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Aging and disease    2019, Vol. 10 Issue (5) : 949-963     DOI: 10.14336/AD.2019.0120
Orginal Article |
Metformin Alters Locomotor and Cognitive Function and Brain Metabolism in Normoglycemic Mice
Wenjun Li1#, Kiran Chaudhari1#, Ritu Shetty1, Ali Winters1, Xiaofei Gao2, Zeping Hu2, Woo-Ping Ge2,3, Nathalie Sumien1, Michael Forster1, Ran Liu1, Shao-Hua Yang1,*
1Department of Pharmacology and Neuroscience University of North Texas Health Science Centre, Fort Worth, TX76107, USA.
2Children's Research Institute, Department of Paediatrics, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA
3Department of Neuroscience, Department of Neurology & Neurotherapeutics, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA
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Abstract  

Metformin is currently the most effective treatment for type-2 diabetes. The beneficial actions of metformin have been found even beyond diabetes management and it has been considered as one of the most promising drugs that could potentially slow down aging. Surprisingly, the effect of metformin on brain function and metabolism has been less explored given that brain almost exclusively uses glucose as substrate for energy metabolism. We determined the effect of metformin on locomotor and cognitive function in normoglycemic mice. Metformin enhanced locomotor and balance performance, while induced anxiolytic effect and impaired cognitive function upon chronic treatment. We conducted in vitro assays and metabolomics analysis in mice to evaluate metformin’s action on the brain metabolism. Metformin decreased ATP level and activated AMPK pathway in mouse hippocampus. Metformin inhibited oxidative phosphorylation and elevated glycolysis by inhibiting mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) in vitro at therapeutic doses. In summary, our study demonstrated that chronic metformin treatment affects brain bioenergetics with compound effects on locomotor and cognitive brain function in non-diabetic mice.

Keywords metformin      metabolism      diabetes      AMP-activated protein kinase      cognition     
Corresponding Authors: Yang Shao-Hua   
About author: These authors contributed equally to this study.
Just Accepted Date: 25 January 2019   Issue Date: 27 September 2019
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Li Wenjun
Chaudhari Kiran
Shetty Ritu
Winters Ali
Gao Xiaofei
Hu Zeping
Ge Woo-Ping
Sumien Nathalie
Forster Michael
Liu Ran
Yang Shao-Hua
Cite this article:   
Li Wenjun,Chaudhari Kiran,Shetty Ritu, et al. Metformin Alters Locomotor and Cognitive Function and Brain Metabolism in Normoglycemic Mice[J]. Aging and disease, 2019, 10(5): 949-963.
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http://www.aginganddisease.org/EN/10.14336/AD.2019.0120     OR     http://www.aginganddisease.org/EN/Y2019/V10/I5/949
Figure 1.  Effect of metformin treatment on spontaneous locomotor activity in young male normoglycemic C57BL/6J mice. The locomotor activity was measured in terms of total distance travelled in cm (A), vertical activity counts (B), and time spent in the center zone (C). CTL: control mice fed with drink water. MET: mice fed with drink water with metformin (2 mg/ml). Each value represents mean ± SEM, n=10. * p<0.05 vs control.
Figure 2.  Metformin improved coordinated running and balance performance in young male normoglycemic mice. Session wise (A) and learning index and maximum performance (B) of rotarod test demonstrated metformin treatment improved coordinated running. Wire suspension test demonstrated that metformin did not affect motor reflex (C) and muscle strength (D). Bridge walking test demonstrated that metformin treatment improved balance performance (E & F). Session wise performance and (E) and session 4 and average of balance beam test (F) in bridge walking test. Each value represents mean ± SEM, n=10. * p<0.05 vs control.
Figure 3.  Metformin did not alter Morris water maze spatial learning in young male normoglycemic C57BL/6J mice. The data represents Morris water maze outcome over 9 sessions and shown as path length in cm (A), latency in seconds (B) and swim speed in cm/second (C). Across all sessions, there was no significant difference between control and metformin fed mice. Each value represents mean ± SEM, n=10.
Figure 4.  Metformin treatment impaired spatial memory function and decreased anxiety in young male normoglycemic mice. Morris water maze (MWM) test (A to D) demonstrated metformin treatment impaired delayed spatial memory: session wise time (%) (A) and average time (%) (B) spent in annulus 40 across probe trials 2,4,5,7 and 9. (C) Delayed spatial memory measured as time (%) spent in annulus 40 in session 10 in MWM test. (D) Representative path of control (CTL) and metformin (MET) treated mice in session 10 in MWM test. Discriminative avoidance test (E & F) demonstrated that metformin treatment impaired acquisition, cognitive flexibility and delayed reversal performance. Trials (n) to reach avoidance criterion (E) and trials (n) to reach discrimination criterion (F) in discriminative avoidance test. Elevated Zero maze test demonstrated that metformin treatment decreased anxiety. Time (s) spent in open arms (G) and representative path of CTL) and MET mice (H). Each value represents mean ± SEM, n=10. *p<0.05 compared to control.
Figure 5.  Metformin treatment altered metabolomic profile in hippocampus of young male normoglycemic mice. A) Heatmap of 145 metabolites (Supplementary Table) in mice hippocampus after 7-day treatment with metformin in drinking water (2mg/ml). B) Metformin treatment significantly increased levels of dimethylglycine, histidine, and choline in the hippocampus. Significant decreased levels of malic acid, thymidine, dihydroxyacetone-phosphate (DHAP), and myo-inositol were observed in the hippocampus of metformin-treated mice (* p<0.05) (n=4).
Figure 6.  Metformin treatment decreased ATP level and activated AMPK in the hippocampus of young male normoglycemic mice. A) ATP assay of mouse hippocampus lysate after 7-day treatment with metformin. ATP level was normalized to protein concentration (n=4). B) Representative and quantitative analysis Western blots of total and phosphorylated AMPKα, TSC2 and Raptor in hippocampus of metformin treated (MET) and control (CTL) mice (n=4) (* p<0.05). C) Western blot analysis of phosphorylation of total and phosphorylated ERK in hippocampus of metformin treated (MET) and control (CTL) mice (n=4) (*, p<0.05).
Figure 7.  High dose metformin induces cell death and inhibits mitochondrial complex I. Primary astrocytes were treated with 2 mM metformin for 48 hours. A) Left panel, flow cytometer analysis after Annexin V and PI; right panel: percentage of cell in each state. B) Bright image of astrocytes after 48-hour metformin or control treatment. C) Oxygen consumption rate (OCR) of primary astrocytes immediately (left panel), at 6 (middle panel), or 24 hours (right panel) after metformin treatment or control (final concentration of metformin was 2 mM). D) ATP level after 6-hour and 24-hour treatment with 2 mM metformin. E. Complex I activity of mitochondria isolated from adult mice after incubation with different concentrations of metformin for 10 minutes. Metformin inhibited mitochondrial complex I activity at 2 and 20 mM. (* p<0.05).
Figure 8.  Prolonged treatment with clinically relevant concentrations of metformin inhibited oxygen consumption rate (OCR) and increased ATP production through enhancement of glycolysis pathway in vitro. Primary astrocytes (A) and primary neurons (B) were treated with metformin (20 µM and 200 µM) for 24 hours before seahorse extracellular flux analysis; bar graph indicated base OCR of each condition (n=6). C) ATP assay in primary astrocyte culture after treatment with 20 µM and 200 µM metformin for 3, 6 and 24 hours (n=6). D) Total ATP in primary astrocytes was increased after 24-hour treatment with 50 µM metformin. Astrocyte was treated with 10 mg/ml oligomycin for 2 hours to inhibit ATP production from mitochondrial oxidative phosphorylation. Lactate production was increased by metformin treatment (n=6). E) Total ATP (24-hour treatment) and ATP from glycolysis (2-hour treatment) in primary neurons were increased by 50 µM metformin treatment (n=6) (* p<0.05).
Figure 9.  Metformin inhibited brain mGPDH. A) mGPDH activity in mitochondria isolated from mouse brain was inhibited by 50 µM metformin (n=4). B) Metformin inhibited G3P induced oxygen consumption in primary astrocytes in seahorse extracellular flux assay (n=8).
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