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

• Published in: International immunopharmacology 2022-01, Vol.102, p.108415-108415, Article 108415
• Main Authors: Mendonça, Ingrid Prata, Paiva, Igor Henrique Rodrigues de, Duarte-Silva, Eduardo Pereira, Melo, Michel Gomes de, Silva, Rodrigo Soares da, Oliveira, Wilma Helena de, Costa, Belmira Lara da Silveira Andrade da, Peixoto, Christina Alves
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antidepressants; Antidepressive Agents, Second-Generation - administration & dosage; Antidepressive Agents, Second-Generation - therapeutic use; Blotting, Western; Brain-derived neurotrophic factor; Caspase-3; Cell death; Clinical aspects; Combined treatment; Depression; Depression - drug therapy; Depression - etiology; Drug Therapy, Combination; Fluorescent Antibody Technique; Fluoxetine; Fluoxetine - administration & dosage; Fluoxetine - therapeutic use; Glial fibrillary acidic protein; Health services; Hindlimb Suspension; Hippocampus; Hippocampus - pathology; Inflammation; Male; Mental depression; Metformin; Metformin - administration & dosage; Metformin - therapeutic use; Mice; Mice, Inbred C57BL; Movement disorders; Neurodegenerative diseases; Neurogenesis; Neurogenesis - drug effects; Neuroinflammatory Diseases - drug therapy; Neuromodulation; Neuronal Plasticity - drug effects; Neuroplasticity; NF-κB protein; Nitric-oxide synthase; Parkinson's disease; Parkinsonian Disorders - drug therapy; Parkinsonian Disorders - pathology; Parkinsonian Disorders - psychology; Patients; Prefrontal cortex; Prefrontal Cortex - pathology; Quality of life; Rotarod Performance Test; Rotenone; Symptom management
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.108415

•Metformin has antidepressant effect in Parkinson's disease model.•Metformin attenuates activation of astrocytes and microglia as well as reduces inflammatory markers NF-kB, IL-1β and iNOS.•Metformin and fluoxetine induce hippocampal neurogenesis in a PD model.•Combined metformin and fluoxetine treatment enhance hippocampal neuronal survival in the PD model.•Metformin potentiates the effect of fluoxetine on hippocampal BDNF expression in PD model. 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-1β 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.