Abstract
ObjectiveAccumulating 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.MethodStreptozotocin (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.ResultsAdministration 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.ConclusionsLinagliptin may have a beneficial effect on diabetes-related dementia by inhibiting oxidative stress and microglial activation, independently of glucose-lowering.
Highlights
The number of people with dementia is increasing with the aging of the world’s population
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
Linagliptin may have a beneficial effect on diabetes-related dementia by inhibiting oxidative stress and microglial activation, independently of glucose-lowering
Summary
The number of people with dementia is increasing with the aging of the world’s population. It has been reported that diabetes is an independent risk factor for cognitive impairment[1,2], and dementia has been recognised as a complication of diabetes[3]. It is important to further examine the mechanisms underlying diabetes-related dementia and explore effective treatment strategies. Hyperglycaemia causes oxidative stress, which plays a pivotal role in the development of diabetes complications [4]. Immune cells in the brain, are neuroprotective under normal conditions, they produce proinflammatory cytokines and reactive oxygen species (ROS) when activated by inflammation, nerve damage or infection[5]. We have recently reported that diabetes-related cognitive impairment is at least partially caused by oxidative stress via microglial activation in the brain[6]
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