Abstract
Diabetes mellitus and depression are comorbid diseases affecting many patients all over the world. The current study was designed to compare the antidepressant effect of some antidiabetic drugs such as vildagliptin, pioglitazone, glyburide, and metformin on depression-related or unrelated to type 2 diabetes mellitus (T2DM). T2DM was induced by high-fat diet and streptozotocin, while diabetes-unrelated depression was induced by reserpine. Antidiabetic agents reduced diabetes-associated depression as indicated by the reduction in the immobility time in the forced swim test, elevation of cortical and hippocampal serotonin and brain-derived neurotrophic factor (BDNF), and the increase in serum β-Amyloid 1–42 (Aβ1–42) levels. Antidiabetic agents also reduced serum corticosterone levels suggesting their inhibitory effect on hypothalamus-pituitary-adrenal axis activity. The antidepressant activity of the tested compounds was associated with reduction of oxidative stress and inflammation in brain. Vildagliptin showed the highest, while glyburide showed the least antidiabetic and antidepressant activity. Antidepressant activities of pioglitazone and metformin were comparable. The difference in antioxidant and anti-inflammatory activities between groups showed the same pattern of the antidepressant effect suggesting that these two pathways may play role in ameliorating depression in diabetic rats. On the other hand, the administration of reserpine in small doses (0.2 mg/kg) induced depression associated with hyperglycemia in non-diabetic rats. Although all treatments improved glycemic parameters to similar levels, vildagliptin showed the greatest effect on Aβ1–42, serotonin, norepinephrine, and BDNF levels. In conclusion, vildagliptin seems to be the leading drug among the tested antidiabetics and may be the most appropriate antidiabetic for managing diabetes-associated depression.
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Abbreviations
- Aβ40/42:
-
β-Amyloid 40/42
- Aβ1–42:
-
β-Amyloid 1-42
- AGEs:
-
Advanced glycation end products
- AMPK:
-
Adenosine monophosphate-activated protein kinase
- ANOVA:
-
Analysis of variance
- BBB:
-
Blood brain barrier
- BDNF:
-
Brain-derived neurotrophic factor
- CAT:
-
Catalase
- CT:
-
Control
- DM:
-
Diabetes mellitus
- DMSO:
-
Dimethyl sulfoxide
- DPP-4:
-
Dipeptidyl peptidase-4 inhibitor
- ELISA:
-
Enzyme-linked immunosorbent assay
- F:
-
Fluoxetine
- FST:
-
Forced swim test
- G:
-
Glyburide
- GLP-1:
-
Glucagon-like peptide 1
- GSH:
-
Reduced glutathione
- H&E:
-
Hematoxylin and eosin
- HFD:
-
High-fat diet
- HOMA-IR:
-
Homeostatic model assessment of insulin resistance
- HPA:
-
Hypothalamic–pituitary–adrenal
- IDO:
-
Indoleamine 2,3-dioxygenase
- M:
-
Metformin
- MDA:
-
Malondialdehyde
- NF-kB:
-
Nuclear factor-kappa B
- P:
-
Pioglitazone
- PBS:
-
Phosphate-buffered saline
- PKC:
-
Protein kinase C
- p.NF-KB:
-
Phospho-nuclear factor-kappa B
- PPAR-γ:
-
Peroxisome proliferator activated receptor-gamma
- ROS:
-
Reactive oxygen species
- SEM:
-
Standard error of the mean
- SOD:
-
Superoxide dismutase
- SSRIs:
-
Selective serotonin reuptake inhibitors
- STZ:
-
Streptozotocin
- T2DM:
-
Type 2 diabetes mellitus
- TNF-α:
-
Tumor necrosis factor-alpha
- V:
-
Vildagliptin
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Acknowledgments
The authors acknowledge Dr. Rehab Hasan, Department of Histology, Faculty of Medicine, Al-Azhar University, Egypt, for her great effort in the histopathological examination. The authors would like also to thank Dr. Tracey L. Woodlief, Department of Pharmacology and Toxicology, East Carolina University, USA, for the English language review.
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MFM and AAAM conceived and designed research. NE conducted the experiments. NE, AAAM, and ES analyzed the data. NE, AAAM, and ES wrote the first draft of manuscript. MFM and AAAM revised and edited the manuscript. All the authors read and approved the manuscript.
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All procedures were conducted in accordance with the accepted principles for care and use of laboratory animals and were approved by the animal ethics committee of Faculty of Pharmacy, Zagazig University, Egypt (Approval number: P1-12-2017).
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Soliman, E., Essmat, N., Mahmoud, M.F. et al. Impact of some oral hypoglycemic agents on type 2 diabetes-associated depression and reserpine-induced depression in rats: the role of brain oxidative stress and inflammation. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1391–1404 (2020). https://doi.org/10.1007/s00210-020-01838-w
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DOI: https://doi.org/10.1007/s00210-020-01838-w