Metformin Eased Cognitive Impairment Induced by Chronic L-methionine Administration: Potential Role of Oxidative Stress

Alzoubi, Karem H.; Khabour, Omar F.; Al‐Azzam, Sayer; Tashtoush, Murad H; Mhaidat, Nizar M.

doi:10.2174/1570159x11666131120223201

Cited by 57 publications

(32 citation statements)

References 41 publications

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“…But research of its role in cognitive function has produced controversial findings. Some studies have reported beneficial effects of metformin on memory function in mice (41)(42)(43)(44). Other studies, however, point to its role in the increased risk for AD and potential adverse effects on the cognitive performance of diabetic patients, in which scenario metformin is a routine prescription (16,17).…”

Section: Discussionmentioning

confidence: 99%

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

et al. 2019

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Aging and apolipoprotein E4 (ApoE4) can increase the risk of cognitive impairment and neurodegenerative disorders, including Alzheimer's disease (AD), and patients with type 2 diabetes mellitus are highly susceptible to cognitive dysfunction. Recent research has indicated that metformin, a prescribed drug for type 2 diabetes, may affect cognitive function; however, findings regarding its efficacy are largely controversial. The current study reported that a 5‐mo metformin administration (300 mg/kg/d) starting at 13 mo old improved the spatial memory of ApoE3‐target replacement (TR) mice, not ApoE4‐TR mice. It found that in aged ApoE3‐TR mice, metformin treatment, at a molecular level, inhibited AMPK activity, increased insulin signaling, and activated mammalian target of rapamycin signaling, resulting in an enhanced expression of postsynaptic proteins; but the response of the neuronal AMPK activity and insulin signaling to metformin was blunt in aged ApoE4‐TR mice. Meanwhile, metformin treatment also increased the phosphorylation of tau in both ApoE3‐TR and ApoE4‐TR mice, implying that metformin may have side effects in human. These findings suggest that metformin can improve the cognitive performance of aged mice in an APOE genotype–dependent manner, which provides empirical insights into the clinical value of metformin for ApoE4‐ and age‐related AD prevention and treatment.—Zhang, J., Lin, Y., Dai, X., Fang, W., Wu, X., Chen, X. Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner. FASEB J. 33, 7748–7757 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

et al. 2019

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“…GSH levels in brain and spinal cord did not differ compared to control. This attenuation proves the antioxidant property of MET [Pintana et al, ; Alzoubi et al, ]. MET activates AMPK, which has a crucial role in stabilizing mitochondrial membrane potential, decreasing endoplasmic reticulum stress along with ROS production consequently avoiding the oxidative damage [Barreto‐Torres et al, ].…”

Section: Discussionmentioning

confidence: 99%

Metformin Protects against Experimental Acrylamide Neuropathy in Rats

Oda

2017

Drug Development Research

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Preclinical Research To investigate the potential neuroprotective effects of metformin against experimental acrylamide neuropathy in rats, 24 rats were distributed into four equal groups (6 each). Group 1 was kept as a control. Group 2 (MET) was orally given metformin (200 mg/kg BW/day). Group 3 (ACR) was injected IP with acrylamide (50 mg/kg BW/day). Animals in group 4 (ACR + MET) were administered both MET and ACR at the same dose and route used in groups 2 and 3. Treatments were administered three times a week for three weeks. ACR induced an increase in lipid peroxidation in brain and spinal cord. This was associated with down regulation of bcl2 and up regulation of caspase3 in cerebrum, cerebellum, spinal cord, and sciatic nerve in the ACR-treated group. ACR-treated rats revealed neuronal degeneration and glial cell reaction in brain and spinal cord with axonal degeneration and myelin sheath irregularities in sciatic nerve. MET restored lipid peroxidation in brain and spinal cord, decreased caspase3 activity and up regulated bcl2 expression in cerebrum and sciatic nerve. Histopathological findings in ACR + MET group were lesser severe than those established in ACR-group indicating that MET ameliorates the neuropathic effects of ACR in rats. Drug Dev Res 78 : 349-359, 2017. © 2017 Wiley Periodicals, Inc.

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“…Metformin had no effect on spatial learning. Other studies have shown improved cognitive performance with metformin using similar testing paradigms [18, 49, 50]. Interestingly, a sub group analysis of participants from the Primary Research in Memory Clinics study showed that among patients with diabetes, worse cognitive performance was associated with metformin use [51].…”

Section: Discussionmentioning

confidence: 99%

Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice

Allard

Perez

Fukui

et al. 2016

Behavioural Brain Research

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Long-term use of anti-diabetic agents has become commonplace as rates of obesity, metabolic syndrome and diabetes continue to escalate. Metformin, a commonly used anti-diabetic drug, has been shown to have many beneficial effects outside of its therapeutic regulation of glucose metabolism and insulin sensitivity. Studies on metformin’s effects on the central nervous system are limited and predominantly consist of in vitro studies and a few in vivo studies with short-term treatment in relatively young animals; some provide support for metformin as a neuroprotective agent while others show evidence that metformin may be deleterious to neuronal survival. In this study, we examined the effect of long-term metformin treatment on brain neurotrophins and cognition in aged male C57Bl/6 mice. Mice were fed control (C), high-fat (HF) or a high-fat diet supplemented with metformin (HFM) for 6 months. Metformin decreased body fat composition and attenuated declines in motor function induced by a HF diet. Performance in the Morris water maze test of hippocampal based memory function, showed that metformin prevented impairment of spatial reference memory associated with the HF diet. Quantitative RT-PCR on brain homogenates revealed decreased transcription of BDNF, NGF and NTF3; however protein levels were not altered. Metformin treatment also decreased expression of the antioxidant pathway regulator, Nrf2. The decrease in transcription of neurotrophic factors and Nrf2 with chronic metformin intake, cautions of the possibility that extended metformin use may alter brain biochemistry in a manner that creates a vulnerable brain environment and warrants further investigation.

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Metformin Eased Cognitive Impairment Induced by Chronic L-methionine Administration: Potential Role of Oxidative Stress

Cited by 57 publications

References 41 publications

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

Metformin Protects against Experimental Acrylamide Neuropathy in Rats

Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice

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