Differential metformin dose-dependent effects on cognition in rats: role of Akt
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.
KeywordsCognitive impairment Metformin Scopolamine Akt Phosphorylated tau Acetyl cholinesterase activity
Tumour necrosis factor-alpha
Morris water maze
Initial acquisition latency
Phosphatidyl inositol 3 kinase
Adenosine monophosphate-activated protein kinase
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.
- Allard JS, Sankavaram K, Perez E, Minor R, De Cabo R (2011) Metformin treatment increases mRNA levels of inflammatory factors and decreases mRNA levels of neurotrophic factors in brains of C57BL/6 mice. 2011 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience OnlineGoogle Scholar
- Barreto-Torres G, Hernandez JS, Jang S, Rodríguez-Muñoz AR, Torres-Ramos CA, Basnakian AG, Javadov S (2015) The beneficial effects of AMP kinase activation against oxidative stress are associated with prevention of PPARα-cyclophilin D interaction in cardiomyocytes. Am J Physiol Heart Circ Physiol 308(7):H749–H758. doi: 10.1152/ajpheart.00414.2014 CrossRefPubMedPubMedCentralGoogle Scholar
- Belkhelfa M, Rafa H, Medjeber O, Arroul-Lammali A, Behairi N, Abada-Bendib M, Makrelouf M, Belarbi S, Masmoudi AN, Tazir M, Touil-Boukoffa C (2014) IFN-γ and TNF-α are involved during Alzheimer disease progression and correlate with nitric oxide production: a study in Algerian patients. J Interferon Cytokine Res 34(11):839–847CrossRefPubMedGoogle Scholar
- Chen Y, Zhou K, Wang R, Liu Y, Kwak YD, Ma T, Thompson RC, Zhao Y, Smith L, Gasparini L, Luo Z, Xu H, Liao FF (2009) Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci U S A 106(10):3907–3912CrossRefPubMedPubMedCentralGoogle Scholar
- Dickey CA, Koren J, Zhang YJ, Xu YF, Jinwal UK, Birnbaum MJ, Monks B, Sun M, Cheng JQ, Patterson C, Bailey RM, Dunmore J, Soresh S, Leon C, Morgan D, Petrucelli L (2008) Akt and CHIP coregulate tau degradation through coordinated interactions. Proc Natl Acad Sci U S A 105(9):3622–3627CrossRefPubMedPubMedCentralGoogle Scholar
- González CR, Caminos JE, Vázquez MJ, Garcés MF, Cepeda LA, Angel A, González AC, García-Rendueles ME, Sangiao-Alvarellos S, López M, Bravo SB, Nogueiras R, Diéguez C (2009) Regulation of visceral adipose tissue-derived serine protease inhibitor by nutritional status, metformin, gender and pituitary factors in rat white adipose tissue. J Physiol 587(Pt 14):3741–3750CrossRefPubMedPubMedCentralGoogle Scholar
- Ishrat T, Hoda MN, Khan MB, Yousuf S, Ahmad M, Khan MM, Ahmad A, Islam F (2009) Amelioration of cognitive deficits and neurodegeneration by curcumin in rat model of sporadic dementia of Alzheimer’s type (SDAT). Eur Neuropsychopharmacol 19(9):636–647. doi: 10.1016/j.euroneuro.2009.02.002 CrossRefPubMedGoogle Scholar
- Lennox R, Porter DW, Flatt PR, Holscher C, Irwin N, Gault VA (2014) Comparison of the independent and combined effects of sub-chronic therapy with metformin and a stable GLP-1 receptor agonist on cognitive function, hippocampal synaptic plasticity and metabolic control in high-fat fed mice. Neuropharmacology 86:22–30CrossRefPubMedGoogle Scholar
- Montgomery HAC, Dymock JF (1961) The determination of nitrite in water. Analyst 86:414–416Google Scholar
- Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, Brodaty H, Woodward M, Boundy K, Ellis KA, Bush AI, Faux NG, Martins R, Szoeke C, Rowe C, Watters DA, Investigators AIBL (2013) Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 36(10):2981–2987CrossRefPubMedPubMedCentralGoogle Scholar