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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

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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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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt

    Eman Soliman, Nariman Essmat, Mona F. Mahmoud & Amr A. A. Mahmoud

  2. Department of Pharmacology, Pharmacy Program, Oman College of Health Sciences, 114, Muscat, Oman

    Amr A. A. Mahmoud

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  1. Eman Soliman
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  2. Nariman Essmat
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Contributions

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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Correspondence to Eman Soliman.

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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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The authors declare that they have no conflicts of interest.

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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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