Inhibition of Noncanonical Ca2+ Oscillation/Calcineurin/GSK-3β Pathway Contributes to Anti-Inflammatory Effect of Sigma-1 Receptor Activation
Inhibition of Noncanonical Ca2+ Oscillation/Calcineurin/GSK-3β Pathway Contributes to Anti-Inflammatory Effect of Sigma-1 Receptor Activation
复制标题
抑制非规范 Ca2 振荡/钙调神经磷酸酶/GSK–3β 途径有助于 Sigma–1 受体激活的抗炎作用
DOI：
10.1007/s11064-021-03439-2
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发表时间：
2021-09-01
影响因子：
4.4
通讯作者：
Guo, Lin
中科院分区：
文献类型：
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作者：
Gao, Tianyu;Gao, Ce;Guo, Lin
进一步了解小胶质细胞激活的机制对于开发新的抗炎策略是必要的。我们前期研究发现，激活sigma-1受体可以有效抑制神经炎症，不依赖于NF-kappa B、JNK、ERK等典型的炎症通路。因此，这是合理的，一个未确定的，非规范的途径有助于小胶质细胞的激活。在本研究中，我们发现sigma-1受体激动剂2-morpholin-4-乙基乙基-1-苯基环己烷-1-羧酸盐（预-084）抑制脂多糖（LPS）升高BV-2小胶质细胞培养上清中一氧化氮（NO）含量，LPS升高BV-2小胶质细胞中肿瘤坏死因子- α (tnf - α)、白细胞介素-1 β (IL-1 β)、诱导型一氧化氮合酶（iNOS） mRNA水平。此外，PRE-084还能缓解lps -增加糖原合成酶激酶3 β (GSK-3 β)的丝氨酸9去磷酸化，lps -提高钙调磷酸酶的催化活性，lps -提高Ca2+振荡BV-2细胞的百分比和频率。我们进一步发现，PRE-084的抑制作用被绿原酸钙调磷酸酶激活剂和吡啶激酶-3 β激活剂逆转。此外，2-氨基乙氧基二苯硼酸酯的IP3受体抑制剂模拟了PRE-084的抗炎活性。因此，我们确定了Ca2+振荡/Calcineurin/GSK-3 β的非典型前神经炎症途径，并且抑制该途径对于sigma-1受体激活的抗炎活性是必要的。
Further understanding the mechanism for microglia activation is necessary for developing novel anti-inflammatory strategies. Our previous study found that the activation of sigma-1 receptor can effectively inhibit the neuroinflammation, independent of the canonical mechanisms, such as NF-kappa B, JNK and ERK inflammatory pathways. Thus, it is reasonable that an un-identified, non-canonical pathway contributes to the activation of microglia. In the present study, we found that a sigma-1 receptor agonist of 2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate (PRE-084) suppressed lipopolysaccharide (LPS) elevated nitric oxide (NO) content in BV-2 microglia culture supernatant and LPS-raised mRNA levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), inducible nitric oxide synthase (iNOS) in BV-2 microglia. Moreover, PRE-084 alleviated LPS-increased Ser 9 de-phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta), LPS-elevated catalytic activity of calcineurin, and LPS-raised percent and frequency of Ca2+ oscillatory BV-2 cells. We further found that the inhibitory effect of PRE-084 was reversed by a calcineurin activator of chlorogenic acid and a GSK-3 beta activator of pyrvinium. Moreover, an IP3 receptor inhibitor of 2-aminoethoxydiphenyl borate mimicked the anti-inflammatory activity of PRE-084. Thus, we identified a noncanonical pro-neuroinflammary pathway of Ca2+ oscillation/Calcineurin/GSK-3 beta and the inhibition of this pathway is necessary for the anti-inflammatory activity of sigma-1 receptor activation.