Activated STAT3 signaling pathway by ligature-induced periodontitis could contribute to neuroinflammation and cognitive impairment in rats

Abstract

Background Increasing evidence suggests a causal link between periodontitis and cognitive disorders. Systemic inflammation initiated by periodontitis may mediate the development of cognitive impairment. Our study aims to investigate the effect of ligature-induced periodontitis on cognitive function and the role of signal transducers and activators of transcription 3 (STAT3) in this process. Materials and methods Ligature-induced periodontitis was established, and the rats were treated intraperitoneally with/without the pSTAT3 inhibitor cryptotanshinone (CTS). Alveolar bone resorption and periodontal inflammation were detected by micro-computed tomography analysis and histopathological evaluation. Locomotor activity and cognitive function were evaluated by the open field test and the Morris water maze test, respectively. The activation of microglia and astrocytes in the hippocampus and cortex was assessed by immunohistochemistry (IHC). The expression of interleukins (IL-1β, IL-6, IL-8, IL-21) in both the periphery and cortex was evaluated by RT-PCR and ELISA. The expression of TLR/NF-κB and ROS cascades was evaluated by RT-PCR. The expression of pSTAT3 and the activation of the STAT3 signaling pathway (JAK2, STAT3, and pSTAT3) in the periodontal tissue and cortex were assessed by IHC and Western blot. The expression of amyloid precursor protein (APP) and its key secretases was evaluated by RT-PCR. The level of amyloid β-protein (Aβ) and the ratio of Aβ1-40/1-42 were measured via ELISA in the plasma and cortex while IHC was used to detect the level of Aβ1-42 in the brain. Results In periodontal ligature rats, significant alveolar bone resorption and local inflammatory cell infiltration were present. Apparent increases in inflammatory cytokines (IL-1β, IL-6, IL-8, and IL-21) were detected in peripherial blood and brain. Additionally, spatial learning and memory ability was impaired, while locomotor activity was not affected. Activated microglia and astrocytes were found in the cortex and hippocampus, presenting as enlarged cell bodies and irregular protrusions. Levels of TLR/NF-kB, PPAR and ROS were altered. The STAT3 signaling pathway was activated in both the periodontal tissue and cortex, and the processing of APP by β- and γ-secretases was promoted. The changes mentioned above could be relieved by the pSTAT3 inhibitor CTS. Conclusions Ligature-induced periodontitis in rats resulted in systemic inflammation and further abnormal APP processing, leading to cognitive impairments. In this progress, the activation of the STAT3 signaling pathway may play an important role by increasing inflammatory load and promoting neuroinflammation.

Positive effects of running exercise on astrocytes in the medial prefrontal cortex in an animal model of depression

“…GFAP, a class III intermediate filament, is a cell-specific marker that distinguishes astrocytes from other glial cells during the development of the central nervous system. A rabbit polyclonal GFAP antibody from Abcam (Abcam Cat# ab7260, RRID: AB_2893014) was used in the present study because this antibody has been demonstrated to specifically react with GFAP in rats and mice (Hu et al, 2021;Sinha et al, 2021). The immunizing antigen of the antibody is the recombinant full-length protein corresponding to human GFAP.…”

α-Synuclein Induces Neuroinflammation Injury through the IL6ST-AS/STAT3/HIF-1α Axis

“…The phosphorylation and activation of STAT3 influences the transcription of HIF1A , which affects hypoxia-mediated cell damage [ 18 , 19 ]. When the inflammatory response was intensified, the JAK2-STAT3 pathway was activated in HMC3 cells.…”

Integrative Analysis of Deregulated miRNAs Reveals Candidate Molecular Mechanisms Linking H. pylori Infected Peptic Ulcer Disease with Periodontitis

“…STAT3 (signal transducer and activator of transcription 3) activation is implicated in inflammation-associated carcinogenesis, and its phosphorylation by H. pylori has been documented [ 61 ]. STAT3 pathway activation is documented in periodontitis [ 62 ] and is also found to contribute to neuroinflammation [ 63 ]. EZH2 encodes for a methyltransferase enzyme that is involved in osteoclast regulation and is proposed as a target for periodontitis [ 64 ].…”