title: Delayed cell cycle pathway modulation facilitates recovery after spinal cord injury.
abstract: 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.
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA. jwu@anes.umm.edu
authors.forename: Junfang
authors.initials: J
authors.lastname: Wu
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Stoica
authors.forename: Michael
authors.initials: M
authors.lastname: Dinizo
authors.forename: Ahdeah
authors.initials: A
authors.lastname: Pajoohesh-Ganji
authors.forename: Chunshu
authors.initials: C
authors.lastname: Piao
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000818:Animals; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D008124:Locomotion; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000503:physiopathology*; D013997:Time Factors
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; C530106:Ccnd1 protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D050687:E2F1 Transcription Factor; C493755:E2f1 protein, rat; D005419:Flavonoids; D008840:Microfilament Proteins; D010880:Piperidines; D018809:Proliferating Cell Nuclear Antigen; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C077990:alvocidib; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4