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

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 UCMSinduced
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.