Is metformin neuroprotective against diabetes mellitus-induced neurodegeneration? An updated graphical review of molecular basis

Karami, Fatemeh; Jamaati, Hamidreza; Coleman-Fuller, Natalie; Zeini, Maryam Shokrian; Hayes, A. Wallace; Gholami, Mina; Salehirad, Mahsa; Darabi, Mohammad Ali; Motaghinejad, Majid

doi:10.1007/s43440-023-00469-1

Cited by 12 publications

(3 citation statements)

References 319 publications

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“…Several pathways are involved in oxidative stress in individuals with DM. Metformin had a notable impact on diabetic GK rats' brains, leading to significant reductions in thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA), and carbonyl groups [126,127]. These findings indicate that metformin exhibited antioxidant effects in the brain cells of GK diabetic rats, resulting in decreased levels of H 2 O 2 and oxidized form of glutathione (GSSG), along with increased levels of reduced form of glutathione (GSH) and vitamin E [126,127].…”

Section: Antioxidant Mechanism Of Metforminmentioning

confidence: 99%

“…Metformin had a notable impact on diabetic GK rats' brains, leading to significant reductions in thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA), and carbonyl groups [126,127]. These findings indicate that metformin exhibited antioxidant effects in the brain cells of GK diabetic rats, resulting in decreased levels of H 2 O 2 and oxidized form of glutathione (GSSG), along with increased levels of reduced form of glutathione (GSH) and vitamin E [126,127]. Additionally, metformin activated glutathione peroxidase, glutathione reductase, and manganese superoxide dismutase enzymes (MnSOD), further contributing to its antioxidant benefits.…”

Section: Antioxidant Mechanism Of Metforminmentioning

confidence: 99%

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Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders

Isop,

Neculau,

Necula

et al. 2023

Pharmaceuticals

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Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention for its potential neuroprotective properties due to the growing demand for treatments for Alzheimer’s, Parkinson’s, and motor neuron diseases. This review synthesizes experimental and clinical studies on metformin’s mechanisms of action and potential therapeutic benefits for neurodegenerative disorders. A comprehensive search of electronic databases, including PubMed, MEDLINE, Embase, and Cochrane library, focused on key phrases such as “metformin”, “neuroprotection”, and “neurodegenerative diseases”, with data up to September 2023. Recent research on metformin’s glucoregulatory mechanisms reveals new molecular targets, including the activation of the LKB1–AMPK signaling pathway, which is crucial for chronic administration of metformin. The pleiotropic impact may involve other stress kinases that are acutely activated. The precise role of respiratory chain complexes (I and IV), of the mitochondrial targets, or of the lysosomes in metformin effects remains to be established by further research. Research on extrahepatic targets like the gut and microbiota, as well as its antioxidant and immunomodulatory properties, is crucial for understanding neurodegenerative disorders. Experimental data on animal models shows promising results, but clinical studies are inconclusive. Understanding the molecular targets and mechanisms of its effects could help design clinical trials to explore and, hopefully, prove its therapeutic effects in neurodegenerative conditions.

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Section: Antioxidant Mechanism Of Metforminmentioning

confidence: 99%

Section: Antioxidant Mechanism Of Metforminmentioning

confidence: 99%

Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders

Isop,

Neculau,

Necula

et al. 2023

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“…Some other reviews have extended the analysis to the mechanisms possibly involved, but none have analyzed positive effects upon GLUT4 yet. A recent important review, evaluating protective mechanisms of metformin against DMinduced neurodegeneration, points out that metformin has beneficial effects against central inflammatory, mitochondrial, and oxidative stress, as well as anti-apoptotic effects [145].…”

Section: Ad Dm and Glut4 In The Hippocampusmentioning

confidence: 99%

Glucose Transport and Utilization in the Hippocampus: From Neurophysiology to Diabetes-Related Development of Dementia

Yonamine,

Michalani,

Moreira

et al. 2023

IJMS

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The association of diabetes with cognitive dysfunction has at least 60 years of history, which started with the observation that children with type 1 diabetes mellitus (T1D), who had recurrent episodes of hypoglycemia and consequently low glucose supply to the brain, showed a deficit of cognitive capacity. Later, the growing incidence of type 2 diabetes mellitus (T2D) and dementia in aged populations revealed their high association, in which a reduced neuronal glucose supply has also been considered as a key mechanism, despite hyperglycemia. Here, we discuss the role of glucose in neuronal functioning/preservation, and how peripheral blood glucose accesses the neuronal intracellular compartment, including the exquisite glucose flux across the blood–brain barrier (BBB) and the complex network of glucose transporters, in dementia-related areas such as the hippocampus. In addition, insulin resistance-induced abnormalities in the hippocampus of obese/T2D patients, such as inflammatory stress, oxidative stress, and mitochondrial stress, increased generation of advanced glycated end products and BBB dysfunction, as well as their association with dementia/Alzheimer’s disease, are addressed. Finally, we discuss how these abnormalities are accompained by the reduction in the expression and translocation of the high capacity insulin-sensitive glucose transporter GLUT4 in hippocampal neurons, which leads to neurocytoglycopenia and eventually to cognitive dysfunction. This knowledge should further encourage investigations into the beneficial effects of promising therapeutic approaches which could improve central insulin sensitivity and GLUT4 expression, to fight diabetes-related cognitive dysfunctions.

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Metformin improves cognitive dysfunction through SIRT1/NLRP3 pathway–mediated neuroinflammation in db/db mice

Hu,

Wei,

Zheng

et al. 2024

J Mol Med

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Is metformin neuroprotective against diabetes mellitus-induced neurodegeneration? An updated graphical review of molecular basis

Cited by 12 publications

References 319 publications

Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders

Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders

Glucose Transport and Utilization in the Hippocampus: From Neurophysiology to Diabetes-Related Development of Dementia

Metformin improves cognitive dysfunction through SIRT1/NLRP3 pathway–mediated neuroinflammation in db/db mice

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