Neuroprotection with the proteasome inhibitor MLN519 in focal ischemic brain injury: Relation to nuclear factor κB (NF-κB), inflammatory gene expression, and leukocyte infiltration☆

2006 ◽  
Vol 49 (2) ◽  
pp. 106-112 ◽  
Author(s):  
A WILLIAMS ◽  
J DAVE ◽  
F TORTELLA
Keyword(s):  
Gene Expression ◽  
Brain Injury ◽  
Proteasome Inhibitor ◽  
Nuclear Factor Κb ◽  
Ischemic Brain Injury ◽  
Nuclear Factor ◽  
Leukocyte Infiltration ◽  
Ischemic Brain ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

scholarly journals Delayed Treatment with MLN519 Reduces Infarction and Associated Neurologic Deficit Caused by Focal Ischemic Brain Injury in Rats via Antiinflammatory Mechanisms Involving Nuclear Factor-κB Activation, Gliosis, and Leukocyte Infiltration

2003 ◽  
Vol 23 (1) ◽  
pp. 75-87 ◽  
Author(s):  
Anthony J. Williams ◽  
Sarah L. Hale ◽  
John R. Moffett ◽  
Jitendra R. Dave ◽  
Peter J. Elliott ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Nuclear Factor Κb ◽  
Therapeutic Window ◽  
Secondary Brain Injury ◽  
Ischemic Brain Injury ◽  
Nuclear Factor ◽  
Leukocyte Infiltration ◽  
Sprague Dawley ◽  
Ischemic Brain

Secondary brain injury due to ischemia includes the infiltration of leukocytes into the brain parenchyma mediated by activation of nuclear factor-κB (NF-κB), which is activated by proteasome degradation. Neuroprotection with the proteasome inhibitor MLN519 has previously been reported to decrease ischemic brain injury in rats. The authors used higher doses of MLN519 to evaluate the neuroprotection therapeutic window after 24 hours of brain injury in rats as correlated to proteasome levels, activated NF-κB immunoreactivity, and leukocyte infiltration. Male Sprague-Dawley rats were subjected to 2-hour middle cerebral artery occlusion (MCAO) and recovery. MLN519 or vehicle was administered after injury with a single injection given in delayed increments of 2 hours (i.e., 4, 6, or 8 hours after MCAO). Treatment with MLN519 up to 6 hours after MCAO (4 hours after reperfusion) effectively reduced neuronal and astrocytic degeneration, decreased cortical infarct volume, and increased neurologic recovery. These effects were related to >80% reductions in blood proteasome levels, reduced neutrophil infiltration, and a decrease in activated NF-κB immunoreactivity. This improved neuroprotection profile and antiinflammatory effect of MLN519 provides an exciting avenue for potential treatment of focal ischemic brain injury in humans.

scholarly journals The Nurr1 Activator 1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane Blocks Inflammatory Gene Expression in BV-2 Microglial Cells by Inhibiting Nuclear Factor κB

2015 ◽  
Vol 87 (6) ◽  
pp. 1021-1034 ◽  
Author(s):  
Briana R. De Miranda ◽  
Katriana A. Popichak ◽  
Sean L. Hammond ◽  
Bryce A. Jorgensen ◽  
Aaron T. Phillips ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nuclear Factor Κb ◽  
Microglial Cells ◽  
Nuclear Factor ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

Erythropoietin Downregulates Bax and DP5 ProApoptotic Gene Expression in Neonatal Hypoxic-Ischemic Brain Injury

Neonatology ◽  
2006 ◽  
Vol 89 (3) ◽  
pp. 205-210 ◽  
Author(s):  
Abdullah Kumral ◽  
Sermin Genc ◽  
Erdener Ozer ◽  
Osman Yilmaz ◽  
Necati Gokmen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Injury ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Hypoxic Ischemic Brain Injury ◽  
Proapoptotic Gene

scholarly journals Silencing the lncRNA Maclpil in pro-inflammatory macrophages attenuates acute experimental ischemic stroke via LCP1 in mice

2019 ◽  
Vol 40 (4) ◽  
pp. 747-759 ◽  
Author(s):  
Yan Wang ◽  
Ying Luo ◽  
Yang Yao ◽  
Yuhua Ji ◽  
Liangshu Feng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ischemic Stroke ◽  
Expression Profiles ◽  
Brain Infarction ◽  
Cell Types ◽  
Specific Cell ◽  
Ischemic Brain ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Ischemic Brain Infarction

Long noncoding RNAs (lncRNA) expression profiles change in the ischemic brain after stroke, but their roles in specific cell types after stroke have not been studied. We tested the hypothesis that lncRNA modulates brain injury by altering macrophage functions. Using RNA deep sequencing, we identified 73 lncRNAs that were differentially expressed in monocyte-derived macrophages (MoDMs) and microglia-derived macrophages (MiDMs) isolated in the ischemic brain three days after stroke. Among these, the lncRNA, GM15628, is highly expressed in pro-inflammatory MoDMs but not in MiDMs, and are functionally related to its neighbor gene, lymphocyte cytosolic protein 1 (LCP1), which plays a role in maintaining cell shape and cell migration. We termed this lncRNA as Macrophage contained LCP1 related pro-inflammatory lncRNA, Maclpil. Using cultured macrophages polarized by LPS, M(LPS), we found that downregulation of Maclpil in M(LPS) decreased pro-inflammatory gene expression while promoting anti-inflammatory gene expression. Maclpil inhibition also reduced the migration and phagocytosis ability of MoDMs by inhibiting LCP1. Furthermore, adoptive transfer of Maclpil silenced M(LPS), reduced ischemic brain infarction, improved behavioral performance and attenuated penetration of MoDMs in the ischemic hemisphere. We conclude that by blocking macrophage, Maclpil protects against acute ischemic stroke by inhibiting neuroinflammation.

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