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

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

Research output: Contribution to journalArticle

Abstract

Objective Accumulating epidemiological studies have demonstrated that diabetes is an important risk factor for dementia. However, the underlying pathological and molecular mechanisms, and effective treatment, have not been fully elucidated. Herein, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, on diabetes-related cognitive impairment. Method Streptozotocin (STZ)-induced diabetic mice were treated with linagliptin (3 mg/kg/24 h) for 17 weeks. The radial arm water maze test was performed, followed by evaluation of oxidative stress using DNP-MRI and the expression of NAD(P)H oxidase components and proinflammatory cytokines and of microglial activity. Results Administration of linagliptin did not affect the plasma glucose and body weight of diabetic mice; however, it improved cognitive impairment. Additionally, linagliptin reduced oxidative stress and the mRNA expression of NAD(P)H oxidase component and TNF-α, and the number and body area of microglia, all of which were significantly increased in diabetic mice. Conclusions Linagliptin may have a beneficial effect on diabetes-related dementia by inhibiting oxidative stress and microglial activation, independently of glucose-lowering.

Original languageEnglish
Article numbere0228750
JournalPloS one
Volume15
Issue number2
DOIs
Publication statusPublished - 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Ide, M., Sonoda, N., Inoue, T., Kimura, S., Minami, Y., Makimura, H., Hayashida, E., Hyodo, F., Yamato, M., Takayanagi, R., & Inoguchi, T. (2020). The dipeptidyl peptidase-4 inhibitor, linagliptin, improves cognitive impairment in streptozotocin-induced diabetic mice by inhibiting oxidative stress and microglial activation. PloS one, 15(2), [e0228750]. https://doi.org/10.1371/journal.pone.0228750