Umezawa Hiroki, Naito Yusuke, Tanaka Kensuke, Yoshioka Kento, Suzuki Kenichi, Sudo Tatsuhiko, Hagihara Masahiko, Hatano Masahiko, Tatsumi Koichiro, Kasuya Yoshitoshi
Department of Respirology, Graduate School of Medicine, Chiba UniversityChiba, Japan; Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba UniversityChiba, Japan; Department of Biomedical Science, Graduate School of Medicine, Chiba UniversityChiba, Japan.
Department of Respirology, Graduate School of Medicine, Chiba UniversityChiba, Japan; Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba UniversityChiba, Japan.
Front Pharmacol. 2017 Feb 17;8:72. doi: 10.3389/fphar.2017.00072. eCollection 2017.
One of the mitogen-activated protein kinases, p38α plays a crucial role in various inflammatory diseases and apoptosis of various types of cells. In this study, we investigated the pathophysiological roles of p38α in spinal cord injury (SCI), using a mouse model. Lateral hemisection at T9 of the SC was performed in wild type (WT) and p38α mice (p38α showed embryonic lethality). p38α mice showed a better functional recovery from SCI-associated paralyzed hindlimbs compared to WT mice at 7 days post-injury (dpi), which remained until 28 dpi (an end time point of monitoring the behavior). In histopathological analysis at 28 dpi, there was more axonal regeneration with remyelination on the caudal side of the lesion epicenter in p38α mice than in WT mice. At 7 dpi, infiltration of inflammatory cells into the lesion and expression of cytokines in the lesion were reduced in p38α mice compared with WT mice. At the same time point, the number of apoptotic oligodendrocytes in the white matter at the caudal boarder of the lesion of p38α mice was lower than that of WT mice. At 14 dpi, more neural and oligodendrocyte precursor cells in the gray matter and white matter, respectively, were observed around the lesion epicenter of p38α mice compared with the case of WT mice. At the same time point, astrocytic scar formation was less apparent in p38α than in WT mice, while compaction of inflammatory immune cells associated with the wound contraction was more apparent in p38α than in WT mice. Furthermore, we verified the effectiveness of oral administration of SB239063, a p38α inhibitor on the hindlimb locomotor recovery after SCI. These results suggest that p38α deeply contributes to the pathogenesis of SCI and that inhibition of p38α is a beneficial strategy to recovery from SCI.
丝裂原活化蛋白激酶之一的p38α在各种炎症性疾病和各类细胞凋亡中发挥着关键作用。在本研究中，我们使用小鼠模型研究了p38α在脊髓损伤（SCI）中的病理生理作用。在野生型（WT）小鼠和p38α基因敲除小鼠（p38α表现出胚胎致死性）中进行T9节段脊髓半横断。与野生型小鼠相比，p38α基因敲除小鼠在损伤后7天（dpi）时SCI相关的后肢麻痹功能恢复更好，这种情况一直持续到28 dpi（行为监测的终点时间点）。在28 dpi的组织病理学分析中，与野生型小鼠相比，p38α基因敲除小鼠损伤灶中心尾侧有更多的轴突再生和髓鞘再生。在7 dpi时，与野生型小鼠相比，p38α基因敲除小鼠损伤部位炎症细胞浸润和损伤部位细胞因子表达减少。在同一时间点，p38α基因敲除小鼠损伤灶尾侧白质中凋亡少突胶质细胞的数量低于野生型小鼠。在14 dpi时，与野生型小鼠相比，在p38α基因敲除小鼠损伤灶中心周围分别观察到灰质和白质中更多的神经和少突胶质前体细胞。在同一时间点，p38α基因敲除小鼠星形胶质细胞瘢痕形成比野生型小鼠不明显，而与伤口收缩相关的炎性免疫细胞压实现象在p38α基因敲除小鼠中比野生型小鼠更明显。此外，我们验证了口服p38α抑制剂SB239063对SCI后后肢运动恢复的有效性。这些结果表明，p38α在SCI发病机制中起重要作用，抑制p38α是促进SCI恢复的有益策略。
