1 gene ablation confers neuroprotection in traumatic brain injury.
abstract: Cell cycle activation (CCA) is one of the principal secondary injury mechanisms following brain trauma, and it leads to neuronal cell death, microglial activation, and neurological dysfunction. Cyclin D1 (CD1) is a key modulator of CCA and is upregulated in neurons and microglia following traumatic brain injury (TBI). In this study we subjected CD1-wild-type (CD1(+/+)) and knockout (CD1(-/-)) mice to controlled cortical impact (CCI) injury to evaluate the role of CD1 in post-traumatic neurodegeneration and neuroinflammation. As early as 24 h post-injury, CD1(+/+) mice showed markers of CCA in the injured hemisphere, including increased CD1, E2F1, and proliferating cell nuclear antigen (PCNA), as well as increased Fluoro-Jade B staining, indicating neuronal degeneration. Progressive neuronal loss in the hippocampus was observed through 21 days post-injury in these mice, which correlated with a decline in cognitive function. Microglial activation in the injured hemisphere peaked at 7 days post-injury, with sustained increases at 21 days. In contrast, CD1(-/-) mice showed reduced CCA and neurodegeneration at 24 h, as well as improved cognitive function, attenuated hippocampal neuronal cell loss, decreased lesion volume, and cortical microglial activation at 21 days post-injury. These findings indicate that CD1-dependent CCA plays a significant role in the neuroinflammation, progressive neurodegeneration, and related neurological dysfunction resulting from TBI. Our results further substantiate the proposed role of CCA in post-traumatic secondary injury, and suggest that inhibition of CD1 may be a key therapeutic target for TBI.
authors: Center for Shock, Trauma and Anesthesiology Research (STAR), Department of Anesthesiology, University of Maryland, School of Medicine, Baltimore, Maryland 21201, USA.
authors: Shruti V
authors: SV
authors: Kabadi
authors: Bogdan A
authors: BA
authors: Stoica
authors: David J
authors: DJ
authors: Loane
authors: Kimberly R
authors: KR
authors: Byrnes
authors: Marie
authors: M
authors: Hanscom
authors: Rainier M
authors: RM
authors: Cabatbat
authors: Ming T
authors: MT
authors: Tan
authors: Alan I
authors: AI
authors: Faden
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D002453:Cell Cycle / Q000502:physiology*; D019938:Cyclin D1 / Q000235:genetics*; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control
chemical_list: C530105:Ccnd1 protein, mouse; D019938:Cyclin D1