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We tested whether inhibiting mixed-lineage kinases (MLKs), which can drive inflammatory microglial activation and neuronal degeneration, could protect hippocampal synapses in C57BL\/6 mice with experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates the excitatory synaptic injury that occurs widely within the gray matter in MS. URMC-099, a broad spectrum MLK inhibitor with additional activity against leucine-rich repeat kinase 2 (LRRK2) and other kinases, prevented loss of PSD95-positive postsynaptic structures, shifted activated microglia toward a less inflammatory phenotype, and reversed deficits in hippocampal-dependent contextual fear conditioning in EAE mice when administered after the onset of motor symptoms. A narrow spectrum inhibitor designed to be highly selective for MLK3 failed to protect synapses in EAE hippocampi, and could not rescue cultured neurons from trophic deprivation in an<jats:italic>in vitro<\/jats:italic>model of MLK-driven neuronal degeneration. These results suggest that URMC-099 may have potential as a neuroprotective treatment in MS and demonstrate that a broad spectrum of inhibition against a combination of MLK and other kinases is more effective in neuroinflammatory disease than selectively targeting a single kinase.<\/jats:p>","DOI":"10.1523\/eneuro.0245-18.2018","type":"journal-article","created":{"date-parts":[[2018,11,19]],"date-time":"2018-11-19T10:44:11Z","timestamp":1542624251000},"page":"ENEURO.0245-18.2018","source":"Crossref","is-referenced-by-count":17,"title":["The Mixed-Lineage Kinase Inhibitor URMC-099 Protects Hippocampal Synapses in Experimental Autoimmune Encephalomyelitis"],"prefix":"10.1523","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6103-2442","authenticated-orcid":false,"given":"Matthew J.","family":"Bellizzi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3949-1594","authenticated-orcid":false,"given":"Jennetta W.","family":"Hammond","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Herman","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary A.","family":"Gantz Marker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel F.","family":"Marker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert S.","family":"Freeman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harris A.","family":"Gelbard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"393","published-online":{"date-parts":[[2018,11,16]]},"reference":[{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0100-x"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.2","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000129544.79539.D5"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.3","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1038\/s41593-018-0192-3","article-title":"Epigenetic regulation of brain region-specific microglia clearance activity","volume":"21","year":"2018","journal-title":"Nat Neurosci"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.4","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181d7d651"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI25444"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.6","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1171-15.2016"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1525528113"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.8","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5804-08.2009"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.9","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13062"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2005.04.016"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.11","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh126"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.12","doi-asserted-by":"publisher","DOI":"10.1038\/srep20926"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.13","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-016-0646-z"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.14","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22337"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902962"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.16","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21423"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1803583"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.18","doi-asserted-by":"crossref","first-page":"8032","DOI":"10.1021\/jm401094t","article-title":"Discovery, synthesis and characterization of an orally bioavailable, brain penetrant inhibitor of mixed lineage kinase 3","volume":"56","year":"2013","journal-title":"J Med Chem"},{"key":"2023041302131586000_5.6.ENEURO.0245-18.2018.19","unstructured":"Goodfellow VSN , Nguyen TX , Ravula SB , Gelbard , HA (2016) Mixed lineage kinase inhibitors and method of treatments. 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