Depressive disorder, a common and debilitating public health condition, is characterized by persistent emotional distress, alongside cognitive dysfunction and decreased volitional activity (Limenih et al., 2023; Ma et al., 2023). A more serious concern is that depression is not only becoming more prevalent yearly, but also has a high rate of recurrence and suicide (Watts et al., 2023). Depression poses a significant threat to patient well-being, imposes a significant societal burden, and has garnered widespread attention (Liwinski and Lang, 2023). Despite the progress made in research, the specific pathogenesis of depression remains elusive. Many commonly prescribed antidepressants, such as monoamines, have obvious side effects and limited efficacy (Corponi et al., 2019). Therefore, it is urgent to further investigate the pathogenesis of depression and to develop effective therapeutic agents.

The neuroinflammatory response is closely associated with the development of depression. Patients with inflammatory or autoimmune diseases may be at increased risk for depression (Zhang et al., 2024). Neuroinflammation plays a key role in the pathogenesis of depression by activating microglia in the brain, leading to increased pro-inflammatory cytokines and affecting serotonin synthesis and metabolism (Wang et al., 2018). Microglia activation, a signature of neuroinflammation, typically manifests in two phenotypes: M1 and M2. Classical M1 activation promotes pro-inflammatory responses, while M2 activation mediates anti-inflammatory repair (Tchantchou et al., 2014). Elevated levels of inflammatory factors in depressed patients promotes the transformation of microglia to a pro-inflammatory phenotype, leading to excessive inflammation and intensifying depression (Wang et al., 2016). Additionally, interleukin-4 (IL-4) and interleukin-10 (IL-10) trigger microglia to adopt an M2 phenotype that exerts anti-inflammatory effects, boosts brain-derived neurotrophic factor (BDNF) secretion, reverses hippocampal atrophy, and produces antidepressant effects (Tang and Le, 2016). Thus, microglia regulate the immune system by dynamically maintaining different phenotypes, and modulation of microglia activation phenotype represents a potential therapeutic strategy for depression (Zhou et al., 2012).

Silent information regulator 2 homolog 1 (SIRT1), a NAD+-dependent deacetylase, plays a pivotal role in regulating critical physiological processes in the body (Lee and Kemper, 2010). SIRT1 is implicated in neuroinflammation, neurogenesis, and endoplasmic reticulum stress, which are crucial processes in neurodegenerative diseases and depression (Jablonska et al., 2016). Research has demonstrated that activation of SIRT1 leads to decreased TNF-α and IL-6 secretion by microglia, while SIRT1 inhibition promotes the release of inflammatory factors (Zhang et al., 2022a, b, c). AMPK, a serine/threonine kinase, plays a pivotal role in monitoring ATP levels and phosphorylating metabolic enzymes (Carling, 2017). Furthermore, it has been shown that SIRT1 can activate AMPK signaling (Mohamad et al., 2022). The Notch1 signaling pathway is a crucial regulator of microglia activation and is negatively regulated by AMPK (Yang et al., 2020; Zhang et al., 2022a, b, c). The activation of the Notch1 pathway promotes microglia activation and inflammatory cell infiltration, leading to neuronal damage (Yang et al., 2023). Therefore, targeting SIRT1/AMPK/Notch1 pathway might serve as a potential therapeutic strategy for depression.

Akebia trifoliata (Thunb) koidz (family: Lardizabalaceae) is a liana plant widely distributed in Japan, Korea, and China. The fruits of A. trifoliata are newly valued food with attractive color and delicious taste. The dried fruit, also known as “Yu-Zhi-Zi” in China, is listed in Chinese Pharmacopeia for the treatment of psychiatric disorders in clinic (Maciąg D, et al., 2021). Arjunolic acid, a natural pentacyclic triterpenoid derived from A. trifoliata showed a variety of bioactivities including antioxidant, anti-hepatic injury, improvement of diabetes mellitus, anti-inflammatory, and other pharmacological effects (Ghosh and Sil, 2013; Gupta et al., 2020; Mshengu et al., 2023; Zhang et al., 2022a, b, c). In our previous, we found that arjunolic acid was neuroprotective in corticosterone induced PC12 cell model (Tong et al., 2018). However, its antidepressant effect and underlying mechanism are not yet well understood.

In the present study, we evaluated the antidepressant effects of arjunolic acid in LPS-induced mice and clarify the potential mechanism.