Department of Nursing, Mackay Medicine, Nursing and Management College, Taipei, Taiwan.
PLoS One. 2012;7(7):e39656. doi: 10.1371/journal.pone.0039656. Epub 2012 Jul 23.
Chronic hyperglycemia-associated inflammation plays critical roles in disease initiation and the progression of diabetic complications, including Alzheimer's disease (AD). However, the association of chronic hyperglycemia with acute inflammation of the central nervous system in the progression of AD still needs to be elucidated. In addition, recent evidence suggests that Glucagon-like peptide-1 receptor (GLP-1R) protects against neuronal damage in the brain. Therefore, the neuroprotective effects of the GLP-1R agonist exendin-4 (EX-4) against hyperglycemia/lipopolysaccharides (LPS) damage were also evaluated in this study.
METHODOLOGY/PRINCIPAL FINDINGS: Ten days after streptozotocin (STZ) or vehicle (sodium citrate) treatment in mice, EX-4 treatment (10 µg/kg/day) was applied to the mice before intrahippocampal CA1 injection of LPS or vehicle (saline) and continued for 28 days. This study examined the molecular alterations in these mice after LPS and EX4 application, respectively. The mouse cognitive function was evaluated during the last 6 days of EX-4 treatment. The results showed that the activation of NF-κB-related inflammatory responses induced cognitive dysfunction in both the hyperglycemic mice and the mice that received acute intrahippocampal LPS injection. Furthermore, acute intrahippocampal LPS injection exacerbated the impairment of spatial learning and memory through a strong decrease in monoaminergic neurons and increases in astrocytes activation and apoptosis in the hyperglycemic mice. However, EX-4 treatment protected against the cognitive dysfunction resulting from hyperglycemia or/and intrahippocampal LPS injection.
CONCLUSIONS/SIGNIFICANCE: These findings reveal that both hyperglycemia and intrahippocampal LPS injection induced cognitive dysfunction via activation of NF-κB-related inflammatory responses. However, acute intrahippocampal LPS injection exacerbated the progression of cognitive dysfunction in the hyperglycemic mice via a large increase in astrocytes activation-related responses. Furthermore, EX-4 might be considered as a potential adjuvant entity to protect against neurodegenerative diseases.
慢性高血糖相关炎症在疾病的发生和糖尿病并发症的进展中起着关键作用，包括阿尔茨海默病（AD）。然而，慢性高血糖与 AD 进展中中枢神经系统的急性炎症之间的关系仍需阐明。此外，最近的证据表明胰高血糖素样肽-1 受体（GLP-1R）可保护大脑神经元免受损伤。因此，本研究还评估了 GLP-1R 激动剂 exendin-4（EX-4）对高血糖/脂多糖（LPS）损伤的神经保护作用。
方法/主要发现：在小鼠链脲佐菌素（STZ）或载体（柠檬酸钠）处理 10 天后，给予 EX-4（10 µg/kg/天）治疗，然后向海马 CA1 内注射 LPS 或载体（生理盐水），并持续 28 天。本研究分别在 LPS 和 EX4 应用后检测这些小鼠的分子变化。在 EX-4 治疗的最后 6 天，评估了小鼠的认知功能。结果表明，高血糖小鼠和海马内注射急性 LPS 组的 NF-κB 相关炎症反应激活均导致认知功能障碍。此外，急性海马内 LPS 注射通过强烈减少单胺能神经元并增加星形胶质细胞激活和细胞凋亡，加剧了高血糖小鼠空间学习和记忆的损伤。然而，EX-4 治疗可防止由高血糖或/和海马内 LPS 注射引起的认知功能障碍。
结论/意义：这些发现表明，高血糖和海马内 LPS 注射均可通过激活 NF-κB 相关炎症反应导致认知功能障碍。然而，急性海马内 LPS 注射通过增加与星形胶质细胞激活相关的反应，加剧了高血糖小鼠认知功能障碍的进展。此外，EX-4 可被视为一种潜在的辅助实体，以预防神经退行性疾病。
