DPP-4 inhibition with linagliptin ameliorates cognitive impairment and brain atrophy induced by transient cerebral ischemia in type 2 diabetic mice

Abstract

BackgroundIt is unclear whether dipeptidylpeptidase-4 (DPP-4) inhibition can counteract the impairment of cognitive function and brain injury caused by transient cerebral ischemia in type 2 diabetes. The present study was undertaken to test our hypothesis that linagliptin, a DPP-4 inhibitor, administration following transient cerebral ischemia can ameliorate cognitive impairment and brain injury in diabetic mice.Methodsdb/db mice, a model of obese type 2 diabetes, were subjected to transient cerebral ischemia by 17 min of bilateral common carotid artery occlusion (BCCAO), and were administered (1) vehicle or (2) linagliptin for 8 weeks or 1 week. For the long-term experiment on 8 weeks of linagliptin treatment, cognitive function, and volume and neuronal cell number of hippocampus and cortex were estimated in each group of mice. For the short-term experiment on 1 week of linagliptin treatment, cerebral IgG extravasation, Iba-1 positive cell number (reactive microglia), oxidative stress, and claudin-5 and gp91phox protein levels were measured in each group of mice.ResultsLinagliptin administration almost completely suppressed the circulating DPP-4 activity in db/db mice, but did not significantly reduce blood glucose or ameliorate glucose intolerance in db/db mice. Linagliptin administration following transient cerebral ischemia significantly counteracted cognitive impairment in diabetic mice, as estimated by water maze test and passive avoidance test. Linagliptin administration ameliorated the decrease in cerebral volume and neuronal cell number in hippocampus and cortex of diabetic mice. Linagliptin administration significantly reduced the increase in cerebral IgG extravasation and the increase in reactive microglia caused by transient cerebral ischemia in diabetic mice. Furthermore, linagliptin significantly suppressed the increase in cerebral oxidative stress in transient cerebral ischemia-subjected diabetic mice. Furthermore, linagliptin significantly increased cerebral claudin-5 and significantly decreased gp91phox in diabetic mice subjected to transient cerebral ischemia.ConclusionsDPP-4 inhibition with linagliptin counteracted cognitive impairment and brain atrophy induced by transient cerebral ischemia in diabetic mice, independently of blood glucose lowering effect. This cerebroprotective effect of linagliptin was associated with the suppression of blood-brain barrier disruption and the attenuation of cerebral oxidative stress. Thus, our present work highlights DPP-4 inhibition as a promising therapeutic strategy for cognitive impairment and cerebral vascular complications in type 2 diabetes.

Effect of BCCAO Duration and Animal Models Sex on Brain Ischemic Volume After 24 Hours Reperfusion

“…TBCCAO duration of 8 to 30 minutes followed by 60 to 10,080 minutes reperfusion can damage striatum 4,26,10,[28][29][30] . TBCCAO for 10 to 17 minutes followed by 1,440 to 10,080 minutes reperfusion can lead to a damaged hippocampus 30,31 . TBCCAO for 10 minutes followed by 2,880 minutes reperfusion will damage caudoputamen 32 .…”

“…TBCCAO for 10 minutes followed by 2,880 minutes reperfusion will damage caudoputamen 32 . TBCCAO for 10 to 30 minutes followed by 60 to 10,080 minutes of reperfusion can damage the cerebral cortex 26,29,31,32 . While 14 minutes of TBCCAO followed by 1,440 minutes reperfusion will damage thalamus 29 .…”

“…While 14 minutes of TBCCAO followed by 1,440 minutes reperfusion will damage thalamus 29 . Only one study that assess mice hippocampus and cortex volume post transient bilateral common carotid artery ligation 31 . TTC staining method can be used to observe tissue ischemia macroscopically.…”

Neuroprotective properties of incretin mimetics in brain ischemia and neurodegenerative diseases

“…В последние 2-3 года опубликованы обзоры, обобщающие дополнительные свойства этих групп гипогликемических средств, отражаю-щие их кардиоваскулярные и нейропсихотропные свойства [8, 15,16].…”

“…Можно предположить, что повышение концентраций этих факторов непредсказуемо влия-ет в условиях острого или хронического ишемиче-ского процесса. Однако имеются работы, показыва-ющие наличие нейропротективного потенциала у ингибитора ДПП-4 -линаглиптина [16]. Это может быть связано с его более высокой селективностью к Механизмы нейропротективного действия ана-логов ГПП-1 связаны не только с ингибированием апоптоза нейронов, снижением воспаления и уско-рением репаративных процессов, но, по большей ча-сти, и со снижением риска развития самого инсульта: уменьшением эндотелиальной дисфункции, систем-ного воспаления и прокоагулянтного потенциала крови.…”