Ortolano Fabrizio, Colombo Alessio, Zanier Elisa Roncati, Sclip Allessandra, Longhi Luca, Perego Carlo, Stocchetti Nino, Borsello Tiziana, De Simoni Maria Grazia
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.
J Neuropathol Exp Neurol. 2009 Sep;68(9):964-71. doi: 10.1097/NEN.0b013e3181b20670.
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.
c-Jun氨基末端激酶（JNK）通路参与细胞应激和凋亡。我们通过评估人脑组织以及遭受控制性皮质撞击脑损伤的小鼠大脑中的JNK激活情况，来验证该通路在创伤性脑损伤（TBI）中发挥作用的假说。我们还评估了细胞可渗透的JNK抑制剂肽D-JNKI1对JNK通路的特异性抑制作用对小鼠神经行为功能和创伤后细胞丢失的影响。在损伤后10分钟腹腔注射该抑制剂。在损伤后1小时、4小时和48小时，JNK通路在人挫伤标本以及TBI损伤小鼠的损伤皮质和海马中均表现出强烈激活。与生理盐水处理相比，D-JNKI1处理在损伤后48小时和7天时显著改善了运动性能，并减小了挫伤体积；处理48小时后，损伤小鼠海马中末端脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性细胞数量显著减少。因此，由于JNK通路在人类和实验性TBI后被激活，且抑制剂肽D-JNKI1在实验性TBI后能提供显著的神经保护并改善神经行为缺陷，靶向JNK激活通路进行治疗可能对未来临床应用具有前景。
