Department of Pharmacology and Toxicology, School of Medicine, Faculty of Medicine, Complutense University of Madrid (UCM), Hospital 12 de Octubre Research Institute (Imas12), Neurochemistry Research Institute UCM (IUIN), Pza. Ramón y Cajal s/n, Madrid, 28040, Spain.
Biomedical Network Research Center of Mental Health (CIBERSAM), Institute of Health Carlos III, Madrid, Spain.
J Neuroinflammation. 2024 Sep 8;21(1):219. doi: 10.1186/s12974-024-03213-5.
Depression is a chronic psychiatric disease of multifactorial etiology, and its pathophysiology is not fully understood. Stress and other chronic inflammatory pathologies are shared risk factors for psychiatric diseases, and comorbidities are features of major depression. Epidemiological evidence suggests that periodontitis, as a source of low-grade chronic systemic inflammation, may be associated with depression, but the underlying mechanisms are not well understood.
Periodontitis (P) was induced in Wistar: Han rats through oral gavage with the pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum for 12 weeks, followed by 3 weeks of chronic mild stress (CMS) to induce depressive-like behavior. The following four groups were established (n = 12 rats/group): periodontitis and CMS (P + CMS+), periodontitis without CMS, CMS without periodontitis, and control. The morphology and inflammatory phenotype of microglia in the frontal cortex (FC) were studied using immunofluorescence and bioinformatics tools. The endocannabinoid (EC) signaling and proteins related to synaptic plasticity were analyzed in FC samples using biochemical and immunohistochemical techniques.
Ultrastructural and fractal analyses of FC revealed a significant increase in the complexity and heterogeneity of Iba1 + parenchymal microglia in the combined experimental model (P + CMS+) and increased expression of the proinflammatory marker inducible nitric oxide synthase (iNOS), while there were no changes in the expression of cannabinoid receptor 2 (CB2). In the FC protein extracts of the P + CMS + animals, there was a decrease in the levels of the EC metabolic enzymes N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), and monoacylglycerol lipase (MAGL) compared to those in the controls, which extended to protein expression in neurons and in FC extracts of cannabinoid receptor 1 (CB1) and to the intracellular signaling molecules phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). The protein levels of brain-derived neurotrophic factor (BDNF) and synaptophysin were also lower in P + CMS + animals than in controls.
The combined effects on microglial morphology and inflammatory phenotype, the EC signaling, and proteins related to synaptic plasticity in P + CMS + animals may represent relevant mechanisms explaining the association between periodontitis and depression. These findings highlight potential therapeutic targets that warrant further investigation.
抑郁症是一种多因素病因的慢性精神疾病，其病理生理学尚未完全阐明。应激和其他慢性炎症性病理是精神疾病的共同风险因素，合并症是重度抑郁症的特征。流行病学证据表明，作为低水平慢性全身炎症源的牙周炎可能与抑郁症有关，但潜在机制尚不清楚。
通过口腔灌胃将牙龈卟啉单胞菌和具核梭杆菌等致病菌诱导给 Wistar：Han 大鼠，诱导牙周炎 12 周，随后进行 3 周的慢性轻度应激（CMS）以诱导抑郁样行为。建立以下四组（每组 n = 12 只大鼠）：牙周炎和 CMS（P + CMS + ）、牙周炎无 CMS、CMS 无牙周炎和对照组。使用免疫荧光和生物信息学工具研究前额皮质（FC）中小胶质细胞的形态和炎症表型。使用生化和免疫组织化学技术分析 FC 样本中的内源性大麻素（EC）信号和与突触可塑性相关的蛋白。
FC 的超微结构和分形分析显示，在联合实验模型（P + CMS + ）中小胶质细胞的复杂性和异质性显著增加，诱导型一氧化氮合酶（iNOS）的促炎标志物表达增加，而大麻素受体 2（CB2）的表达没有变化。在 P + CMS + 动物的 FC 蛋白提取物中，与对照组相比，EC 代谢酶 N-酰基磷酯酰乙醇胺特异性磷脂酶 D（NAPE-PLD）、二酰基甘油脂肪酶（DAGL）和单酰基甘油脂肪酶（MAGL）的水平降低，这种情况延伸至神经元蛋白表达和 FC 中大麻素受体 1（CB1）的蛋白表达，以及细胞内信号分子磷脂酰肌醇-3-激酶（PI3K）、蛋白激酶 B（Akt）和细胞外信号调节激酶 1/2（ERK1/2）。与对照组相比，P + CMS + 动物的脑源性神经营养因子（BDNF）和突触小体蛋白的水平也较低。
P + CMS + 动物中小胶质细胞形态和炎症表型、EC 信号以及与突触可塑性相关的蛋白的联合作用可能代表了解释牙周炎与抑郁症之间关联的相关机制。这些发现强调了潜在的治疗靶点，值得进一步研究。
