Showing papers by "Tim Magnus published in 2011"

Evidence that gamma-secretase-mediated Notch signaling induces neuronal cell death via the nuclear factor-kappaB-Bcl-2-interacting mediator of cell death pathway in ischemic stroke.

Abstract: Notch-1 (Notch) is a cell surface receptor that regulates cell-fate decisions in the developing nervous system, and it may also have roles in synaptic plasticity in the adult brain. Binding of its ligands results in the proteolytic cleavage of Notch by the γ-secretase enzyme complex, thereby causing the release of a Notch intracellular domain (NICD) that translocates to the nucleus, in which it regulates transcription. Here we show that activation of Notch modulates ischemic neuronal cell death in vitro and in vivo. Specifically, our findings from the use of Notch-1 siRNA or the overexpression of NICD indicate that Notch activation contributes to cell death. Using modified NICD, we demonstrate an apoptosis-inducing function of NICD in both the nucleus and the cytosol. NICD transfection-induced cell death was reduced by blockade of calcium signaling, caspase activation, and Janus kinase signaling. Inhibition of the Notch-activating enzyme, γ-secretase, protected against ischemic neuronal cell death by targeting an apoptotic protease, cleaved caspase-3, nuclear factor-κB (NF-κB), and the pro-death BH3-only protein, Bcl-2-interacting mediator of cell death (Bim). Treatment of mice with a γ-secretase inhibitor, compound E, reduced infarct size and improved functional outcome in a model of focal ischemic stroke. Furthermore, γ-secretase inhibition reduced NICD, p-p65, and Bim levels in vivo. These findings suggest that Notch signaling endangers neurons after ischemic stroke by modulating the NF-κB, pro-death protein Bim, and caspase pathways.

CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia.

Abstract: The black and white fill in Figure 4c is incorrect. Please view the correct Figure 4 here: ttp://www.plosone.org/corrections/pone.0019046.g004.cn.tif

Calorie restriction and stroke

Abstract: Stroke, a major cause of disability and mortality in the elderly, occurs when a cerebral blood vessel is occluded or ruptured, resulting in ischemic damage and death of brain cells. The injury mechanism involves metabolic and oxidative stress, excitotoxicity, apoptosis and inflammatory processes, including activation of glial cells and infiltration of leukocytes. In animal models, dietary energy restriction, by daily calorie reduction (CR) or intermittent fasting (IF), extends lifespan and decreases the development of age-related diseases. Dietary energy restriction may also benefit neurons, as suggested by experimental evidence showing that CR and IF protect neurons against degeneration in animal models. Recent findings by our group and others suggest the possibility that dietary energy restriction may protect against stroke induced brain injury, in part by inducing the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF); protein chaperones, including heat shock protein 70 (Hsp70) and glucose regulated protein 78 (GRP78); antioxidant enzymes, such as superoxide dismutases (SOD) and heme oxygenase-1 (HO-1), silent information regulator T1 (SIRT1), uncoupling proteins and anti-inflammatory cytokines. This article discusses the protective mechanisms activated by dietary energy restriction in ischemic stroke.

Nitroxyl in the central nervous system.

Abstract: Nitroxyl (HNO) is the one-electron-reduced and protonated congener of nitric oxide (NO). Compared to NO, it is far more reactive with thiol groups either in proteins or in small antioxidant molecules either converting those into sulfinamides or inducing disulfide bond formation. HNO might mediate cytoprotective changes of protein function through thiol modifications. However, HNO is a strong oxidant that in vitro reacts with glutathione to form glutathione disulfide and glutathione sulfinamide. The resulting oxidative stress might aggravate tissue damage in inflammatory diseases. In this review, we will summarize the current knowledge of how exogenous HNO affects the central nervous system, especially nerve cells and glia in health and disease. Unlike most other organs, the brain is separated from the circulation by the blood-brain barrier, which limits access of many pharmacological compounds. Given that, we will review what is known about the ability of currently used HNO donors to cross the blood-brain barrier. Moreover, considering that the physiology and composition of the brain has unique properties, for example, expression of brain-specific enzymes like neuronal NO synthase, its high iron content, and increased energy metabolism, we will discuss possible sources of endogenous HNO in the brain.