c-Jun N-terminal kinase pathway activation in human and experimental cerebral contusion.
The c-Jun N-terminal kinase (JNK) pathway is involved in cell stress and apoptosis. We tested the hypothesis that this pathway plays a role in traumatic brain injury (TBI) by assessing JNK activation in human brain tissues and in brains of mice subjected to controlled cortical impact brain injury. We also assessed the effects of specific inhibition of the JNK pathway by the cell-permeable JNK inhibitor peptide, D-JNKI1, on neurobehavioral function and posttraumatic cell loss in mice. The inhibitor was administered intraperitoneally 10 minutes after injury. The JNK pathway showed robust activation both in human contusion specimens and in injured cortex and hippocampi of TBI-injured mice, 1, 4, and 48 hours after injury. D-JNKI1 treatment significantly improved motor performance at 48 hours and 7 days after injury and reduced the contusion volume compared with saline treatment; the numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were significantly decreased in the hippocampi of injured mice 48 hours after treatment. Thus, because the JNK pathway is activated after human and experimental TBI and the inhibitor peptide D-JNKI1 affords significant neuroprotection and amelioration of neurobehavioral deficits after experimental TBI, therapeutic targeting of the JNK activation pathway may hold promise for future clinical applications.
Ortolano
Fabrizio
F
Department of Neuroscience, Mario Negri Institute; Università di Milan, Neurosurgical Intensive Care Unit, Department of Anesthesia and Critical Care Medicine, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy.
Colombo
Alessio
A
Zanier
Elisa Roncati
ER
Sclip
Allessandra
A
Longhi
Luca
L
Perego
Carlo
C
Stocchetti
Nino
N
Borsello
Tiziana
T
De Simoni
Maria Grazia
MG
D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014057:Tomography, X-Ray Computed
D004791:Enzyme Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases