Correlation between the microRNA-874-Sirtuin2-p53/nuclear factor-kappa B signaling pathway and depressive symptoms: a prospective multicenter study

Background and objective: Impaired hippocampal neurogenesis and local inflammatory responses are considered to be important mechanisms underlying depression. Sirtuin2 can inhibit cellular oxidative stress by regulating p53/nuclear factor-κB expression, prevent high-glucose-induced vascular endothelial cell damage, and interfere with neuroinflammation and blood-brain barrier destruction. Endogenous small RNAs or microRNAs (miRs) can be involved in the development and plasticity of the nervous system, which has been associated with depression. Our preliminary studies discovered that the 3′-untranslated region of Sirtuin2 messenger RNA (mRNA) is rich in miR-874 binding sites, suggesting that miR-874 may act as an upstream regulatory molecule for Sirtuin2. Therefore, we aim to explore the association between miR-874 and depressive symptoms through clinical trials. Participants and methods: This study will be conducted as a multicenter, prospective, clinical trial, at the Department of Rehabilitation at Tangdu Hospital of the Air Force Military Medical University and at the Department of Psychosomatic Medicine at Xijing Hospital of the Air Force Military Medical University, located in Xi’an, Shaanxi Province, China. A total of 50 patients with depression and 50 healthy controls will be recruited from these two locations. All patients with depression will be newly diagnosed, characterized by experiencing their first attack, and with no history of antidepressant administration. Moreover, no drug interventions will be utilized in this trial, for either the depressed or healthy cohorts. The trial protocol was approved by the Medical Ethics Committee of Tangdu Hospital of the Fourth Military Military Medical University in Xi’an, Shaanxi Province, China on June 1, 2018 (approval No. K201806-03). Protocol version is 1.0. All participants or their legal representatives will sign informed consent forms prior to the initiation of the trial. Patient recruitment began on October 31, 2018, and is expected to end on February 28, 2021. All data analysis was completed on August 1, 2021, and the trial will be completed on September 1, 2021. Outcome measures: Primary outcome measures include the expression levels miR-874 and Sirtuin2 mRNA in the blood. The secondary outcome measures include the levels of inflammatory factors, including interleukin-1β, interleukin-6, and tumor necrosis factor α, in the blood, the Hamilton Depression Rating Scale score, the Hamilton Anxiety Rating Scale score, the Global Assessment Function score, and the incidence of overall adverse events. We will also analyze the association between miR-874 expression levels and depression. Discussion: Determining whether any association exists between the miR-874-Sirtuin2-p53/nuclear factor-κB signaling pathway and depressive symptoms will assist in the exploration of the pathogenesis of depression and may provide novel therapeutic targets for the treatment of depression. Trial registration: This study was registered with the Chinese Clinical Trial Registry on October 17, 2018 (registration number: ChiCTR1800018933).