Neuroglobin (Ngb) is a recently discovered tissue globin with a high affinity for oxygen that is widely and specifically expressed in neurons of vertebrate central and peripheral nervous systems. Our laboratory and others have showed Ngb over-expression can protect neurons against hypoxic/ ischemic insults, but the underlying mechanisms remain poorly understood. In this study, we examined the effects of Ngb over-expression on mitochondrial function, oxidative stress and neurotoxicity in primary cortical neurons following hypoxia/reoxygenation (H/R). Ngb overexpressing transgenic neurons (Ngb-Tg) were significantly protected against H/R-induced cell death. Rates of decline in ATP levels, MTT reduction and mitochondrial membrane potential were significantly ameliorated in Ngb-Tg neurons. Furthermore, Ngb overexpression reduced superoxide anion generation after H/R, whereas glutathione levels were significantly improved compared to WT controls. Taken together, these data suggest that Ngb is neuroprotective against hypoxia, in part by improving mitochondria function and decreasing oxidative stress.

After stroke, peripheral immune cells are activated and these systemic responses may amplify brain damage, but how the injured brain sends out signals to trigger systemic inflammation remains unclear. Here we show that a brain-to-cervical lymph node (CLN) pathway is involved. In rats subjected to focal cerebral ischemia, lymphatic endothelial cells proliferate and macrophages are rapidly activated in CLNs within 24 h, in part via VEGF-C/VEGFR3 signalling. Microarray analyses of isolated lymphatic endothelium from CLNs of ischemic mice confirm the activation of transmembrane tyrosine kinase pathways. Blockade of VEGFR3 reduces lymphatic endothelial activation, decreases pro-inflammatory macrophages, and reduces brain infarction. In vitro, VEGF-C/VEGFR3 signalling in lymphatic endothelial cells enhances inflammatory responses in co-cultured macrophages. Lastly, surgical removal of CLNs in mice significantly reduces infarction after focal cerebral ischemia. These findings suggest that modulating the brain-to-CLN pathway may offer therapeutic opportunities to ameliorate systemic inflammation and brain injury after stroke.

Accumulating studies suggest that overnutrition-associated obesity may lead to development of type 2 diabetes mellitus and metabolic syndromes (MetS). MetS and its components are important risk factors of mild cognitive impairment, age-related cognitive decline, vascular dementia, and Alzheimer’s disease. It has been recently proposed that development of a disease-course modification strategy toward early and effective risk factor management would be clinically significant in reducing the risk of metabolic disorder-initiated cognitive decline. In the present study, we propose that fibroblast growth factor 21 (FGF21) is a novel candidate for the disease-course modification approach. Using a high-fat diet (HFD) consumption-induced obese mouse model, we tested our hypothesis that recombinant human FGF21 (rFGF21) administration is effective for improving obesity-induced cognitive dysfunction and anxiety-like behavior, by its multiple metabolic modulation and anti-pro-inflammation actions. Our experimental findings support our hypothesis that rFGF21 is protective to HFD-induced cognitive impairment, at least in part by metabolic regulation in glucose tolerance impairment, insulin resistance, and hyperlipidemia; potent systemic pro-inflammation inhibition; and improvement of hippocampal dysfunction, particularly by inhibiting proneuroinflammation and neurogenesis deficit. This study suggests that FGF21 might be a novel molecular target of the disease-course-modifying strategy for early intervention of MstS-associated cognitive decline.