牙齦卟啉單胞菌造成腦部內皮細胞死亡之機制探討

Emerging studies have shown the interconnection between the brain-oral axis, especially for the pathophysiology of brain disorders and oral pathogens. Porphyromonas gingivalis (P. gingivalis), a prominent microorganism responsible for periodontal disease, has been reported to increase the risk of developing cerebrovascular damage. A previous study from the master’s thesis has shown that P. gingivalis adhered and invaded bEnd.3 cells, thus triggering cell death by upregulating pro-inflammatory cytokines proteins tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β). However, the underlying mechanisms of the effect of this periodontal bacterium on brain vascular endothelial cell death remain unknown. The purpose of this work was to explore the regulatory mechanisms of P. gingivalis on the inflammation and death of bEnd.3 and primary mouse brain endothelial cells (MBECs). Moreover, the therapeutic effects of THSG (2,3,5,4ʹ-Tetrahydroxystilbene-2-O-β-glucoside), a Chinese herbal medicine extract, in P. gingivalis-stimulated brain endothelial cells were examined in this study. Results revealed that the viable form of P. gingivalis but not heat-inactivated caused apoptosis in bEnd.3 cells. Moreover, P. gingivalis elevated intracellular reactive oxygen species (ROS) and promoted the activation of the nuclear factor kappa B (NF-κB) p65 transcription factor. The toxicity effect of P. gingivalis was reversed by treatment with antioxidant agents N-Acetyl-L-cysteine (NAC), thereby confirming that P. gingivalis provoked cytokine expression and induced cell death via the oxidative stress pathway in brain endothelial cells. MBECs were further exploited to examine the impact of P. gingivalis on brain endothelial cell death. Moreover, THSG offered anti-inflammatory and anti-apoptosis in bEnd.3 and MBECs stimulated with P. gingivalis with a comparable efficacy as the well-established nicotinamide adenine dinucleotide phosphate (NADPH) inhibitor apocynin. To conclude, this study has proven that P. gingivalis stimulates the expression of TNF-α and IL-1β proteins, thereby inducing apoptotic cell death in brain endothelial cells via the ROS/NF-κB pathway. This study strongly supports the hypothesis that a periodontal infection increases the risk of developing a cerebrovascular disease. We further reported the therapeutic effects of THSG in preventing brain endothelial cell death from periodontal pathogen infection.