Long-term administration of metformin ameliorates age-dependent oxidative stress and cognitive function in rats

Gorgich, Enam Alhagh Charkhat; Parsaie, Houman; Yarmand, Sazin; Baharvand, Farzaneh; Sarbishegi, Maryam

doi:10.1016/j.bbr.2021.113343

Cited by 17 publications

(9 citation statements)

References 44 publications

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“…The potential mechanisms of the relationship between metformin and cognitive performance have yet to be elucidated. Previous studies in animals have indicated that metformin could reduce cognitive impairment by reversing the harmful effects of impaired insulin signaling that causes a cascade of deleterious events, such as oxidative stress, inflammation, and tau hyper-phosphorylation (Farr et al, 2019 ; Gorgich et al, 2021 ). Moreover, the current study provides primary evidence suggesting that adults with diabetes facing a high risk of cognitive dysfunction should consider metformin as a first-line therapy.…”

Section: Discussionmentioning

confidence: 99%

Metformin use is associated with a reduced risk of cognitive impairment in adults with diabetes mellitus: A systematic review and meta-analysis

Zhang

Sun

et al. 2022

Front. Neurosci.

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ObjectiveControversy exists regarding the impact of metformin and whether it prevents or promotes the incidence of cognitive dysfunction. This systematic review and meta-analysis were conducted to identify the effect of metformin therapy on cognitive function in patients with diabetes.MethodsElectronic databases (PubMed, EMBASE, PsycINFO, the Cochrane Library, and Web of Science) were systematically searched by two investigators from the date of inception until March 1, 2022. The study followed PRISMA guidelines. Inclusion criteria were defined according to the PECOSmodel. Eligible studies investigated cognitive dysfunction in metformin users compared with non-users in adults with diabetes. Only observational study designs (such as cohort, cross-section, and case-control) were included.ResultsA systematic search identified 1,839 articles, of which 28 (17 cohort, 8 case-control, and 3 cross-sectional studies) were included in the meta-analysis. Metformin reduced the occurrence of cognitive impairment in patients with diabetes [unadjusted hazard ratio (HR) = 0.67, 95% CI: 0.62–0.73; adjusted hazard ratio (aHR) = 0.92, 95% CI: 0.85–0.99]. In addition, the use of metformin was associated with a decreased risk of dementia (HR = 0.64, 95% CI: 0.59–0.69; aHR = 0.90, 95% CI: 0.84–0.96), while a random-effects meta-analysis indicated no significant effect of metformin on the risk of Alzheimer's disease (AD) (HR = 0.85, 95% CI: 0.60–1.22; aHR = 1.10, 95% CI: 0.95–1.28).ConclusionMetformin therapy decreased the occurrence risk of cognitive decline in patients with diabetes mellitus. Moreover, the use of metformin by adults with diabetes for the prevention of dementia, but not AD, is supported by the available evidence.

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Section: Discussionmentioning

confidence: 99%

Metformin use is associated with a reduced risk of cognitive impairment in adults with diabetes mellitus: A systematic review and meta-analysis

Zhang

Sun

et al. 2022

Front. Neurosci.

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“…These conflicting results may be due to the short administration regimen in the present study. Particularly, previous studies reported that long-term use of MET (100 mg/kg in drinking water daily for 6 months) in normal male Wistar rats or administration for more than 6 years in older persons was required for MET to exhibit a significant neuroprotective effect ( Ng et al, 2014 ; Gorgich et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of Tanshinone IIA on Gut Microbiome in Diabetes-Induced Cognitive Impairment

et al. 2022

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Diabetes-induced cognitive impairment (DCI) presents a major public health risk among the aging population. Previous clinical attempts on known therapeutic targets for DCI, such as depleted insulin secretion, insulin resistance, and hyperglycaemia have delivered poor patient outcomes. However, recent evidence has demonstrated that the gut microbiome plays an important role in DCI by modulating cognitive function through the gut–brain crosstalk. The bioactive compound tanshinone IIA (TAN) has shown to improve cognitive and memory function in diabetes mellitus models, though the pharmacological actions are not fully understood. This study aims to investigate the effect and underlying mechanism of TAN in attenuating DCI in relation to regulating the gut microbiome. Metagenomic sequencing analyses were performed on a group of control rats, rats with diabetes induced by a high-fat/high-glucose diet (HFD) and streptozotocin (STZ) (model group) and TAN-treated diabetic rats (TAN group). Cognitive and memory function were assessed by the Morris water maze test, histopathological assessment of brain tissues, and immunoblotting of neurological biomarkers. The fasting blood glucose (FBG) level was monitored throughout the experiments. The levels of serum lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunoassays to reflect the circulatory inflammation level. The morphology of the colon barrier was observed by histopathological staining. Our study confirmed that TAN reduced the FBG level and improved the cognitive and memory function against HFD- and STZ-induced diabetes. TAN protected the endothelial tight junction in the hippocampus and colon, regulated neuronal biomarkers, and lowered the serum levels of LPS and TNF-α. TAN corrected the reduced abundance of Bacteroidetes in diabetic rats. At the species level, TAN regulated the abundance of B. dorei, Lachnoclostridium sp. YL32 and Clostridiodes difficile. TAN modulated the lipid metabolism and biosynthesis of fatty acids in related pathways as the main functional components. TAN significantly restored the reduced levels of isobutyric acid and butyric acid. Our results supported the use of TAN as a promising therapeutic agent for DCI, in which the underlying mechanism may be associated with gut microbiome regulation.

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“…Metformin is recommended as a base medication for all T2D patients without contraindications [ 12 ]. To our knowledge, metformin can also decelerate the progression of neurodegenerative diseases and has a positive effect on the improvement of cognitive dysfunction in T2D patients [ 13 , 14 ]. Previous studies have shown that STZ-induced diabetic mice are characterized by impaired cognitive performance so that being considered as a useful model to explore cognitive impairment attributable to diabetes [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, metformin has also received much attention in the field of neurodegenerative disease [ 13 ]. Recent studies have shown that Metformin can rapidly cross the blood-brain barrier after being absorbed into the blood and accumulate at high concentrations in most brain regions, thus exerting beneficial neuroprotective effects on the aging brain and cognitive functions [ 14 ]. Furthermore, a clinical study by Hsu et al showed that metformin can significantly reduce the risk of cognitive impairment in patients with T2DM [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Metformin improves cognitive impairment in diabetic mice induced by a combination of streptozotocin and isoflurane anesthesia

Zhang

Zhao

et al. 2021

Bioengineered

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To investigate the protective effects of metformin on the diabetic mice with cognitive impairment induced by the combination of streptozotocin (STZ) and isoflurane anesthesia. The isoflurane-anesthetized cognitive impairment model mice were established and then observed via behavioral tests and histopathological examination. Then these model mice were randomly assigned to three groups, which received the PBS, low and high doses of metformin, respectively. The body weight, food and water consumption of model mice were measured every other day. The mechanisms of metformin on ameliorating the cognitive dysfunction were further investigated by histomorphological, biochemical and Western blot analysis. After 14-days treatment of metformin, the diabetic symptoms in STZ-induced diabetic mice were significantly alleviated. Metformin could restore the isoflurane- and STZ-induced hippocampal tissue damage, cognitive and memory impairment in exposed space via improving the oxidative stress, upregulating the contents of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in the hippocampus tissues of diabetic mice. Furthermore, chronic treatment of metformin significantly down-regulated the expression of AGEs, RAGE, pNF-κB, iNOS, and COX-2. In conclusion, metformin can improve the isoflurane- and STZ-induced cognitive impairment in diabetic mice via improving oxidative stress and inhibiting the AGEs/RAGE/NF-κB signaling pathway.

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Long-term administration of metformin ameliorates age-dependent oxidative stress and cognitive function in rats

Cited by 17 publications

References 44 publications

Metformin use is associated with a reduced risk of cognitive impairment in adults with diabetes mellitus: A systematic review and meta-analysis

Metformin use is associated with a reduced risk of cognitive impairment in adults with diabetes mellitus: A systematic review and meta-analysis

Effect of Tanshinone IIA on Gut Microbiome in Diabetes-Induced Cognitive Impairment

Metformin improves cognitive impairment in diabetic mice induced by a combination of streptozotocin and isoflurane anesthesia

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