Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China; Department of Cariology and Endodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
Department of Medicine, Weill Cornell Medical School, Cornell University, New York, NY 10065, USA.
Int Immunopharmacol. 2023 Mar;116:109767. doi: 10.1016/j.intimp.2023.109767. Epub 2023 Feb 2.
Increasing evidence supports the association between periodontitis and depression. However, the specific mechanisms remain to be further elucidated. The present study aimed to mechanistically investigate the regional roles of proBDNF (the precursor of brain-derived neurotrophic factor) in periodontitis induced depression-like behavior in mice.
Experimental periodontitis model was established by periodontal injection of Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) in 8-week-old male Bdnf-HA/HA mice for 3 weeks. The depression-like behaviors, spontaneous exploratory activity and the level of anxiety were assessed by behavior tests. The activation of microglia and astrocytes, as well as the expression of Interleukin (IL)-1β and Tumor necrosis factor (TNF)-α in the hippocampus, prefrontal cortex, and cortex were further assessed by immunofluorescence and western blots. The levels of IL-1β in blood serum and expression of occludin as well as claudin5 in the hippocampus, prefrontal cortex, and cortex were further determined by enzyme-linked immunosorbent assay and western blot. Finally, the expression of proBDNF, its receptors, and mature BDNF (mBDNF), as well as neuronal activity were measured by western blots and immunofluorescence.
Pg-LPS successfully induced periodontitis in mice and caused obvious depression-like behavior. Furthermore, we observed an increased activation of astrocytes and microglia, as well as a significant increase in expression of IL-1β and TNF-α in the hippocampus of mice treated with Pg-LPS, with elevated level of IL-1β in serum and decreased expression of occludin and claudin5 in the hippocampus. Importantly, we found that the levels of proBDNF and its receptors, SorCS2 and p75NTR, were increased significantly; however, the level of mBDNF was decreased, therefor leading to greater ratio of proBDNF/mBDNF. In addition, we also detected decreased neuronal activity in the hippocampus of mice treated with Pg-LPS.
Our results indicate that Pg-LPS-induced periodontitis could cause depression-like behaviors in mice, and the proBDNF signaling is involved in the process.
越来越多的证据支持牙周炎与抑郁症之间存在关联。然而，具体的机制仍有待进一步阐明。本研究旨在从机制上探讨脑源性神经营养因子前体(proBDNF)在牙周炎诱导的小鼠抑郁样行为中的区域作用。
将牙龈卟啉单胞菌脂多糖（Pg-LPS）注射到 8 周龄雄性 Bdnf-HA/HA 小鼠的牙周组织中，建立牙周炎模型，共 3 周。通过行为测试评估抑郁样行为、自发探索活动和焦虑水平。通过免疫荧光和蛋白质印迹进一步评估海马体、前额叶皮层和皮质中小胶质细胞和星形胶质细胞的激活以及白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α的表达。通过酶联免疫吸附试验和蛋白质印迹进一步测定血清中 IL-1β的水平以及海马体、前额叶皮层和皮质中 occludin 和 claudin5 的表达。最后，通过蛋白质印迹和免疫荧光测定 proBDNF、其受体和成熟 BDNF（mBDNF）以及神经元活性的表达。
Pg-LPS 成功诱导了小鼠的牙周炎，并导致明显的抑郁样行为。此外，我们观察到用 Pg-LPS 处理的小鼠海马体中星形胶质细胞和小胶质细胞的激活增加，IL-1β和 TNF-α的表达显著增加，血清中 IL-1β水平升高，海马体中 occludin 和 claudin5 的表达降低。重要的是，我们发现 proBDNF 及其受体 SorCS2 和 p75NTR 的水平显著增加，而 mBDNF 的水平降低，导致 proBDNF/mBDNF 比值增加。此外，我们还检测到用 Pg-LPS 处理的小鼠海马体中神经元活性降低。
我们的结果表明，Pg-LPS 诱导的牙周炎可导致小鼠出现抑郁样行为，proBDNF 信号参与其中。
