Impairment of cognitive flexibility in type 2 diabetic db/db mice

Yermakov, Leonid M.; Griggs, Ryan B.; Drouet, Domenica E.; Sugimoto, Chiho; Williams, Michael T.; Vorhees, Charles V.; Susuki, Keiichiro

doi:10.1016/j.bbr.2019.111978

Cited by 27 publications

(19 citation statements)

References 75 publications

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“…Older type 2 diabetic patients have several impaired cognitive domains, with the highest ratio of impaired psychomotor speed ( McCrimmon et al 2012 ). In accordance with other reports ( Infante-Garcia et al 2017 , Yan et al 2019 , Yermakov et al 2019 ), in the Morris water maze test, diabetic mice showed exacerbated cognitive performance. Overexpression of neuritin ameliorated cognitive impairment, and the JAK2 inhibitor showed the same effects in diabetic mice.…”

Section: Discussionsupporting

confidence: 93%

Neuritin inhibits astrogliosis to ameliorate diabetic cognitive dysfunction

Zuo

Zhou

2021

Journal of Molecular Endocrinology

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Earlier, it was shown that reversing the downregulation of neuritin expression in the brain improves central neuropathy in diabetic rats. We investigated the protective mechanism of neuritin in diabetic cognitive dysfunction via astrocytes. Further, the impact of the overexpression of neuritin in the cortex and the hippocampus on diabetic cognitive dysfunction and astrogliosis in type 2 diabetic (db/db) mice was assessed. Antagonists were used to inhibit the JAK2/STAT3 signaling pathway in U-118MG, an astrocyte cell line. Immunofluorescence, western blotting, and real-time PCR were performed. Neuritin overexpression in the hippocampus of db/db mice significantly ameliorated cognitive dysfunction, hippocampal neuronal impairment, and synaptic plasticity deterioration, and inhibited astrogliosis and the JAK2/STAT3 signaling pathway in the hippocampus. Neuritin suppressed the JAK2/STAT3 signaling pathway to inhibit lipopolysaccharide-induced gliosis in U-118MG cells. It was observed that neuritin regulates the JAK2/STAT3 signaling pathway in astrocytes to inhibit astrogliosis and improve diabetic cognitive dysfunction.

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Section: Discussionsupporting

confidence: 93%

Neuritin inhibits astrogliosis to ameliorate diabetic cognitive dysfunction

Zuo

Zhou

2021

Journal of Molecular Endocrinology

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“…Animal studies may help to identify the mechanisms that underlie the adverse impact of diabetes on cognition and advance our understanding of its pathophysiology and may provide potential treatment on DACD. The leptin receptor-deficient db/db mice, one of the most widely used type 2 diabetes mellitus (T2DM) animal models, showed a series of diabetic symptoms such as obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications like DACD as leptin plays a critical role in memory and learning [ 7 , 8 ]. Therefore, db/db mice were used as DACD animal model in this study.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effects of ZiBuPiYin Recipe on db/db Mice via PI3K-Akt Signaling Pathway by Activating Grb2

Ren

Weng

et al. 2021

Neural Plasticity

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Background. Diabetes-associated cognitive decline (DACD) is one of the nervous system dysfunctions induced by diabetes mellitus with cognitive impairment as the major symptom. In a previous preliminary proteomic study, we found that endoplasmic reticulum processing and PI3K-Akt signaling pathway might be impaired in DACD pathogenesis. In addition, growth factor receptor-bound protein 2 might be a crucial protein as a molecular target of the neuroprotective effects of ZiBuPiYin recipe (ZBPYR). Methods. In this study, 6-8 weeks aged db/db mice were treated with excipients or ZBPYR for 6 weeks. Body weight and RBG were recorded weekly. Oral glucose tolerance and insulin tolerance tests were used to assess insulin sensitivity. Morris water maze (MWM) tests were used to assess memory function. The expression of Grb2, Gab2, Akt, and GSK3β in mouse hippocampus and cerebral cortex were analyzed by Western blotting. Results. ZBPYR not only significantly reduced RGB and improved glucose tolerance and insulin resistance, but also improved spatial cognition in DACD mice. The expression of Grb2 and Gab2 in hippocampus and cerebral cortex of db/db mice was upregulated after treated with ZBPYR, and then affected the PI3K/Akt signaling pathway, and inhibited GSK3β overactivity. Conclusions. This study showed that ZBPYR could enhance the memory and learning ability of db/db mice. Such neuroprotective effect might be related to the activation of Grb2-PI3K/Akt signaling which might provide a novel therapeutic target for the clinical treatment of DACD.

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“…In another fMRI study exploring the diabetic DMN regions, T2DM patients showed increased connectivity in the medial prefrontal cortex ( Cui et al, 2015 ). In addition, animal experiment also suggested that axon initial segments were significantly shortened in medial prefrontal cortex of db/db mice, a diabetic animal model, compared with controls ( Yermakov et al, 2019 ). In the current study, higher blood glucose levels were correlated with lower CBF values in tinnitus patients, indicating that hyperglycemic state has a negative impact on the brain perfusion in tinnitus patients, and tinnitus patients may benefit from controlled glucose levels to maintain better cognitive functions.…”

Section: Discussionmentioning

confidence: 99%

Glucose Control Has an Impact on Cerebral Blood Flow Alterations in Chronic Tinnitus Patients

et al. 2021

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PurposeBoth tinnitus and type 2 diabetes mellitus (T2DM) are linked with cognitive decline and brain dysfunction. This study used arterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) to examine the abnormal cerebral blood flow (CBF) patterns existed in tinnitus patients and potential relationships between the abnormal CBF and cognitive performance. The impact of T2DM on CBF alterations in tinnitus patients was further explored.MethodsSixty tinnitus patients and 40 non-tinnitus subjects were recruited. CBF images were collected and analyzed using ASL perfusion fMRI. Brain regions with CBF alterations between tinnitus patients and non-tinnitus controls were identified by one-way analysis of variance. Interaction effects between tinnitus and T2DM for CBF changes were also selected. Then, correlation analyses were calculated to specify the link between CBF changes and cognitive performance and between CBF changes and diabetic characteristics.ResultsTinnitus patients showed decreased CBF, primarily in the auditory area and default mode network (DMN), compared with non-tinnitus controls. Decreased CBF in these regions was correlated with executive function and attention. The interaction effect between tinnitus and T2DM was significant in the right medial prefrontal gyrus. Additionally, CBF in the right medial prefrontal gyrus was correlated with tinnitus distress and cognitive performance. In tinnitus patients, Hemoglobin A1c was associated with CBF in the right medial prefrontal gyrus.ConclusionTinnitus affects brain perfusion in the auditory area and DMN. T2DM and uncontrolled glucose levels may aggravate a CBF decrease in tinnitus patients. These new findings implied that tinnitus patients may benefit from blood glucose control in terms of their cognitive function and tinnitus distress.

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Impairment of cognitive flexibility in type 2 diabetic db/db mice

Cited by 27 publications

References 75 publications

Neuritin inhibits astrogliosis to ameliorate diabetic cognitive dysfunction

Neuritin inhibits astrogliosis to ameliorate diabetic cognitive dysfunction

Neuroprotective Effects of ZiBuPiYin Recipe on db/db Mice via PI3K-Akt Signaling Pathway by Activating Grb2

Glucose Control Has an Impact on Cerebral Blood Flow Alterations in Chronic Tinnitus Patients

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