Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, P.O. Box 33516, Egypt.
Int Immunopharmacol. 2021 Dec;101(Pt B):108370. doi: 10.1016/j.intimp.2021.108370. Epub 2021 Nov 15.
Septic encephalopathy results from the intense reaction of the immune system to infection. The role of growth hormone (GH) signaling in maintaining brain function is well established; however, the involvement of the vascular endothelial growth factor receptor-2 (VEGFR2) in the potential modulatory effect of GH on septic encephalopathy-associated endoplasmic reticulum stress (ERS) and blood-brain barrier (BBB) permeability is not well-understood. Therefore, after the induction of mid-grade sepsis by cecal ligation/perforation, rats were subcutaneously injected with recombinant human GH (rhGH)/somatropin alone or preceded by the VEGFR2 antagonist WAG-4S for 7 days. rhGH/somatropin reduced bodyweight loss and plasma endotoxin, maintained the hyperthermic state, and improved motor/memory functions. Additionally, rhGH/somatropin increased the junctional E-cadherin and β-catenin pool in the cerebral cortex to enhance the BBB competency, effects that were abolished by VEGFR2 blockade. Also, it activated cortical VEGFR2/mammalian target of the Rapamycin (mTOR) axis to mitigate ERS. The latter was reflected by the deactivation of the inositol-requiring enzyme-1α (IRE1α)/spliced X-box binding protein-1 (XBP1s) trajectory and the reduction in the protein levels of the death markers, C/EBP homologous protein (CHOP)/growth arrest and DNA damage-153 (GADD153), c-jun-N-terminal kinase (JNK), and caspase-3 with the simultaneous augmentation of expression of the unfolded protein response transducer proteinkinaseR-like ERkinase (PERK). Furthermore, rhGH/somatropin suppressed the phosphorylation of eukaryotic initiation factor-2α (eIF2α), upregulated the gene expression of activating transcription factor-4 (ATF4), GADD34, and glucose-regulated protein-78/binding immunoglobulin (GRP78/Bip). Moreover, it increased the glutathione level and reduced lipid peroxidation in the cerebral cortex. The VEGFR2 antagonist reversed the effect of rhGH/somatropin on PERK and IRE1α and boosted the apoptotic markers but neither affected p-eIF2α nor GADD34. Hence, we conclude that VEGFR2 activation by rhGH/somatropin plays a crucial role in assembling the BBB adherens junctions via its antioxidant capacity, ERS relief, and reducing endotoxemia in septic encephalopathy.
败血性脑病是由免疫系统对感染的强烈反应引起的。生长激素（GH）信号在维持大脑功能方面的作用已得到充分证实；然而，血管内皮生长因子受体-2（VEGFR2）在 GH 对与败血性脑病相关的内质网应激（ERS）和血脑屏障（BBB）通透性的潜在调节作用中的参与尚未得到充分理解。因此，通过盲肠结扎/穿孔诱导中度脓毒症后，大鼠连续 7 天皮下注射重组人生长激素（rhGH）/生长激素或预先注射 VEGFR2 拮抗剂 WAG-4S。rhGH/somatropin 减轻了体重减轻和血浆内毒素，维持了高热状态，并改善了运动/记忆功能。此外，rhGH/somatropin 增加了大脑皮层中的连接 E-钙粘蛋白和β-连环蛋白池，以增强 BBB 能力，而 VEGFR2 阻断则消除了这些作用。此外，它激活了皮质 VEGFR2/雷帕霉素（mTOR）轴以减轻 ERS。这反映在肌醇需要酶-1α（IRE1α）/剪接 X 盒结合蛋白-1（XBP1s）轨迹的失活以及死亡标志物 C/EBP 同源蛋白（CHOP）/生长停滞和 DNA 损伤 153（GADD153）、c-jun-N-末端激酶（JNK）和半胱天冬酶-3 的蛋白水平降低，同时增加未折叠蛋白反应转导蛋白激酶 R 样内质网激酶（PERK）的表达。此外，rhGH/somatropin 抑制了真核起始因子-2α（eIF2α）的磷酸化，上调了激活转录因子-4（ATF4）、GADD34 和葡萄糖调节蛋白-78/结合免疫球蛋白（GRP78/Bip）的基因表达。此外，它增加了大脑皮层中的谷胱甘肽水平并减少了脂质过氧化。VEGFR2 拮抗剂逆转了 rhGH/somatropin 对 PERK 和 IRE1α 的作用，并增强了凋亡标志物，但既不影响 p-eIF2α 也不影响 GADD34。因此，我们得出结论，rhGH/somatropin 通过其抗氧化能力、缓解 ERS 和降低败血性脑病中的内毒素血症，通过激活 VEGFR2 在组装 BBB 黏附连接中发挥关键作用。
