Genetic and Pharmacological Inhibition of p38α Improves Locomotor Recovery after Spinal Cord Injury.
Genetic and Pharmacological Inhibition of p38α Improves Locomotor Recovery after Spinal Cord Injury.
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DOI：
10.3389/fphar.2017.00072
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发表时间：
2017
影响因子：
5.6
通讯作者：
Kasuya Y
中科院分区：
文献类型：
--
作者：
Umezawa H;Naito Y;Tanaka K;Yoshioka K;Suzuki K;Sudo T;Hagihara M;Hatano M;Tatsumi K;Kasuya Y
p38α是丝裂原活化蛋白激酶之一，在多种炎症性疾病和细胞凋亡中起着重要作用。在这项研究中，我们研究了p38α在脊髓损伤（SCI）的病理生理作用，使用小鼠模型。在野生型（WT）和p38α+/-小鼠（p38α-/-显示胚胎致死性）中进行SC T9侧半切。与WT小鼠相比，p38α+/-小鼠在损伤后7天（dpi）从SCI相关瘫痪的后肢中表现出更好的功能恢复，并保持至28 dpi（监测行为的结束时间点）。在28 dpi的组织病理学分析中，p38α+/-小鼠中病变中心尾侧的轴突再生和髓鞘再生比WT小鼠更多。在7 dpi时，与WT小鼠相比，p38α+/-小鼠中炎性细胞向病变中的浸润和病变中细胞因子的表达减少。在同一时间点，p38α+/-小鼠病变尾侧边缘白色物质中凋亡的少突胶质细胞数量低于WT小鼠。在14 dpi时，与WT小鼠相比，在p38α+/-小鼠的病变中心周围的灰质和白色物质中分别观察到更多的神经和少突胶质细胞前体细胞。在同一时间点，星形胶质细胞瘢痕形成在p38α+/-小鼠中比在WT小鼠中更不明显，而与伤口收缩相关的炎性免疫细胞的压实在p38α+/-小鼠中比在WT小鼠中更明显。此外，我们验证了口服p38α抑制剂SB 239063对SCI后后肢运动恢复的有效性。提示p38α在脊髓损伤的发病机制中起重要作用，抑制p38α表达是脊髓损伤后恢复的有效策略。
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.