The Stroke-Induced Increase of Somatostatin-Expressing Neurons is Inhibited by Diabetes: A Potential Mechanism at the Basis of Impaired Stroke Recovery

Type 2 diabetes (T2D) hampers recovery after stroke, but the underling mechanisms are mostly unknown. In a recently published study (Pintana et al. in Clin Sci (Lond) 133(13):1367\u20131386, 2019), we showed that impaired recovery in T2D was associated with persistent atrophy of parvalbumin+ interneurons in the damaged striatum. In the current work, which is an extension of the abovementioned study, we investigated whether somatostatin (SOM)+ interneurons are also affected by T2D during the stroke recovery phase. C57Bl/6j mice were fed with high-fat diet or standard diet (SD) for 12\ua0months and subjected to 30-min transient middle cerebral artery occlusion (tMCAO). SOM+ cell number/density in the striatum was assessed by immunohistochemistry 2 and 6\ua0weeks after tMCAO in peri-infarct and infarct areas. This was possible by establishing a computer-based quantification method that compensates the post-stroke tissue deformation and the irregular cell distribution. SOM+ interneurons largely survived the stroke as seen at 2\ua0weeks. Remarkably, 6\ua0weeks after stroke, the number of SOM+ interneurons increased (vs. contralateral striatum) in SD-fed mice in both peri-infarct and infarct areas. However, this increase did not result from neurogenesis. T2D completely abolished this effect specifically in the in the infarct area. The results suggest that the up-regulation of SOM expression in the post-stroke phase could be related to neurological recovery and T2D could inhibit this process. We also present a new and precise method for cell counting in the stroke-damaged striatum that allows to reveal accurate, area-related effects of stroke on cell number

Методология синтеза архитектуры программно-технического комплекса автоматизированной системы мониторинга обстановки

Предложен подход к проектированию архитектуры программно-технического комплекса автоматизированной системы мониторинга обстановки в реальном времени, основанный на классификации решаемых функциональных задач на основе методов кластерного анализа и выбранного множества признаков подобия. Разработанный подход позволяет из множества функций системы выделить подобные (по определенным признакам) и объединить их в архитектурные компоненты (унифицированные функциональные модули).Запропоновано підхід до проектування архітектури центру обробки інформації автоматизованої системи моніторингу середовища в реальному часі, що заснований на класифікації функціональних задач на підставі методів кластерного аналізу і обраної множини ознак схожості. Розроблений підхід дозволяє вибрати із множини функцій системи схожі (за певними ознаками) і поєднати їх в архітектурні компоненти (уніфіковані функціональні модулі).The approach to designing architecture of the information processing complex of the automated real time conditions monitoring system based on classification of functional tasks on the basis of methods of cluster analysis and the chosen set of similarity attributes is offered. The developed approach allows to allocate from a set of functions the systems similar (on certain attributes) and to unite them in architectural components (unified functional modules)

The effect of DPP-4 inhibition to improve functional outcome after stroke is mediated by the CXCR4/SDF-1alpha pathway

Abstract AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) decrease hyperglycemia by inhibiting glucagon-like peptide-1 (GLP-1)-cleavage. Gliptins can also improve stroke outcome in rodents independently from GLP1R. However, the underlying mechanisms are unknown. We aimed to determine whether gliptins improve stroke outcome via the stromal cell-derived factor-1 \u3b1 (SDF-1\u3b1)/ Chemokine Receptor Type 4 (CXCR4) pathway, and identify additional effectors behind the efficacy. MATERIALS AND METHODS: Mice were subjected to stroke by transient middle cerebral artery occlusion (MCAO). Linagliptin was administered for 3 days or 3 weeks from stroke onset. The CXCR4-antagonist AMD3100 was administered one day before MCAO until three days thereafter. Stroke outcome was assessed by measuring upper-limb function, stroke volume and neuronal survival. Brain GLP-1, GIP and SDF-1\u3b1 were quantified by ELISA. To identify additional gliptin-mediated molecular effectors, brain samples were analyzed by mass spectrometry. RESULTS: Linagliptin specifically increased active SDF-1\u3b1 but not GIP or GLP-1 brain levels. Blocking of SDF-1\u3b1/CXCR4 pathway abolished the positive effects of Linagliptin on upper-limb function and histological outcome after stroke. Moreover, Linagliptin treatment after stroke decreased the presence of peptides derived from Neurogranin and from an isoform of the Myelin basic protein. CONCLUSIONS: We showed that Linagliptin improves functional stroke outcome in a CXCR4/SDF-1\u3b1-dependent manner. Considering that Calpain activity and intracellular Ca2+ regulate Neurogranin and Myelin basic protein detection, we propose a gliptin-mediated neuroprotective mechanism via the SDF-1\u3b1/CXCR4 pathway that involves the regulation of Ca2+ homeostasis and the reduction of Calpain activity. These results provide new insights into restorative gliptin-mediated effects against stroke

The effect of the DPP-4 inhibitor linagliptin to improve functional outcome after stroke is mediated by the CXCR4/SDF-1\u3b1 pathway.

Abstract Background and Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) decrease hyperglycemia by inhibiting glucagon-like peptide-1 (GLP-1)-cleavage. Gliptins can also improve stroke outcome in rodents independently from GLP-1 receptor [1,2]. However, the underlying mechanisms are unknown. We aimed to determine whether gliptins improve stroke outcome via the stromal cell-derived factor-1 \u3b1 (SDF-1\u3b1)/ Chemokine Receptor Type 4 (CXCR4) pathway, and identify additional effectors behind the efficacy. Methods: Mice were subjected to stroke by transient middle cerebral artery occlusion (MCAO). Linagliptin was administered for 3 days or 3 weeks from stroke onset. The CXCR4-antagonist AMD3100 was administered one day before MCAO until three days thereafter. Stroke outcome was assessed by measuring upper-limb function, stroke volume and neuronal survival. Brain GLP-1, GIP and SDF-1\u3b1 were quantified by ELISA. To identify additional gliptin-mediated molecular effectors, brain samples were analyzed by mass spectrometry. Results: Linagliptin specifically increased active SDF-1\u3b1 (p<0,001) but not GIP or GLP-1 brain levels. Blocking of SDF-1\u3b1/CXCR4 pathway abolished the positive effects of Linagliptin on upper-limb function and histological outcome after stroke. Moreover, Linagliptin treatment after stroke decreased the presence of peptides derived from Neurogranin and from an isoform of the Myelin basic protein. Conclusion: We showed that Linagliptin improves functional stroke outcome in a CXCR4/SDF-1\u3b1-dependent manner. Considering that Calpain activity and intracellular Ca2+ regulate Neurogranin and Myelin basic protein detection, we propose a gliptin-mediated neuroprotective mechanism via the SDF-1\u3b1/CXCR4 pathway that involves the regulation of Ca2+ homeostasis and the reduction of Calpain activity. These results provide new insights into restorative gliptin-mediated effects against stroke. References: [1] Darsalia et al., Diabetes 2013, 62(4):1289-1296. [2] Darsalia et al., Diabetes Obes Metab 2016, 18(5):537-41

The effect of the DPP-4 inhibitor linagliptin to improve functional outcome after stroke is mediated by the CXCR4/SDF-1\u3b1 pathway

Abstract Background and Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) decrease hyperglycemia by inhibiting glucagon-like peptide-1 (GLP-1)-cleavage. Evidence from most clinical and experimental studies indicated that DPP-4 inhibitors have favorable effects on cardiovascular diseases, despite they failed to show superiority vs. placebo in the prevention of cardiovascular events in patients with T2DM and high CV risk [1]. We have recently demonstrated that DPP-4 inhibitors improve stroke outcome in rodents independently from GLP-1 receptor [2,3]. However, the underlying mechanisms are unknown. The present study aims to determine whether gliptins improve stroke outcome via the stromal cell-derived factor-1 \u3b1 (SDF-1\u3b1)/ Chemokine Receptor Type 4 (CXCR4) pathway, and identify additional effectors behind the efficacy. Methods: Mice were subjected to stroke by transient middle cerebral artery occlusion (MCAO). Linagliptin was administered for 3 days or 3 weeks from stroke onset. The CXCR4-antagonist AMD3100 was administered one day before MCAO until three days thereafter. Stroke outcome was assessed by measuring upper-limb function, stroke volume and neuronal survival. Brain GLP-1, GIP and SDF-1\u3b1 were quantified by ELISA. To identify additional gliptin-mediated molecular effectors, brain samples were analyzed by mass spectrometry. Results: Linagliptin specifically increased active SDF-1\u3b1 (p<0,001) but not GIP or GLP-1 brain levels. Blocking of SDF-1\u3b1/CXCR4 pathway abolished the positive effects of Linagliptin on upper-limb function and histological outcome after stroke. Moreover, Linagliptin treatment after stroke decreased the presence of peptides derived from Neurogranin and from an isoform of the Myelin basic protein. Conclusion: We showed that Linagliptin improves functional stroke outcome in a CXCR4/SDF-1\u3b1-dependent manner. Considering that Calpain activity and intracellular Ca2+ regulate Neurogranin and Myelin basic protein detection, we propose a gliptin-mediated neuroprotective mechanism via the SDF-1\u3b1/CXCR4 pathway that involves the regulation of Ca2+ homeostasis and the reduction of Calpain activity. These results provide new insights into the beneficial effects of gliptins in stroke, thus suggesting further innovative pharmacological target for preventing cerebrovascular injury. References: [1] Scheen, Circulation Research. 2018;122:1439-1459 [1] Darsalia et al., Diabetes 2013, 62(4):1289-1296

The effect of the DPP-4 inhibitor Linagliptin to improve functional outcome after stroke is mediated by the CXCR4/SDF-1\u3b1 pathway

Abstract Background and Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) decrease hyperglycemia by inhibiting glucagon-like peptide-1 (GLP-1)-cleavage. Gliptins can also improve stroke outcome in rodents independently from GLP-1 receptor [1,2]. However, the underlying mechanisms are unknown. We aimed to determine whether gliptins improve stroke outcome via the stromal cell-derived factor-1 \u3b1 (SDF-1\u3b1)/ Chemokine Receptor Type 4 (CXCR4) pathway, and identify additional effectors behind the efficacy. Methods: Mice were subjected to stroke by transient middle cerebral artery occlusion (MCAO). Linagliptin was administered for 3 days or 3 weeks from stroke onset. The CXCR4-antagonist AMD3100 was administered one day before MCAO until three days thereafter. Stroke outcome was assessed by measuring upper-limb function, stroke volume and neuronal survival. Brain GLP-1, GIP and SDF-1\u3b1 were quantified by ELISA. To identify additional gliptin-mediated molecular effectors, brain samples were analyzed by mass spectrometry. Results: Linagliptin specifically increased active SDF-1\u3b1 (p<0,001) but not GIP or GLP-1 brain levels. Blocking of SDF-1\u3b1/CXCR4 pathway abolished the positive effects of Linagliptin on upper-limb function and histological outcome after stroke. Moreover, Linagliptin treatment after stroke decreased the presence of peptides derived from Neurogranin and from an isoform of the Myelin basic protein. Conclusion: We showed that Linagliptin improves functional stroke outcome in a CXCR4/SDF-1\u3b1-dependent manner. Considering that Calpain activity and intracellular Ca2+ regulate Neurogranin and Myelin basic protein detection, we propose a gliptin-mediated neuroprotective mechanism via the SDF-1\u3b1/CXCR4 pathway that involves the regulation of Ca2+ homeostasis and the reduction of Calpain activity. These results provide new insights into restorative gliptin-mediated effects against stroke. References: [1] Darsalia et al., Diabetes 2013, 62(4):1289-1296. [2] Darsalia et al., Diabetes Obes Metab 2016, 18(5):537-41

Type 2 diabetes impairs odour detection, olfactory memory and olfactory neuroplasticity; effects partly reversed by the DPP-4 inhibitor Linagliptin

Recent data suggest that olfactory deficits could represent an early marker and a pathogenic mechanism at the basis of cognitive decline in type 2 diabetes (T2D). However, research is needed to further characterize olfactory deficits in diabetes, their relation to cognitive decline and underlying mechanisms.The aim of this study was to determine whether T2D impairs odour detection, olfactory memory as well as neuroplasticity in two major brain areas responsible for olfaction and odour coding: the main olfactory bulb (MOB) and the piriform cortex (PC), respectively. Dipeptidyl peptidase-4 inhibitors (DPP-4i) are clinically used T2D drugs exerting also beneficial effects in the brain. Therefore, we aimed to determine whether DPP-4i could reverse the potentially detrimental effects of T2D on the olfactory system.Non-diabetic Wistar and T2D Goto-Kakizaki rats, untreated or treated for 16 weeks with the DPP-4i linagliptin, were employed. Odour detection and olfactory memory were assessed by using the block, the habituation-dishabituation and the buried pellet tests. We assessed neuroplasticity in the MOB by quantifying adult neurogenesis and GABAergic inhibitory interneurons positive for calbindin, parvalbumin and carletinin. In the PC, neuroplasticity was assessed by quantifying the same populations of interneurons and a newly identified form of olfactory neuroplasticity mediated by post-mitotic doublecortin (DCX)\u2009+\u2009immature neurons.We show that T2D dramatically reduced odour detection and olfactory memory. Moreover, T2D decreased neurogenesis in the MOB, impaired the differentiation of DCX+ immature neurons in the PC and altered GABAergic interneurons protein expression in both olfactory areas. DPP-4i did not improve odour detection and olfactory memory. However, it normalized T2D-induced effects on neuroplasticity.The results provide new knowledge on the detrimental effects of T2D on the olfactory system. This knowledge could constitute essentials for understanding the interplay between T2D and cognitive decline and for designing effective preventive therapies