Document Detail

Delayed cell cycle pathway modulation facilitates recovery after spinal cord injury.
MedLine Citation:
PMID:  22510563     Owner:  NLM     Status:  MEDLINE    
Traumatic spinal cord injury (SCI) causes tissue loss and associated neurological dysfunction through mechanical damage and secondary biochemical and physiological responses. We have previously described the pathobiological role of cell cycle pathways following rat contusion SCI by examining the effects of early intrathecal cell cycle inhibitor treatment initiation or gene knockout on secondary injury. Here, we delineate changes in cell cycle pathway activation following SCI and examine the effects of delayed (24 h) systemic administration of flavopiridol, an inhibitor of major cyclin-dependent kinases (CDKs), on functional recovery and histopathology in a rat SCI contusion model. Immunoblot analysis demonstrated a marked upregulation of cell cycle-related proteins, including pRb, cyclin D1, CDK4, E2F1 and PCNA, at various time points following SCI, along with downregulation of the endogenous CDK inhibitor p27. Treatment with flavopiridol reduced induction of cell cycle proteins and increased p27 expression in the injured spinal cord. Functional recovery was significantly improved after SCI from day 7 through day 28. Treatment significantly reduced lesion volume and the number of Iba-1(+) microglia in the preserved tissue and increased the myelinated area of spared white matter as well as the number of CC1(+) oligodendrocytes. Furthermore, flavopiridol attenuated expression of Iba-1 and glactin-3, associated with microglial activation and astrocytic reactivity by reduction of GFAP, NG2, and CHL1 expression. Our current study supports the role of cell cycle activation in the pathophysiology of SCI and by using a clinically relevant treatment model, provides further support for the therapeutic potential of cell cycle inhibitors in the treatment of human SCI.
Junfang Wu; Bogdan A Stoica; Michael Dinizo; Ahdeah Pajoohesh-Ganji; Chunshu Piao; Alan I Faden
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-05-01
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-17     Completed Date:  2012-09-17     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1782-95     Citation Subset:  IM    
Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.
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MeSH Terms
Calcium-Binding Proteins / metabolism
Cell Cycle*
Cell Cycle Proteins / metabolism
Cyclin D1 / metabolism
Cyclin-Dependent Kinase 4 / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
E2F1 Transcription Factor / metabolism
Flavonoids / administration & dosage,  pharmacology*
Microfilament Proteins / metabolism
Microglia / drug effects,  metabolism
Neurons / drug effects
Oligodendroglia / drug effects,  metabolism
Piperidines / administration & dosage,  pharmacology*
Proliferating Cell Nuclear Antigen / metabolism
Rats, Sprague-Dawley
Spinal Cord / metabolism,  physiopathology
Spinal Cord Injuries / drug therapy,  physiopathology*
Time Factors
Grant Support
Reg. No./Substance:
0/Aif1 protein, rat; 0/Calcium-Binding Proteins; 0/Ccnd1 protein, rat; 0/Cdkn1b protein, rat; 0/Cell Cycle Proteins; 0/E2F1 Transcription Factor; 0/E2f1 protein, rat; 0/Flavonoids; 0/Microfilament Proteins; 0/Piperidines; 0/Proliferating Cell Nuclear Antigen; 136601-57-5/Cyclin D1; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 45AD6X575G/alvocidib; EC protein, rat; EC Kinase 4

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