1. Attenuation of scratch-induced reactive astrogliosis by novel EphA4 kinase inhibitors.
- Author
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Parmentier-Batteur S, Finger EN, Krishnan R, Rajapakse HA, Sanders JM, Kandpal G, Zhu H, Moore KP, Regan CP, Sharma S, Hess JF, Williams TM, Reynolds IJ, Vacca JP, Mark RJ, and Nantermet PG
- Subjects
- Animals, Astrocytes pathology, Blotting, Western, CHO Cells, Cell Movement drug effects, Cells, Cultured, Cricetinae, Cricetulus, Gliosis pathology, Humans, Immunohistochemistry, Ischemic Attack, Transient pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Fluorescence, Rats, Rats, Sprague-Dawley, Small Molecule Libraries, Wound Healing drug effects, Gliosis drug therapy, Protein Kinase Inhibitors therapeutic use, Receptor, EphA4 antagonists & inhibitors, Wounds and Injuries pathology
- Abstract
The EphA4 receptor and its ephrin ligands are involved in astrocytic gliosis following CNS injury. Therefore, a strategy aimed at the blockade of EphA4 signaling could have broad therapeutic interest in brain disorders. We have identified novel small molecule inhibitors of EphA4 kinase in specific enzymatic and cell-based assays. In addition, we have demonstrated in two in vitro models of scratch injury that EphA4 receptor kinase is activated through phosphorylation and is involved in the repopulation of the wound after the scratch. A potent EphA4 kinase inhibitor significantly inhibited wound closure and reduced the accumulation of the reactive astrocytes inside the scratch. We have also shown that after the transient focal cerebral ischemia in rats, a large glial scar is formed by the accumulation of astrocytes and chondroitin sulfate proteoglycan surrounding the infarcted tissue at 7 days and 14 days of reperfusion. EphA4 protein expression is highly up-regulated in the same areas at these time points, supporting its potential role in the glial scar formation and maintenance. Taken together, these results suggest that EphA4 kinase inhibitors might interfere with the astrogliosis reaction and thereby lead to improved neurological outcome after ischemic injury., (© 2011 Merck Sharp & Dohme Corp. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)
- Published
- 2011
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