Metformin Improves Comorbid Depressive Symptoms in Mice with Allergic Rhinitis by Reducing Olfactory Bulb Damage

Allergic rhinitis (AR) is a widespread disease that is frequently comorbid with depression. However, the mechanisms and treatments for depression in AR remain underexplored. Metformin, a widely used antidiabetic drug, has shown antidepressant effects. The aim of this study was to explore the effects and potential mechanisms of metformin on depression-like behaviors in an AR mouse model. In the present study, mice were sensitized and challenged with ovalbumin (OVA) to induce AR. Results showed that mice with AR exhibited significant depression-like behavior which was attenuated by metformin. In addition, the levels of expression of synaptic plasticity markers (anti-microtubule-associated protein 2, synaptophysin, postsynaptic density protein 95), neurogenesis markers (doublecortin and Ki-67), and brain-derived neurotrophic factor were decreased in the olfactory bulb (OB) of mice with AR, while metformin ameliorated all these alterations and reduced apoptosis in the OB of these mice. Furthermore, it enhanced the phosphorylation of AMP-activated kinase (AMPK) and the levels of ten-eleven translocation 2 (TET2) and 5-hydroxymethylcytosine in the OB. In conclusion, our findings suggest that metformin might be a viable strategy for treating AR-related depression, possibly by modulating neuroplasticity, neurogenesis, apoptosis, and BDNF signaling in the OB via the AMPK/TET2 pathway.