Histidine provides long-term neuroprotection after cerebral ischemia through promoting astrocyte migration.
Histidine provides long-term neuroprotection after cerebral ischemia through promoting astrocyte migration.
复制标题
组氨酸通过促进星形胶质细胞迁移在脑缺血后提供长期神经保护
DOI：
10.1038/srep15356
复制
发表时间：
2015-10-20
影响因子：
4.6
通讯作者：
Hu WW
中科院分区：
文献类型：
--
作者：
Liao RJ;Jiang L;Wang RR;Zhao HW;Chen Y;Li Y;Wang L;Jie LY;Zhou YD;Zhang XN;Chen Z;Hu WW
胶质瘢痕的形成阻碍了脑缺血后神经发生和神经功能的恢复。组胺在脑缺血早期具有神经保护作用，但其长期作用，特别是对胶质瘢痕形成的影响尚不清楚。通过对组胺前体组氨酸的不同给药方案，我们发现早期高剂量组氨酸治疗和晚期低剂量组氨酸治疗表现出最显著的长期神经保护作用，可减少梗死体积和改善神经功能。值得注意的是，该治疗方案还有力地减少了神经胶质瘢痕面积，并促进了星形胶质细胞向梗死核心的迁移。在创伤愈合实验和transwell实验中，组胺显著促进星形胶质细胞迁移。H2受体拮抗剂逆转促进星形胶质细胞迁移和组氨酸提供的神经保护。此外，组胺上调GTP结合的小GTP酶Rac 1，而Rac 1抑制剂，NSC 23766，废除组氨酸的神经保护和促进星形胶质细胞迁移。我们的数据表明，H2受体介导的剂量/阶段依赖性组氨酸治疗，促进星形胶质细胞向梗死核心迁移，这有利于脑缺血后长期神经功能恢复。因此，靶向组胺能系统可能是通过其对星形胶质细胞的作用来治疗长期脑缺血损伤的有效策略。
The formation of glial scar impedes the neurogenesis and neural functional recovery following cerebral ischemia. Histamine showed neuroprotection at early stage after cerebral ischemia, however, its long-term effect, especially on glial scar formation, hasn’t been characterized. With various administration regimens constructed for histidine, a precursor of histamine, we found that histidine treatment at a high dose at early stage and a low dose at late stage demonstrated the most remarkable long-term neuroprotection with decreased infarct volume and improved neurological function. Notably, this treatment regimen also robustly reduced the glial scar area and facilitated the astrocyte migration towards the infarct core. In wound-healing assay and transwell test, histamine significantly promoted astrocyte migration. H2 receptor antagonists reversed the promotion of astrocyte migration and the neuroprotection provided by histidine. Moreover, histamine upregulated the GTP-bound small GTPase Rac1, while a Rac1 inhibitor, NSC23766, abrogated the neuroprotection of histidine and its promotion of astrocyte migration. Our data indicated that a dose/stage-dependent histidine treatment, mediated by H2 receptor, promoted astrocyte migration towards the infarct core, which benefited long-term post-cerebral ischemia neurological recovery. Therefore, targeting histaminergic system may be an effective therapeutic strategy for long-term cerebral ischemia injury through its actions on astrocytes.