Antidiabetic drugs restore abnormal transport of amyloid-β across the blood–brain barrier and memory impairment in db / db mice

Chen, Fang; Dong, Rong; Zhong, Kai; Ghosh, Arijit; Tang, Su Su; Long, Yan; Mei, Hu; Miao, Ming Xing; Liao, Jian Min; Sun, Hong; Kong, Ling Yi; Hong, Hao

doi:10.1016/j.neuropharm.2015.07.023

Cited by 120 publications

(68 citation statements)

References 57 publications

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“…The results indicated that metformin can promote survival of mOECs cultured ex vivo, which was associated with a decreased expression of caspase-3 and a lowered number of dead cells, when compared to mOECs from the CTRL group. The pro-survival action of metformin was described previously by Chang et al, who showed that metformin may inactivate caspase-3, known as a crucial mediator of apoptosis through its protease activity [13]. Additionally, we observed senolytic action of MET on mOECs, as a decrease of SA-β-gal activity, which is a reliable and sensitive marker for the detection of cellular senescence.…”

Section: Resultssupporting

confidence: 79%

“…Furthermore, therapeutic strategies include metformin administration for the treatment of Alzheimer’s disease [3,11,12]. Neuroprotective effects of metformin have been also confirmed by a recent study of Chen et al [13] who investigated the effects of anti-diabetic drugs on hippocampal synaptic plasticity using mice models. These authors showed that metformin could exert anti-apoptotic effects by decreasing the ratio of caspase-3 fragment/procaspase-3 and increasing the ratio of Bcl-2/Bax in the hippocampus.…”

Section: Introductionmentioning

confidence: 95%

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Antioxidant and Anti-Senescence Effect of Metformin on Mouse Olfactory Ensheathing Cells (mOECs) May Be Associated with Increased Brain-Derived Neurotrophic Factor Levels—An Ex Vivo Study

Śmieszek

Stręk

Kornicka

et al. 2017

IJMS

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Metformin, the popular anti-diabetic drug was shown to exert multiple biological effects. The most recent metformin gained attention as an agent that mobilizes endogenous progenitor cells and enhances regenerative potential of organisms, for example by promoting neurogenesis. In the present study, we examined the role of metformin on mouse olfactory ensheathing cells (mOECs) derived from animals receiving metformin for eight weeks at a concentration equal to 2.8 mg/day. The mOECs expanded ex vivo were characterized in terms of their cellular phenotype, morphology, proliferative activity, viability and accumulation of oxidative stress factors. Moreover, we determined the mRNA and protein levels of brain-derived neurotrophic factor (BDNF), distinguishing the secretion of BDNF by mOECs in cultures and circulating serum levels of BDNF. The mOECs used in the experiment were glial fibrillary acidic protein (GFAP) and p75 neurotrophin receptor (p75NTR) positive and exhibited both astrocyte-like and non-myelin Schwann cell-like morphologies. Our results revealed that the proliferation of OECs derived from mice treated with metformin was lowered, when compared to control group. Simultaneously, we noted increased cell viability, reduced expression of markers associated with cellular senescence and a decreased amount of reactive oxygen species. We observed increased mRNA expression of BDNF and its down-stream genes. Obtained results indicate that metformin may exert antioxidant, anti-apoptotic and senolytic action on OECs expanded ex vivo.

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Section: Resultssupporting

confidence: 79%

Section: Introductionmentioning

confidence: 95%

Antioxidant and Anti-Senescence Effect of Metformin on Mouse Olfactory Ensheathing Cells (mOECs) May Be Associated with Increased Brain-Derived Neurotrophic Factor Levels—An Ex Vivo Study

Śmieszek

Stręk

Kornicka

et al. 2017

IJMS

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“…Previous studies demonstrated that Met could rapidly cross the blood-brain barrier (Labuzek et al, 2010) and had several beneficial effects in the brain, such as anti-inflammatory (Wang et al, 2016) and neuroprotective effects (Gupta et al, 2011). Meanwhile, Met could alleviate the impairment of cognitive function in db/db mice (Li et al, 2012; Chen et al, 2016). Many clinic trails were also shown that long-term treatment with Met could reduce the risk of cognitive decline (Guo et al, 2014; Ng et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Berberine Ameliorates Diabetes-Associated Cognitive Decline through Modulation of Aberrant Inflammation Response and Insulin Signaling Pathway in DM Rats

Chen

et al. 2017

Front. Pharmacol.

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Background: Memory-impairment was one of the common characteristics in patients with diabetes mellitus. The release of chronic inflammation mediators and insulin resistance in diabetic brain gave rise to the generation of toxic factor Aβ42 which was the marker of Alzheimer’s disease. In addition, the impairment of memory in diabetes mellitus was also correlated predominantly with uptake/metabolism of glucose in medial prefrontal cortex (mPFC). Previously, anti-inflammation and hypoglycemic effects of berberine (BBr) have been described in peripheral tissues. For better understanding the effects of BBr on cognitive action in diabetics, we investigated the functions of BBr involved in anti-inflammation and ameliorating insulin resistance in prefrontal cortex of diabetic rats.Methods: Intragastric administration of BBr (187.5 mg/Kg/d) was used in diabetic rats. Fear-condition assay was applied for cognitive assessment, and relative protein expressions were detected by western-blot. The glucose uptake in prefrontal cortex of diabetic rats was tested by Positron-Emission Tomography imaging. The levels of inflammation mediators were determined by commercial ELISA kits.Results: The inflammation mediator release and insulin resistance in the mPFC of diabetic rats was inhibited by BBr. The activation of PI3K/Akt/mTOR and MAPK signaling pathway, as well as two novel isoforms PKCη and PKC𝜀 and the translocation of NF-κB in neuron were also down-regulated by BBr; furthermore, the neuron specific glucose transporter GLUT3 was remarkably augmented by 2–3 times when compared with diabetic group; meanwhile, BBr also promoted glucose uptake in the brain. Additionally BBr decreased the expressions of amyloid precursor protein and BACE-1, and the production of oligomeric Aβ42. Finally, it accelerates the reinforcement of the information and ameliorates cognitive impairment.Conclusion: BBr inhibited the activation of inflammation pathway and insulin resistance in the mPFC of diabetic rats. Finally, it improved the lesion of cognition in diabetic rats.

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“…The arterial supply of the hippocampal tail originates from the P3 segment of the posterior cerebral artery, a peripheral artery that is often involved in diabetes (Umemura, Kawamura, & Hotta, 2017). Indeed, a prior clinical study showed that hyperglycemia can lead to small vascular and microvascular lesions in multiple brain regions, including the hippocampus (Sanahuja et al, 2016), while an experimental study using an animal model of diabetes demonstrated that antidiabetic drugs were able to partially restore abnormal amyloidbeta transport across the blood-brain barrier and improve memory function (Chen et al, 2016). Other studies have shown that the hippocampal tail volume of patients with major depression was significantly smaller than that of the controls (Maller et al, 2012) and that diabetes was one of the most important risk factors for senile depression (Semenkovich, Brown, Svrakic, & Lustman, 2015).…”

Section: F I G U R Ementioning

confidence: 99%

Individuals in the prediabetes stage exhibit reduced hippocampal tail volume and executive dysfunction

Sun

Zhang

et al. 2019

Brain and Behavior

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Introduction High glucose levels are associated with cognitive impairment and total hippocampal volume reductions. However, the effects of the blood glucose level on hippocampal subfield volumes remain unclear, especially in the prediabetes stage. Methods Sixty participants were enrolled in this cross‐sectional study and were divided into the nondiabetes, prediabetes, and diabetes groups according to their medical history and A1c level. A full battery of neuropsychological tests was used to assess the global cognition, executive function, attention, verbal fluency, working memory, immediate memory, and delayed memory. FreeSurfer 6.0 was used for the hippocampus parcellation. Hippocampal subfield volumes were adjusted by intracranial volume. Analyses of covariance, multiple linear regression, and partial correlation analysis were used to explore the relationship between A1c level, cognitive function, and hippocampal subfields volume, in which age, sex, education years, body mass index, history of hypertension, level of cholesterol, and the presence of ApoE4‐positive status were adjusted. Results Significant differences in the total left hippocampal volume ( p = 0.046) and left hippocampal tail volume ( p = 0.014) were noted among three groups. Significant correlation was identified between the A1c level and the volume of left hippocampal tail ( r = −0.334, p = 0.009) after adjusting all the covariants. Increased A1c level was significantly associated with executive dysfunction, as assessed by trail making test B ( R = 0.503, p = 0.0016) and Stroop test C ( R = 0.506, p = 0.001). Conclusions Our results support that the left hippocampal tail volume may be served as an early marker of diabetes‐related brain damage, associated with executive dysfunction. Clinicians should pay closer attention to adults in the prediabetes stage to prevent later cognitive impairment.

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Antidiabetic drugs restore abnormal transport of amyloid-β across the blood–brain barrier and memory impairment in db / db mice

Cited by 120 publications

References 57 publications

Antioxidant and Anti-Senescence Effect of Metformin on Mouse Olfactory Ensheathing Cells (mOECs) May Be Associated with Increased Brain-Derived Neurotrophic Factor Levels—An Ex Vivo Study

Antioxidant and Anti-Senescence Effect of Metformin on Mouse Olfactory Ensheathing Cells (mOECs) May Be Associated with Increased Brain-Derived Neurotrophic Factor Levels—An Ex Vivo Study

Berberine Ameliorates Diabetes-Associated Cognitive Decline through Modulation of Aberrant Inflammation Response and Insulin Signaling Pathway in DM Rats

Individuals in the prediabetes stage exhibit reduced hippocampal tail volume and executive dysfunction

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