Potential therapeutic effect of teneligliptin on unpredictable chronic mild stress-induced depression in mice: targeting the role of AMP-activated protein kinase signaling pathway

Background Depression is a widespread and complex mental disorder that is challenging to treat. The unpredictable chronic mild stress (UCMS) model, based on stress diathesis, is used to study depression because antidepressants often reverse its effects, providing predictive validity. However, the mechanisms behind UCMS are not fully understood. AMP-activated protein kinase (AMPK) is essential for regulating neuronal energy metabolism, and disruptions in its activation can impair brain function and synaptic integrity. Teneligliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor with anti-inflammatory, antioxidant, autophagy-modulating, and antiapoptotic properties, has not been studied for its potential to activate AMPK by inhibiting DPP-4, stimulating glucagon-like peptide-1, and decreasing the mammalian target of rapamycin pathway, which may enhance neuroprotection and neurogenesis. This study is the first to show teneligliptin’s potential therapeutic effect on UCMS-induced depression in mice by targeting the AMPK signaling pathway. Objective The current study was performed to assess the behavioral, oxidative stress biomarkers, neurotransmitter assay, and histopathology of the brain in UCMS-induced depression in mice. Materials and methods Mice were divided into five groups: group I (normal control, received saline), group II (UCMS model with 1 week of stress), group III (UCMS+fluoxetine 10 mg/kg daily for 4 weeks), and groups IV and V (UCMS+teneligliptin 30 mg/kg and 60 mg/kg, respectively, for 4 weeks). Body weight, forced swim test, tail suspension, locomotor activity, oxidative biomarkers (malondialdehyde, reduced glutathione, superoxide dismutase, nitrite levels), neurotransmitters (dopamine, serotonin), and brain histopathology were assessed to evaluate antidepressant activity. Results and conclusion Mice treated with teneligliptin (30 and 60 mg/kg) in the UCMS model showed significant weight loss compared with the disease group. They also exhibited reduced immobility in forced swim and tail suspension tests and increased locomotor activity. Significant changes were noted in oxidative stress biomarkers and neurotransmitters (dopamine, serotonin), with improved histopathological conditions. In conclusion, teneligliptin improved behavioral and antidepressant effects by reducing oxidative stress and increasing dopamine and serotonin levels. As a DPP-4 inhibitor, it may activate AMPK in the brain, lower DPP-4 enzyme levels, and enhance glucagon-like peptide-1-R and mammalian target of rapamycin, potentially promoting neurogenesis and neuroprotection, thus being beneficial for depression treatment.