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Attenuation of scratch‐induced reactive astrogliosis by novel EphA4 kinase inhibitors
Author(s) -
ParmentierBatteur Sophie,
Finger Eleftheria N.,
Krishnan Raghu,
Rajapakse Hemaka A.,
Sanders John M.,
Kandpal Geeta,
Zhu Hong,
Moore Keith P.,
Regan Christopher P.,
Sharma Sujata,
Hess J. Fred,
Williams Theresa M.,
Reynolds Ian J.,
Vacca Joseph P.,
Mark Robert J.,
Nantermet Philippe G.
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07375.x
Subject(s) - astrogliosis , gliosis , glial scar , microbiology and biotechnology , ephrin , kinase , neuroscience , cancer research , medicine , chemistry , signal transduction , biology , astrocyte , central nervous system
J. Neurochem. (2011) 118 , 1016–1031. 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.