Psychopharmacology

, Volume 233, Issue 13, pp 2513–2524 | Cite as

Differential metformin dose-dependent effects on cognition in rats: role of Akt

  • Dalia K. Mostafa
  • Cherine A. Ismail
  • Doaa A. Ghareeb
Original Investigation

Abstract

Rational

Epidemiological evidence suggests that individuals with diabetes mellitus are at greater risk of developing Alzheimer’s disease, and controversy overwhelms the usefulness of the widely prescribed insulin-sensitizing drug, metformin, on cognition.

Objectives

Through the scopolamine-induced memory deficit model, we investigated metformin influence on cognitive dysfunction and explored underlying mechanisms.

Methods

Sixty adult male Wistar rats were randomly assigned into 5 groups (12 rats each) to receive either normal saline, scopolamine 1 mg/kg intraperitoneally once daily, scopolamine + oral metformin (100 mg/kg/day), scopolamine + oral metformin (300 mg/kg/day) or scopolamine + oral rivastigmine (0.75 mg/kg/day) for 14 days. Cognitive behaviours were tested using Morris water maze and passive avoidance tasks. Biochemically, brain oxidative (malondialdehyde) and inflammatory (TNF-α) markers, nitric oxide, Akt, phospho-Akt, phospho-tau and acetyl cholinesterase activity in hippocampal and cortical tissues were assessed.

Results

The lower dose of metformin (100 mg/kg) ameliorated scopolamine-induced impaired performance in both Morris water maze and passive avoidance tasks, and was associated with significant reduction of inflammation and to a lesser extent oxidative stress versus rivastigmine. Given the role of total Akt in regulation of abnormal tau accumulation and degradation, our finding that metformin 100 decreased the elevated total Akt while increasing its phosphorylated form explains its beneficial modulatory effect on phosphorylated tau in both tissues, and could further clarify its protection against memory impairment.

Conclusion

Metformin, only in the average human antidiabetic dose, offers a protective effect against scopolamine-induced cognitive impairment, while no deleterious effect was observed with the higher dose, which may support a bonus effect of metformin in type 2 diabetic patients.

Keywords

Cognitive impairment Metformin Scopolamine Akt Phosphorylated tau Acetyl cholinesterase activity 

Abbreviations

AD

Alzheimer’s disease

DM

Diabetes mellitus

AChE

Acetyl cholinesterase

TNF-α

Tumour necrosis factor-alpha

NO

Nitric oxide

MWM

Morris water maze

P-Akt

Phosphorylated Akt

P-tau

Phosphorylated tau

IAL

Initial acquisition latency

RL

Retention latency

STL

Step-through latency

Amyloid beta

PI3K

Phosphatidyl inositol 3 kinase

AMPK

Adenosine monophosphate-activated protein kinase

Notes

Author contributions

DKM and CAI designed the study, performed the experiments, collected and analysed the data, and wrote the manuscript. DAG took part in the preparation and analysis of the samples for the biochemical studies. All the authors contributed to and have approved the final manuscript.

Compliance with ethical standards

Principles of laboratory animal care were followed according to the current version of the Egyptian Law on the Protection of Animals, and the protocol was approved by the Ethics Committee of Faculty of Medicine, Alexandria University.

Role of the funding source

This research was supported by Alexandria University Research Award Centre. The Alexandria University Research Award Centre had no further role in the study.

Conflict of interest

The authors declare no conflict of interest and certify hereby that this work has never been published.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Dalia K. Mostafa
    • 1
  • Cherine A. Ismail
    • 1
  • Doaa A. Ghareeb
    • 2
  1. 1.Department of Clinical Pharmacology, Faculty of MedicineAlexandria UniversityAlexandriaEgypt
  2. 2.Department of Biochemistry, Faculty of ScienceAlexandria UniversityAlexandriaEgypt

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