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Metformin/Donepezil combination modulates brain antioxidant status and hippocampal endoplasmic reticulum stress in type 2 diabetic rats

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Abstract

Purpose

Diabetes mellitus is associated with perturbations in brain biochemical parameters associated with dementia. This study aimed at comparing the effect of metformin and metformin/donepezil combination on oxidative stress, endoplasmic reticulum stress and inflammation in the brain of diabetic Wistar rats.

Methods

Diabetes was induced by single intraperitoneal injection of 40 mg/kg streptozotocin after administration of 10% fructose for 14 days. Animals were randomly assigned to four groups of five animals each. Group 1 was the normal control and received only distilled water. Groups 2 and 3 were diabetic rats treated with metformin/donepezil combination and metformin only respectively, while group 4 was diabetic control. Treatment lasted for 21 days after confirmation of diabetes. Activities of acetylcholinesterase (AchE), butyrylcholinesterase (BchE), superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase were evaluated in the brain of diabetic rats. Enzyme-linked immunosorbent assay was used to estimate brain levels of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) malondialdehyde and glucose transporter-4 (GLUT4), while expression of endoplasmic reticulum stress markers – glucose regulated protein-78 (GRP78), activating transcription factor-4 (ATF4) and C/EBP homologous protein (CHOP) was determined using real-time PCR in the hippocampus of diabetic rats.

Results

Treatment with metformin/donepezil combination significantly reduced the activities of AchE, BchE as well as levels of malondialdehyde, TNF-α and IL-6, while the activities of SOD, GPx and catalase were significantly increased in the brain. Moreover, expression of ER stress markers was attenuated in the hippocampus.

Conclusion

Metformin/donepezil combination appeared more efficacious than metformin only and could be considered for managing diabetes-associated dementia.

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Data availability

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Authors and Affiliations

  1. Biochemistry Programme, Department of Chemical Sciences, Afe Babalola University, Ado-Ekiti, PMB 5454, Nigeria

    Tajudeen Olabisi Obafemi, Oyindamola A. Olaoye, Kikelomo F. Jaiyesimi & Olusola B Adewale

  2. Medical Biochemistry Unit, College of Health Sciences, Afe Babalola University, PMB 5454, Ado-Ekiti, Nigeria

    Oluwaseun R. Olasehinde

  3. Industrial Chemistry Programme, Department of Chemical Sciences, Afe Babalola University, Ado-Ekiti, PMB 5454, Nigeria

    Funmilayo D. Adewumi

  4. Department of Biochemistry, Bowen University, Iwo, PMB 284, Nigeria

    Blessing A. Afolabi

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  1. Tajudeen Olabisi Obafemi
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Contributions

Obafemi T. O. and Olasehinde O. R designed the study; Olaoye O. A, Jaiyesimi K. F and Adewumi D.F. did most of the bench work; Afolabi B. A prepared the first draft of the manuscript; Adewale O. B proof-read and edited the manuscript.

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Correspondence to Tajudeen Olabisi Obafemi.

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Obafemi, T.O., Olasehinde, O.R., Olaoye, O.A. et al. Metformin/Donepezil combination modulates brain antioxidant status and hippocampal endoplasmic reticulum stress in type 2 diabetic rats. J Diabetes Metab Disord 19, 499–510 (2020). https://doi.org/10.1007/s40200-020-00541-0

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