The dipeptidyl peptidase-4 inhibitor, linagliptin, improves cognitive impairment in streptozotocin-induced diabetic mice by inhibiting oxidative stress and microglial activation

Ide, Makoto; Sonoda, Noriyuki; Inoue, Tomoaki; Kimura, Seiichiro; Minami, Yohei; Makimura, Hiroaki; Hayashida, Eiichi; Hyodo, Fuminori; Yamato, Masayuki; Takayanagi, Ryoichi; Inoguchi, Toyoshi

doi:10.1371/journal.pone.0228750

Cited by 24 publications

(26 citation statements)

References 40 publications

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“…This finding of our study is consistent with the previous study of Alam et al highlighting the ability of Sitagliptin to prevent heart and kidney inflammation and fibrosis in 2K1C rats by amelioration of MDA, nitric oxide, and advanced protein oxidation product concentrations (Alam, Chowdhury, Jain, Sagor, & Reza, 2015). Then again, Ide et al concluded that Linagliptin reduced MDA levels in Streptozotocin-induced diabetic mice (Ide et al, 2020).…”

Section: Discussionsupporting

confidence: 93%

Targeting AGE‐RAGE signaling pathway by Saxagliptin prevents myocardial injury in isoproterenol challenged diabetic rats

Kumar

Bhargava

Suchal

et al. 2021

Drug Development Research

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The role of Saxagliptin in diabetes-associated cardiovascular complications is controversial. This study aimed to investigate whether Saxagliptin could prevent Isoproterenolinduced myocardial changes in diabetic rats and to identify the possible mechanism as well. The high-fat diet/low-dose Streptozotocin-induced type 2 diabetic rats were divided into 3 groups: the control group (0.25% CMC for 28 days), the Isoproterenol group (85 mg/kg Isoproterenol for the last 2 days plus 0.25% CMC for 28 days), and the treatment group (10 mg/kg Saxagliptin for 28 days plus 85 mg/kg Isoproterenol for the last 2 days). Hemodynamic measurements were performed, and samples were examined for RAGE and NF-κB expressions, histopathological and ultrastructural changes, AGEs level, myocardial injury markers, oxidative stress, and apoptosis.Saxagliptin significantly recovered cardiac function (p < .001), reverted myocardial injury and oxidative stress levels back to the control value (p < .05 to p < .001). Saxagliptin alleviates Isoproterenol-induced myocardial injury in diabetic rats by suppressing AGE-RAGE pathway.

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Section: Discussionsupporting

confidence: 93%

Targeting AGE‐RAGE signaling pathway by Saxagliptin prevents myocardial injury in isoproterenol challenged diabetic rats

Kumar

Bhargava

Suchal

et al. 2021

Drug Development Research

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“…Further, daily administration of linagliptin reduced the mean blood glucose levels in the T2DM mice in a dosedependent manner, but not significantly. The results of the weak hypoglycemic effect of linagliptin on T2DM mice are consistent with those reported previously in non-diabetic mice (30), streptozotocin-induced diabetic mice (31,32), and T2DM mice (33,34). Importantly, the administration of linagliptin significantly increased serum active GLP-1 concentration in mice without exerting a clear hypoglycemic effect (30,32).…”

Section: Discussionsupporting

confidence: 91%

Effects of the linagliptin, dipeptidyl peptidase-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus in obese mice

Kanda

Furukawa

Izumo

et al. 2020

DD&T

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Dipeptidyl peptidase-4 inhibitor, type 2 diabetes mellitus, bone fragility Recently, it has been suggested that glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide 1 (GLP-1), which play important roles in the homeostasis of glucose metabolism, could be involved in the regulation of bone metabolism. Inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades GIP and GLP-1, are widely used clinically as a therapeutic agent for diabetes. However, the effects of DPP-4 inhibitors on bone metabolism remain unclear. In this study, we investigated the effects of linagliptin, a DPP-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus (T2DM). Non-diabetic mice were used as controls, and T2DM mice were administered linagliptin orally on a daily basis for 12 weeks. In T2DM mice, decreased bone mineral density was observed in the lower limb bones along with low serum osteocalcin levels and high serum tartrate-resistant acid phosphatase-5b (TRAP) levels. In contrast, the decreased serum osteocalcin levels and increased serum TRAP levels observed in T2DM mice were significantly suppressed after the administration of linagliptin 30 mg/kg. Bone histomorphometric analysis revealed a reduced osteoid volume and osteoblast surface with an increase in the eroded surface and number of osteoclasts in T2DM mice. This decreased bone formation and increased bone resorption observed in the T2DM mice were suppressed and trabecular bone volume increased following the administration of 30 mg/kg linagliptin. Collectively, these findings suggest that linagliptin may improve the microstructure of trabecular bone by inhibiting both a decrease in bone formation and an increase in bone resorption induced by T2DM.

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“…For example, the DPP4 inhibitor linagliptin has displayed a beneficial effect on diabetes-related dementia in streptozotocin (STZ)-induced diabetic mice models by inhibiting oxidative stress and microglial activation . Interestingly, another DPP4 inhibitor, Sitagliptin, possesses a neuroprotective property against chronic cerebral hypoperfusion (CHP) in mice by reducing white matter lesions, microglia activation, and the astrocytosis of white matter. − An important limitation of the current study is that it is still unknown whether Trelagliptin has some direct mechanism of action on these immune cells. Our future study will provide further evidence of the biological function of DPP4 and Trelagliptin in immune cell biology in the brain and the pathophysiology of stroke.…”

Section: Discussionmentioning

confidence: 92%

Trelagliptin Mitigates Macrophage Infiltration by Preventing the Breakdown of the Blood–Brain Barrier in the Brain of Middle Cerebral Artery Occlusion Mice

Zang

Yang

Zhang

et al. 2021

Chem. Res. Toxicol.

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Stroke is a significant cardiovascular disease that influences the health of human beings all over the world, especially the elderly population. It is reported that the blood–brain barrier (BBB) can be easily destroyed by stroke, which is one of the main factors responsible for macrophage infiltration and central nervous inflammation. Here, we report the protective effects of Trelagliptin against BBB injury and macrophage infiltration. Our results indicate that the infraction volume, the neurological score, and macrophage infiltration staining with CD68 were increased in middle cerebral artery occlusion (MCAO) mice but significantly reversed by treatment with Trelagliptin. Additionally, Trelagliptin reduced the permeability of the BBB by increasing the expression of the tight junction zonula occludens protein-1 (ZO-1) in the cerebral cortex. In an in vitro hypoxia model of endothelial cells, the increased migration of macrophages, enlarged permeability of endothelial monolayer, downregulation of ZO-1, and elevated expression level of CXCL1 by hypoxic conditions were all reversed by treatment with Trelagliptin in a dose-dependent manner. Our results demonstrate that Trelagliptin might mitigate macrophage infiltration by preventing the breakdown of the blood–brain barrier in the brains of MCAO mice.

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The dipeptidyl peptidase-4 inhibitor, linagliptin, improves cognitive impairment in streptozotocin-induced diabetic mice by inhibiting oxidative stress and microglial activation

Cited by 24 publications

References 40 publications

Targeting AGE‐RAGE signaling pathway by Saxagliptin prevents myocardial injury in isoproterenol challenged diabetic rats

Targeting AGE‐RAGE signaling pathway by Saxagliptin prevents myocardial injury in isoproterenol challenged diabetic rats

Effects of the linagliptin, dipeptidyl peptidase-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus in obese mice

Trelagliptin Mitigates Macrophage Infiltration by Preventing the Breakdown of the Blood–Brain Barrier in the Brain of Middle Cerebral Artery Occlusion Mice

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