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. 2024;27(3):360-365.
doi: 10.22038/IJBMS.2023.73075.15879.

Metformin improves memory via AMPK/mTOR-dependent route in a rat model of Alzheimer's disease

Reza Ale Mahmoud Mehraban  1   2 , Parvin Babaei  1   2   3 , Kambiz Rohampour  3   2 , Adele Jafari  2 , Zoleikha Golipoor  3
Affiliations

Metformin improves memory via AMPK/mTOR-dependent route in a rat model of Alzheimer's disease

Reza Ale Mahmoud Mehraban et al. Iran J Basic Med Sci. 2024.

Abstract

Objectives: Metformin, as an insulin sensitizer, is a familiar antidiabetic drug. Increasing evidence points to metformin's protective effects against Alzheimer's disease (AD). However, the mechanism is not well understood. The present study evaluated whether inhibiting AMPK and activating mTOR could stop metformin from improving memory in rats with streptozotocin (STZ) -induced Alzheimer's disease.

Materials and methods: Twelve-week-old Wistar rats, were injected 3 mg/kg STZ intracerebroventricularly on days 1 and 3 to develop the animal model. Metformin was applied orally at 100 mg/kg (17 days). Forty-five min before the retrieval phase, dorsomorphin (DM; AMPK inhibitor, 2 M) and MHY (mTOR activator, 0.1 M) were administered. Morris Water Maze (MWM) and shuttle box were utilized to measure spatial and passive avoidance memory, respectively. Congo red staining was used to identify cortical amyloid deposition.

Results: The findings exhibited a considerable enhancement in spatial learning and memory in the metformin treatment group (P≤0.05). Injection of DM and MHY alone could not significantly change MWM and passive avoidance. Additionally, co-administration of DM and MHY increased escape latency (P≤0.001) and reduced the total time spent in the target quadrant (TTS) (P≤0.05) compared to the STZ+MET group during retrieval of MWM. Also, co-injection of DM and MHY increased step-through latency (STL) and decreased time spent in the dark compartment (TDC) compared to the STZ+MET group (P≤0.001).

Conclusion: Metformin appears to have a therapeutic impact by activating AMPK and inactivating mTOR. As a result, it could be used as an Alzheimer's treatment strategy.

Keywords: AMP-activated protein – kinase; Alzheimer disease; Memory; Metformin; mTOR.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Experiment design showing the time course of drug administration and behavioral tests in rats in different groups
Figure 2
Figure 2
Effect of STZ, metformin, DM, MHY, and DM+MHY on MWM in rat in different groups
Figure 3
Figure 3
Effect of STZ, metformin, DM, MHY, and DM+MHY in rats in different groups
Figure 4
Figure 4
Effect of STZ, metformin, DM, and DM+MHY on Cogno red stained cortex tissue in rats in different groups
See this image and copyright information in PMC

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