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

Short high fat diet triggers reversible and region specific effects in DCX+ hippocampal immature neurons of adolescent male mice

Adolescence represents a crucial period for maturation of brain structures involved in cognition. Early in life unhealthy dietary patterns are associated with inferior cognitive outcomes at later ages; conversely, healthy diet is associated with better cognitive results. In this study we analyzed the effects of a short period of hypercaloric diet on newborn hippocampal doublecortin+ (DCX) immature neurons in adolescent mice. Male mice received high fat diet (HFD) or control low fat diet (LFD) from the 5th week of age for 1 or 2 weeks, or 1 week HFD followed by 1 week LFD. After diet supply, mice were either perfused for immunohistochemical (IHC) analysis or their hippocampi were dissected for biochemical assays. Detailed morphometric analysis was performed in DCX+ cells that displayed features of immature neurons. We report that 1 week-HFD was sufficient to dramatically reduce dendritic tree complexity of DCX+ cells. This effect occurred specifically in dorsal and not ventral hippocampus and correlated with reduced BDNF expression levels in dorsal hippocampus. Both structural and biochemical changes were reversed by a return to LFD. Altogether these studies increase our current knowledge on potential consequences of hypercaloric diet on brain and in particular on dorsal hippocampal neuroplasticity

Inhibition of I kappa B Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock

R Sordi is supported by the program Science without Borders, CAPES Foundation, Ministry of Education of Brazil, Brasilia/DF, Brazil; NSA Patel is, in part, supported by the Bart’s and The LondonCharity (753/1722). The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union′s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement n° 608765, from the William Harvey Research Foundation and University of Turin (Ricerca Locale ex-60%). This work contributes to the Organ Protection research theme of the Barts Centre for Trauma Sciences, supported by the Barts and The London Charity (Award 753/1722) and forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute of Health Researc

Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems

Abstract Advanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH. RAGE is the main receptor mediating the pro-inflammatory signalling induced by AGEs. Therefore, targeting of RAGE has been proposed for prevention of chronic inflammatory diseases. However, the role of RAGE in the development of NAFLD and NASH remains poorly understood. We thus aimed to analyse the effect of obesity on AGEs accumulation, AGE-receptors and AGE-detoxification, and whether the absence of RAGE might improve hepatosteatosis and inflammation, by comparing the liver of lean control, obese (LeptrDb−/−) and obese RAGE-deficient (RAGE−/− LeptrDb−/−) mice. Obesity induced AGEs accumulation and RAGE expression with hepatosteatosis and inflammation in LeptrDb−/−, compared to lean controls. Despite the genetic deletion of RAGE in the LeptrDb−/− mice, high levels of intrahepatic AGEs were maintained accompanied by decreased expression of the protective AGE-receptor-1, impaired AGE-detoxifying system glyoxalase-1, and increased expression of the alternative AGE-receptor galectin-3. We also found sustained hepatosteatosis and inflammation as determined by persistent activation of the lipogenic SREBP1c and proinflammatory NLRP3 signalling pathways. Thus, RAGE targeting is not effective in the prevention of NAFLD in conditions of obesity, likely due to the direct liver specific crosstalk of RAGE with other AGE-receptors and AGE-detoxifying systems

Deletion of RAGE fails to prevent hepatosteatosis in obese mice due to impairment of other AGEs receptors and detoxifying systems

Advanced glycation endproducts (AGEs) are involved in several diseases, including NAFLD and NASH. RAGE is the main receptor mediating the pro-inflammatory signalling induced by AGEs. Therefore, targeting of RAGE has been proposed for prevention of chronic inflammatory diseases. However, the role of RAGE in the development of NAFLD and NASH remains poorly understood. We thus aimed to analyse the effect of obesity on AGEs accumulation, AGE-receptors and AGE-detoxification, and whether the absence of RAGE might improve hepatosteatosis and inflammation, by comparing the liver of lean control, obese (LeptrDb−/−) and obese RAGE-deficient (RAGE−/− LeptrDb−/−) mice. Obesity induced AGEs accumulation and RAGE expression with hepatosteatosis and inflammation in LeptrDb−/−, compared to lean controls. Despite the genetic deletion of RAGE in the LeptrDb−/− mice, high levels of intrahepatic AGEs were maintained accompanied by decreased expression of the protective AGE-receptor-1, impaired AGE-detoxifying system glyoxalase-1, and increased expression of the alternative AGE-receptor galectin-3. We also found sustained hepatosteatosis and inflammation as determined by persistent activation of the lipogenic SREBP1c and proinflammatory NLRP3 signalling pathways. Thus, RAGE targeting is not effective in the prevention of NAFLD in conditions of obesity, likely due to the direct liver specific crosstalk of RAGE with other AGE-receptors and AGE-detoxifying systems