Involvement of ERK2 in traumatic spinal cord injury.
Activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) are implicated in the pathophysiology of spinal cord injury (SCI). However, the specific functions of individual ERK isoforms in neurodegeneration are largely unknown. We investigated the hypothesis that ERK2 activation may contribute to pathological and functional deficits following SCI and that ERK2 knockdown using RNA interference may provide a novel therapeutic strategy for SCI. Lentiviral ERK2 shRNA and siRNA were utilized to knockdown ERK2 expression in the spinal cord following SCI. Pre-injury intrathecal administration of ERK2 siRNA significantly reduced excitotoxic injury-induced activation of ERK2 (p < 0.001) and caspase 3 (p < 0.01) in spinal cord. Intraspinal administration of lentiviral ERK2 shRNA significantly reduced ERK2 expression in the spinal cord (p < 0.05), but did not alter ERK1 expression. Administration of the lentiviral ERK2 shRNA vector 1 week prior to severe spinal cord contusion injury resulted in a significant improvement in locomotor function (p < 0.05), total tissue sparing (p < 0.05), white matter sparing (p < 0.05), and gray matter sparing (p < 0.05) 6 weeks following severe contusive SCI. Our results suggest that ERK2 signaling is a novel target associated with the deleterious consequences of spinal injury.
Yu
Chen-Guang
CG
Spinal Cord and Brain Injury Research Center and Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA. cyu4@uky.edu
Yezierski
Robert P
RP
Joshi
Aashish
A
Raza
Kashif
K
Li
Yanzhang
Y
Geddes
James W
JW
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D007278:Injections, Spinal / Q000379:methods; D007796:Laminectomy / Q000379:methods; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D016318:Quisqualic Acid; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D013119:Spinal Cord Injuries / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D014162:Transfection / Q000379:methods
D034741:RNA, Small Interfering; D016318:Quisqualic Acid; D019950:Mitogen-Activated Protein Kinase 1