Metformin improves depressive-like behavior in experimental Parkinson's disease by inducing autophagy in the substantia nigra and hippocampus.

Parkinson's disease (PD) remains a disease of little known etiology. In addition to the motor symptoms, depression is present in about 40% of patients, contributing to the loss of quality of life. Recently, the involvement of the autophagy mechanism in the pathogenesis of depression has been studied, in addition to its involvement in PD as well. In this study, we tested the effects of metformin, an antidiabetic drug also with antidepressant effects, on depressive-like behavior in a rotenone-induced PD model and on the autophagy process. Mice 8-week-old male C57BL/6 were induced with rotenone for 20 consecutive days (2.5 mg/kg/day) and treated with metformin (200 mg/kg/day) from the 5th day of induction. All the animals were submitted to rotarod, sucrose preference and tail suspension tests. After euthanasia, the substantia nigra and hippocampus were removed for analysis by western blotting or fixed and analyzed by immunofluorescence. The results show that there was an impairment of autophagy in animals induced by rotenone both in nigral and extranigral regions as well as a depressive-like behavior. Metformin was able to inhibit depressive-like behavior and increase signaling pathway proteins, transcription factors and autophagosome-forming proteins, thus inducing autophagy in both the hippocampus and the substantia nigra. In conclusion, we show that metformin has an antidepressant effect in a rotenone-induced PD model, which may result, at least in part, from the induction of the autophagy process.

Metformin and fluoxetine improve depressive-like behavior in a murine model of Parkinsons disease through the modulation of neuroinflammation, neurogenesis and neuroplasticity.

Thereabout 30-40% of patients with Parkinson's Disease (PD) also have depression contributing to the loss of quality of life. Among the patients who treat depression, about 50% do not show significant improvement due to the limited efficacy of the treatment. So far, there are no effective disease-modifying treatments that can impede its progression. The current clinical approach is based on symptom management. Nonetheless, the reuse of drugs with excellent safety profiles represents an attractive alternative strategy for treating of different clinical aspects of PD. In this study, we evaluated the effects of metformin separately and associated with fluoxetine on depressive like-behavior and motor alterations in experimental Parkinson's disease. C57BL6 mice were induced with rotenone (2.5 mg/kg/day) for 20 days and treated with metformin (200 mg/kg/day) and fluoxetine (10 mg/kg/day) from the 5th day of induction. The animals were submitted to Sucrose Preference, Tail Suspension, and rotarod tests. Hippocampus, prefrontal cortex, and substantia nigra were dissected for molecular and morphological analysis. Metformin and fluoxetine prevented depressive-like behavior and improved motor impairment and increased TH nigral positive cells. Metformin and fluoxetine also reduced IBA-1 and GFAP positive cells in the hippocampus. Moreover, metformin reduced the phospho-NF-kB, IL-1ß in the prefrontal cortex and iNOS levels in the hippocampus. Both metformin and fluoxetine increased neurogenesis by increasing KI67, but only the combined treatment increased neuronal survival by NeuN positive cells in the hippocampus. In addition, fluoxetine reduced cell death, decreasing caspase-3 and PARP-1 levels. Lastly, metformin potentiated the effect of fluoxetine on neuroplasticity by increasing BDNF positive cells. Metformin has antidepressant and antiparkinsonian potential due to anti-inflammatory neurogenic, and neuroplasticity-inducing effects when combined with fluoxetine.