Insulin-like growth factor-1 (IGF-1) is a potent neuroprotective polypeptide that exerts neuroprotective effects via the IGF-1 receptor (IGF-1R). Our previous study reported that G protein-coupled estrogen receptor (GPER) was involved in the anti-apoptotic effect of IGF-1. The present study was designed to investigate the anti-inflammatory effect of IGF-1 in association with astrocyte activation and the molecular details of the interaction between IGF-1R and GPER. We showed that IGF-1 could improve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor deficits and attenuate the upregulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) both in vivo and in vitro. The IGF-1R antagonist JB-1 and the GPER antagonist G15 could antagonize the anti-inflammatory effect of IGF-1. Silencing GPER abrogated the inhibitory effect of IGF-1 on 1-methyl-4-phenylpyridinium (MPP⁺)-induced upregulation of COX-2 and iNOS in primary astrocytes. Moreover, the MPP ⁺ -induced inflammatory response was related to the activation of mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathways. The inhibitory effects of IGF-1 on the phosphorylation of p38, JNK and IκB could be blocked by JB-1. G15 antagonized the inhibitory effects of IGF-1 on p-JNK and p-IκB, but not p-p38. Furthermore, IGF-1 treatment alone increased the expression of GPER, which was blocked by JB-1, the phosphatidylinositol 3-kinase (PI3–K) antagonist LY294002 and the MEK antagonist PD98059 in primary astrocytes. Overall, we show for the first time that GPER may contribute to the anti-inflammatory effect of IGF-1 against MPTP/MPP ⁺ -induced astrocyte activation. IGF-1 could regulate the expression of GPER via the IGF-1R/PI3-K/MAPK signaling pathway in primary astrocytes.

胰岛素样生长因子1（IGF-1）是一种有效的神经保护多肽，可通过IGF-1受体（IGF-1R）发挥神经保护作用。我们先前的研究报道G蛋白偶联雌激素受体（GPER）参与了IGF-1的抗凋亡作用。本研究旨在研究IGF-1与星形胶质细胞活化相关的抗炎作用以及IGF-1R与GPER之间相互作用的分子细节。我们表明，IGF-1可以改善1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的运动功能障碍，并减弱环氧合酶2（COX-2）和诱导型一氧化氮合酶的上调（iNOS）体内和体外。IGF-1R拮抗剂JB-1和GPER拮抗剂G15可以拮抗IGF-1的抗炎作用。⁺）诱导原代星形胶质细胞中COX-2和iNOS的上调。此外，MPP  ⁺ 诱导的炎症反应与丝裂原活化蛋白激酶（MAPK）和NF-κB信号通路的激活有关。IB-1对IGF-1对p38，JNK和IκB磷酸化的抑制作用。G15拮抗IGF-1对p-JNK和p-IκB的抑制作用，但对p-p38没有抑制作用。此外，单独的IGF-1治疗可增加GPER的表达，而JB-1，磷脂酰肌醇3激酶（PI3-K）拮抗剂LY294002和MEK拮抗剂PD98059可以阻断GPER的表达。总体而言，我们首次证明GPER可能有助于IGF-1对MPTP / MPP ⁺的抗炎作用 诱导的星形胶质细胞活化。IGF-1可以通过IGF-1R / PI3-K / MAPK信号通路调节星形胶质细胞中GPER的表达。