Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an, China; Department of Neurology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Neurology Impatient, Second Medical Center of Chinese PLA General Hospital, Beijing, China.
Eur J Pharmacol. 2020 Nov 15;887:173581. doi: 10.1016/j.ejphar.2020.173581. Epub 2020 Sep 16.
Glucagon-like peptide-1 (GLP-1) is an endogenous gut hormone and a key regulator in maintaining glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36), which was formerly considered a "bio-inactive" metabolite mainly due to its low affinity for GLP-1 receptor, possesses unique properties such as cardiovascular protection. Little is known about the effects and mechanisms of GLP-1 (9-36) in cerebral ischemia and reperfusion injury. Here, we report that systemic application of GLP-1 (9-36) in adult mice facilitated functional recovery and reduced infarct volume, astrogliosis, and neuronal apoptosis following middle cerebral artery occlusion and reperfusion. Interestingly, these effects were still observed in GLP-1 receptor knockout (Glp-1r) mice but were partially reversed in insulin-like growth factor 1 (IGF-1) receptor knockdown (Igf-1r) mice. Primary astrocytes were cultured and subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), and enzyme-linked immunosorbent assay indicated that GLP-1 (9-36) pretreatment reduces tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 levels. This effect was not diminished in Glp-1r astrocytes but was reversed in Igf-1r astrocytes, emphasizing that the anti-inflammatory effect of GLP-1 (9-36) in astrocytes is independent of GLP-1 receptor signaling and is instead mediated by IGF-1 receptor. Immunoprecipitation experiments showed that GLP-1 (9-36) directly interacts with IGF-1 receptor in astrocytes. Western blot data indicated that GLP-1 (9-36) activates IGF-1 receptor and downstream PI3K-AKT pathway in astrocytes upon OGD/R injury, which was abrogated by preincubation with IGF-1 receptor autophosphorylation inhibitor picropodophyllin. Thus, our findings suggest that GLP-1 (9-36) improved stroke outcome by reducing inflammation in astrocytes via interaction with IGF-1 receptor.
胰高血糖素样肽-1（GLP-1）是一种内源性肠道激素，通过刺激胰岛素分泌来调节葡萄糖稳态。其天然裂解产物 GLP-1（9-36），以前由于其对 GLP-1 受体的低亲和力而被认为是一种“无生物活性”的代谢产物，具有独特的特性，如心血管保护作用。关于 GLP-1（9-36）在脑缺血再灌注损伤中的作用和机制知之甚少。在这里，我们报告在成年小鼠中全身应用 GLP-1（9-36）可促进功能恢复，并减少大脑中动脉闭塞和再灌注后的梗死体积、星形胶质细胞增生和神经元凋亡。有趣的是，这些作用在 GLP-1 受体敲除（Glp-1r）小鼠中仍然观察到，但在胰岛素样生长因子 1（IGF-1）受体敲低（Igf-1r）小鼠中部分逆转。原代星形胶质细胞培养并进行氧葡萄糖剥夺/再氧合（OGD/R），酶联免疫吸附试验表明 GLP-1（9-36）预处理可降低肿瘤坏死因子-α、白细胞介素（IL）-1β和 IL-6 水平。在 Glp-1r 星形胶质细胞中，这种作用没有减弱，但在 Igf-1r 星形胶质细胞中被逆转，这强调了 GLP-1（9-36）在星形胶质细胞中的抗炎作用独立于 GLP-1 受体信号转导，而是由 IGF-1 受体介导。免疫沉淀实验表明 GLP-1（9-36）在星形胶质细胞中直接与 IGF-1 受体相互作用。Western blot 数据表明，GLP-1（9-36）在 OGD/R 损伤后激活星形胶质细胞中的 IGF-1 受体及其下游 PI3K-AKT 通路，而 IGF-1 受体自身磷酸化抑制剂 picropodophyllin 预处理可阻断该通路。因此，我们的研究结果表明，GLP-1（9-36）通过与 IGF-1 受体相互作用减少星形胶质细胞中的炎症来改善中风的预后。
