Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Department of Pharmacy, Huzhou Maternity and Child Health Care Hospital, Zhejiang, China.
Naunyn Schmiedebergs Arch Pharmacol. 2019 Jul;392(7):801-812. doi: 10.1007/s00210-019-01632-3. Epub 2019 Feb 23.
Astrocyte is considered to be a type of passive supportive cells that preserves neuronal activity and survival. The dysfunction of astrocytes is involved in the pathological processes of major depression. Recent studies implicate sigma-1 receptors as putative therapeutic targets for current available antidepressant drugs. However, it is absent of direct evidences whether sigma-1 receptor could promote activation of astrocyte. In the present study, we took advantage of primary astrocyte culture and a highly selective agonist of sigma-1 receptor, (+)SKF-10047 to determine the effect of sigma-1 receptor on Brdu (bromodeoxyuridine) labeling positive cells, migration as well as GFAP (glial fibrillary acidic protein) expression of astrocyte. The results showed that (+)SKF-10047 notably increased the number of Brdu labeling positive cells, migration, and the expression of GFAP in primary astrocytes, which were blocked by antagonist of sigma-1 receptor. Moreover, we also found that (+)SKF-10047 increased the phosphorylation of ERK1/2 (extracellular signal-regulated kinases 1/2) and GSK3β (glycogen synthase kinase 3β) (ser 9) in the primary astrocytes. In addition, pharmacological inhibition of ERK1/2 and GSK3β (ser 9) abolished sigma-1 receptor-promoted activation of astrocyte. Therefore, sigma-1 receptor could be considerate as a new pattern for modulating astrocytic function might emerge as therapeutic strategies.
星形胶质细胞被认为是一种被动支持细胞，它可以维持神经元的活动和存活。星形胶质细胞的功能障碍与重度抑郁症的病理过程有关。最近的研究表明，sigma-1 受体可能是现有抗抑郁药物的潜在治疗靶点。然而，目前还没有直接的证据表明 sigma-1 受体是否能促进星形胶质细胞的激活。在本研究中，我们利用原代星形胶质细胞培养和 sigma-1 受体的高选择性激动剂 (+)SKF-10047，来确定 sigma-1 受体对 Brdu（溴脱氧尿苷）标记阳性细胞、迁移以及星形胶质细胞 GFAP（胶质纤维酸性蛋白）表达的影响。结果表明，(+)SKF-10047 显著增加了 Brdu 标记阳性细胞的数量、迁移和星形胶质细胞 GFAP 的表达，而 sigma-1 受体拮抗剂则阻断了这些作用。此外，我们还发现(+)SKF-10047 增加了原代星形胶质细胞中 ERK1/2（细胞外信号调节激酶 1/2）和 GSK3β（糖原合成酶激酶 3β）（丝氨酸 9 位）的磷酸化。此外，ERK1/2 和 GSK3β（丝氨酸 9 位）的药理学抑制消除了 sigma-1 受体对星形胶质细胞的激活作用。因此，sigma-1 受体可能被认为是一种调节星形胶质细胞功能的新模式，可能成为治疗策略。
