, 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



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.


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


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.


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.


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.


Cognitive impairment Metformin Scopolamine Akt Phosphorylated tau Acetyl cholinesterase activity 



Alzheimer’s disease


Diabetes mellitus


Acetyl cholinesterase


Tumour necrosis factor-alpha


Nitric oxide


Morris water maze


Phosphorylated Akt


Phosphorylated tau


Initial acquisition latency


Retention latency


Step-through latency

Amyloid beta


Phosphatidyl inositol 3 kinase


Adenosine monophosphate-activated protein kinase


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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