Neuroprotective potential of antihyperglycemic drug metformin in streptozocin-induced rat model of sporadic Alzheimer's disease

Piļipenko, Vladimirs; Narbute, Karīna; Pupure, Jolanta; Langrate, Ilva Kristiāna; Muceniece, Ruta; Kluša, Vija

doi:10.1016/j.ejphar.2020.173290

Cited by 38 publications

(22 citation statements)

References 45 publications

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“…The hippocampus is also one of the major brain regions affected by AD, in which hippocampal synaptic transmission is impaired [ 32 ]. Met has been demonstrated to ameliorate synaptic, memory and cognitive deficits in rodent models of AD [ 12 , 33 , 34 , 35 ]. However, there are few reports about Met effects on synaptic transmission.…”

Section: Discussionmentioning

confidence: 99%

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Chen

Liu

et al. 2020

Brain Sciences

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Metformin (Met) is a first-line drug for type 2 diabetes mellitus (T2DM). Numerous studies have shown that Met exerts beneficial effects on a variety of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). However, it is still largely unclear how Met acts on neurons. Here, by treating acute hippocampal slices with Met (1 μM and 10 μM) and recording synaptic transmission as well as neuronal excitability of CA1 pyramidal neurons, we found that Met treatments significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs), but not amplitude. Neither frequency nor amplitude of miniature inhibitory postsynaptic currents (mIPSCs) were changed with Met treatments. Analysis of paired-pulse ratios (PPR) demonstrates that enhanced presynaptic glutamate release from terminals innervating CA1 hippocampal pyramidal neurons, while excitability of CA1 pyramidal neurons was not altered. Our results suggest that Met preferentially increases glutamatergic rather than GABAergic transmission in hippocampal CA1, providing a new insight on how Met acts on neurons.

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Section: Discussionmentioning

confidence: 99%

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Chen

Liu

et al. 2020

Brain Sciences

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“…Since LOAD represents more than 95% of AD cases, associated animal models are valuable research resources for studying pathogenesis and designing experimental treatments for sporadic AD [ 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. STZ is a diabetogenic agent that is widely used to induce diabetes in animals because it damages and induces IR in pancreatic beta cells.…”

Section: Metformin As An Antidiabetic Drug Strategy For Alzheimer’s Disease Treatmentmentioning

confidence: 99%

“…STZ is a diabetogenic agent that is widely used to induce diabetes in animals because it damages and induces IR in pancreatic beta cells. Decrease of glucose/energy metabolism in brain, corresponds to the severity of dementia symptoms in AD, and is a well-established brain abnormality of sporadic AD [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ]. In ICV-STZ animal models, BIR reduced brain glucose metabolism, tau and Aβ accumulation, gliosis, cholinergic deficits, oxidative stress, and learning and memory deficits [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ].…”

Section: Metformin As An Antidiabetic Drug Strategy For Alzheimer’s Disease Treatmentmentioning

confidence: 99%

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

et al. 2021

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Alzheimer’s disease (AD) is one of the most devastating brain disorders. Currently, there are no effective treatments to stop the disease progression and it is becoming a major public health concern. Several risk factors are involved in the progression of AD, modifying neuronal circuits and brain cognition, and eventually leading to neuronal death. Among them, obesity and type 2 diabetes mellitus (T2DM) have attracted increasing attention, since brain insulin resistance can contribute to neurodegeneration. Consequently, AD has been referred to “type 3 diabetes” and antidiabetic medications such as intranasal insulin, glitazones, metformin or liraglutide are being tested as possible alternatives. Metformin, a first line antihyperglycemic medication, is a 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator hypothesized to act as a geroprotective agent. However, studies on its association with age-related cognitive decline have shown controversial results with positive and negative findings. In spite of this, metformin shows positive benefits such as anti-inflammatory effects, accelerated neurogenesis, strengthened memory, and prolonged life expectancy. Moreover, it has been recently demonstrated that metformin enhances synaptophysin, sirtuin-1, AMPK, and brain-derived neuronal factor (BDNF) immunoreactivity, which are essential markers of plasticity. The present review discusses the numerous studies which have explored (1) the neuropathological hallmarks of AD, (2) association of type 2 diabetes with AD, and (3) the potential therapeutic effects of metformin on AD and preclinical models.

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“…Moreover, metformin alleviates neurodegenerative changes in streptozotocin-induced AD rats by normalization of brain glucose transport, uptake, and metabolism, paralleled with amelioration of microgliosis and astrogliosis. Metformin also preserves hippocampal synaptic plasticity in the cortical and hippocampal tissues of diabetic rats (Pilipenko et al, 2020). Metformin exerts protective effects against spatial cognitive impairment and hippocampal structure abnormalities in db/db mice.…”

Section: Neurodegenerative Diseasesmentioning

confidence: 93%

Metformin: A Novel Weapon Against Inflammation

Bai

Chen

2021

Front. Pharmacol.

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It has become widely accepted that inflammation is a driving force behind a variety of chronic diseases, such as cardiovascular disease, diabetes, kidney disease, cancer, neurodegenerative disorders, etc. However, the existing nonsteroidal anti-inflammatory drugs show a limited utility in clinical patients. Therefore, the novel agents with different inflammation-inhibitory mechanisms are worth pursuing. Metformin, a synthetic derivative of guanidine, has a history of more than 50 years of clinical experience in treating patients with type 2 diabetes. Intense research efforts have been dedicated to proving metformin’s inflammation-inhibitory effects in cells, animal models, patient records, and randomized clinical trials. The emerging evidence also indicates its therapeutic potential in clinical domains other than type 2 diabetes. Herein, this article appraises current pre-clinical and clinical findings, emphasizing metformin’s anti-inflammatory properties under individual pathophysiological scenarios. In summary, the anti-inflammatory effects of metformin are evident in pre-clinical models. By comparison, there are still clinical perplexities to be addressed in repurposing metformin to inflammation-driven chronic diseases. Future randomized controlled trials, incorporating better stratification/targeting, would establish metformin’s utility in this clinical setting.

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Neuroprotective potential of antihyperglycemic drug metformin in streptozocin-induced rat model of sporadic Alzheimer's disease

Cited by 38 publications

References 45 publications

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

Metformin: A Novel Weapon Against Inflammation

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