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Brain 11: what's new in stroke research?
Yenari, Midori A,Lee, Jong Eun Future Drugs Ltd 2011 Expert review of neurotherapeutics Vol.11 No.9
<P>The International Society for Cerebral Blood Flow and Metabolism promotes research centered on furthering the understanding of neurological conditions that result from ischemia and related injuries. This previous meeting (Brain 11) focused on state-of-the-art research, which shed light on the pathophysiology of these conditions as they pertained to the cerebral vasculature - including the BBB - and angiogenesis, immune mechanisms, regeneration and repair following such insults. The meeting also covered a variety of potential therapeutic strategies ranging from cell-based therapy, induced tolerance and the targeting of specific immune or cell death pathways. In addition, there was a focus on how the peripheral circulation contributes to such types of brain injury.</P>
The immune modulating properties of the heat shock proteins after brain injury
Jong Youl Kim,Midori A. Yenari 대한해부학회 2013 Anatomy & Cell Biology Vol.46 No.1
Inflammation within the central nervous system often accompanies ischemia, trauma, infection, and other neuronal injuries. The immune system is now recognized to play a major role in neuronal cell death due to microglial activation, leukocyte recruitment, and cytokine secretion. The participation of heat shock proteins (Hsps) in the immune response following in brain injury can be seen as an attempt to correct the inflammatory condition. The Hsps comprise various families on the basis of molecular size. One of the most studied is Hsp70. Hsp70 is thought to act as a molecular chaperone that is present in almost intracellular compartments, and function by refolding misfolded or aggregated proteins. Hsps have recently been studied in inflammatory conditions. Hsp70 can both induce and arrest inflammatory reactions and lead to improved neurological outcome in experimental brain injury and ischemia. In this review, we will focus on underlying inflammatory mechanisms and Hsp70 in acute neurological injury.
Anti-Inflammatory Effects of the 70 kDa Heat Shock Protein in Experimental Stroke
Zheng, Zhen,Kim, Jong Youl,Ma, Hualong,Lee, Jong Eun,Yenari, Midori A SAGE Publications 2008 Journal of cerebral blood flow and metabolism Vol.28 No.1
<P> The 70-kDa heat shock protein (Hsp70) is involved in protecting the brain from a variety of insults including stroke. Although the mechanism has been largely considered to be because of its chaperone functions, recent work indicates that Hsp70 also modulates inflammatory responses. To explore how and whether Hsp70 regulate immune responses in brain ischemia, mice overexpressing Hsp70 (Hsp Tg) were subjected to 2 h middle cerebral artery occlusion, followed by 24 h reperfusion. Parallel experiments were performed using a brain inflammation model. Hsp Tg microglia cocultured with astrocytes were used to evaluate the direct effects of Hsp70 on cytotoxicity of mcrigolia. Compared with wild-type (Wt) littermates, Hsp Tg mice showed decreased infarct size and improved neurological deficits. The number of activated microglia/macrophages were also reduced in ischemic brains of Hsp Tg mice. Similar observations were made in a model of brain inflammation that does not result in brain cell death. Overexpression of Hsp70 in microglia completely prevented microglia-induced cytotoxicity to astrocytes. Activation of the inflammatory transcription factor, nuclear factor-κB (NF-κB) was inhibited significantly in Hsp Tg mice and microglia. This was associated with decreased phosphorylation of NF-κB inhibitor protein, IκBα, and decreased expression of several NFκB-regulated genes. Co-immunoprecipitation studies revealed an interaction of Hsp70 with NF-κB and IκBα, but not with IkB kinase, IKKγ, suggesting that Hsp70 binds to the NF-κB:IκB complex preventing IκB phosphorylation by IKK. The findings of the present work establish an anti-inflammatory role for Hsp70 in the context of brain ischemia as a novel mechanism of protection. </P>
NOX Inhibitors - A Promising Avenue for Ischemic Stroke
Kim, Jong Youl,Park, Joohyun,Lee, Jong Eun,Yenari, Midori A. The Korean Society for Brain and Neural Science 2017 Experimental Neurobiology Vol.26 No.4
<P>NADPH-oxidase (NOX) mediated superoxide originally found on leukocytes, but now recognized in several types of cells in the brain. It has been shown to play an important role in the progression of stroke and related cerebrovascular disease. NOX is a multisubunit complex consisting of 2 membrane-associated and 4 cytosolic subunits. NOX activation occurs when cytosolic subunits translocate to the membrane, leading to transport electrons to oxygen, thus producing superoxide. Superoxide produced by NOX is thought to function in long-term potentiation and intercellular signaling, but excessive production is damaging and has been implicated to play an important role in the progression of ischemic brain. Thus, inhibition of NOX activity may prove to be a promising treatment for ischemic brain as well as an adjunctive agent to prevent its secondary complications. There is mounting evidence that NOX inhibition in the ischemic brain is neuroprotective, and targeting NOX in circulating immune cells will also improve outcome. This review will focus on therapeutic effects of NOX assembly inhibitors in brain ischemia and stroke. However, the lack of specificity and toxicities of existing inhibitors are clear hurdles that will need to be overcome before this class of compounds could be translated clinically.</P>
70-kDa Heat Shock Protein Downregulates Dynamin in Experimental Stroke : A New Therapeutic Target?
Kim, Jong Youl,Kim, Nuri,Zheng, Zhen,Lee, Jong Eun,Yenari, Midori A. American Heart Association, Inc. 2016 Stroke Vol.47 No.8
<P>Background and Purpose-The 70-kDa heat shock protein (Hsp70) protects brain cells in models of cerebral ischemia. Proteomic screening of mice subjected to middle cerebral artery occlusion identified dynamin as a major downregulated protein in Hsp70-overexpressing mice (Hsp70 transgenic mice). Dynamin-1 is expressed in neurons and participates in neurotransmission, but also transports the death receptor Fas to the cell surface, where it can be bound by its ligand and lead to apoptosis. Methods-Mice were subjected to distal middle cerebral artery occlusion. Neuro-2a cells were subjected to oxygen glucose deprivation. Hsp70 transgenic and Hsp70-deficient (Hsp70 knockout) mice were compared with wild-type mice for histological and behavioral outcomes. Some mice and neuro-2a cell cultures were given dynasore, a dynamin inhibitor. Results-Hsp70 transgenic mice had better outcomes, whereas Hsp70 knockout mice had worse outcomes compared with wild-type mice. This correlated with decreased and increased dynamin expression, respectively. Dynamin colocalized to neurons and Fas, with higher Fas levels and increased caspase-8 expression. Hsp70 induction in neuro-2a cells was protected from oxygen glucose deprivation, while downregulating dynamin and Fas expression. Further, dynamin inhibition was found to be neuroprotective. Conclusions-Dynamin may facilitate Fas-mediated apoptotic death in the brain, and Hsp70 may protect by preventing this trafficking. Dynamin should be explored as a new therapeutic target for neuroprotection.</P>