Abstract
Metformin is an antidiabetic medicine widely used for management of type 2 diabetes with neuroprotective effects and promising potential to attenuate cognitive impairment. The efficacy of metformin in attenuation of Alzheimer’s disease (AD) pathology has not been well-documented. Thus, this study was designed to assess protective effect of metformin against Aβ1−40-instigared cognitive impairment. After intra-CA1 microinjection of aggregated Aβ1−40, rats received oral metformin (50 and/or 200 mg/kg/day) for two weeks. Cognition function was analyzed in various behavioral tasks besides measurement of hippocampal oxidative stress, apoptosis, and inflammation along with H&E staining and 3-nitrotyrosine (3-NT) immunohistochemistry. Obtained data showed significant improvement of discrimination score in novel object recognition test, higher alternation score in Y maze, greater latency in passive avoidance task, and lower working and reference memory errors in radial arm maze in metformin-treated Aβ-injured group. Moreover, metformin treatment attenuated hippocampal levels of nitrite, MDA, protein carbonyl, ROS, TNFα, GFAP, DNA fragmentation intensity, caspase 3 activity, AChE activity, and increased SOD activity and level of IL-10 as an anti-inflammatory factor. In addition, metformin treatment was associated with lower CA1 neuronal loss and it also decreased intensity of 3-NT immunoreactivity as an indicator of nitrosative stress. Taken together, obtained findings showed neuroprotective and anti-dementia property of metformin in male rats and this may have potential benefit in attenuation of cognitive decline and related complications in patients with neurodegenerative disorders such as AD besides diabetes mellitus.
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Code availability
Not applicable.
Data availability
Data of this study will be available from the corresponding author on reasonable request.
Abbreviations
- 3-NT:
-
3-nitrotyrosine
- Akt:
-
Protein kinase B
- Aβ:
-
amyloid beta
- AMPK:
-
AMP-activated protein kinase
- AChE:
-
Acetylcholinesterase
- AD:
-
Alzheimer’s disease
- CA1:
-
Cornu ammonis subfield 1
- GFAP:
-
Glial fibrillary acidic protein
- GSH:
-
Reduced Glutathione
- ICV:
-
Intracerebroventricular
- IL-10:
-
Interleukin 10
- MAPK:
-
Mitogen-activated protein kinase
- MDA:
-
Malondialdehyde
- miR:
-
microRNA
- MMP:
-
Mitochondrial membrane potential
- MPTP:
-
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- NLRP3:
-
NOD-, LRR- and pyrin domain-containing protein 3
- NF-κB:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- PI3K:
-
Phosphoinositide 3-kinase
- ROS:
-
Reactive oxygen species
- PI3K:
-
phosphoinositide 3-kinase
- RAM:
-
Radial arm maze
- SOD:
-
Superoxide dismutase
- STZ:
-
Streptozotocin
- TNFa:
-
Tumor necrosis factor α
- TLR4:
-
Toll-like receptor 4
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This research study was certified and financially supported (grant # p-647-89) by Shahed University (Tehran, Iran).
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MK and SSD performed study experiments and assisted in initial data analysis. AAD and MR conceived and designed the study, supervised the experiments, analyzed data, and prepared the draft of the manuscript. All authors read and approved the submitted manuscript.
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This study was approved by the Ethics Committee of Shahed University (Tehran, Iran) (Approval # IR.Shahed.REC.1395.92).
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Khaleghi-Mehr, M., Delshad, AA., Shafie-Damavandi, S. et al. Metformin mitigates amyloid β1-40-induced cognitive decline via attenuation of oxidative/nitrosative stress and neuroinflammation. Metab Brain Dis 38, 1127–1142 (2023). https://doi.org/10.1007/s11011-023-01170-1
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DOI: https://doi.org/10.1007/s11011-023-01170-1