Department of Biomedical Science, Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, South Korea.
Department of Biomedical Science, Program in Biomedical Science and Engineering, College of Medicine, Inha University, Incheon, South Korea.
Biochem Pharmacol. 2024 Mar;221:116032. doi: 10.1016/j.bcp.2024.116032. Epub 2024 Jan 26.
Repeated sublethal hypoxia exposure induces brain inflammation and affects the initiation and progression of cognitive dysfunction. Experiments from the current study showed that hypoxic exposure downregulates PKA/CREB signaling, which is restored by forskolin (FSK), an adenylate cyclase activator, in both Neuro2a (N2a) cells and zebrafish brain. FSK significantly protected N2a cells from hypoxia-induced cell death and neurite shrinkage. Intraperitoneal administration of FSK for 5 days on zebrafish additionally led to significant recovery from hypoxia-induced social interaction impairment and learning and memory (L/M) deficit. FSK suppressed hypoxia-induced neuroinflammation, as indicated by the observed decrease in NF-κB activation and GFAP expression. We further investigated the potential effect of FSK on O-GlcNAcylation changes induced by hypoxia. Intriguingly FSK induced marked upregulation of the protein level of O-GlcNAc transferase catalyzing addition of the GlcNAc group to target proteins, accompanied by elevated O-GlcNAcylation of nucleocytoplasmic proteins. The hypoxia-induced O-GlcNAcylation decrease in the brain of zebrafish was considerably restored following FSK treatment. Based on the collective results, we propose that FSK rescues hypoxia-induced cognitive dysfunction, potentially through regulation of HBP/O-GlcNAc cycling.
反复的亚致死缺氧暴露会引发脑炎症，并影响认知功能障碍的发生和进展。本研究的实验表明，缺氧暴露会下调 PKA/CREB 信号通路，而腺嘌呤核苷环化酶激活剂 forskolin (FSK) 可以在 Neuro2a (N2a) 细胞和斑马鱼脑中恢复该信号通路。FSK 可显著保护 N2a 细胞免受缺氧诱导的细胞死亡和突起收缩。在斑马鱼中腹腔内给予 FSK 5 天，还可显著改善由缺氧引起的社交互动障碍以及学习和记忆（L/M）缺陷。FSK 抑制了缺氧诱导的神经炎症，表现为 NF-κB 激活和 GFAP 表达减少。我们进一步研究了 FSK 对缺氧诱导的 O-GlcNAc 化变化的潜在影响。有趣的是，FSK 诱导了 O-GlcNAc 转移酶催化将 GlcNAc 基团添加到靶蛋白的蛋白水平的显著上调，同时伴随着核质蛋白的 O-GlcNAc 化水平升高。FSK 处理后，斑马鱼大脑中缺氧诱导的 O-GlcNAc 化减少得到了显著恢复。基于这些结果，我们提出 FSK 通过调节 HBP/O-GlcNAc 循环来挽救缺氧诱导的认知功能障碍。
