Abstract
Treatments to stop gray matter degeneration are needed to prevent progressive disability in multiple sclerosis (MS). 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 in vitro 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.
Footnotes
URMC-099 is the proprietary asset of the University of Rochester Medical Center (US Patents: 8,846,909, 8,877,772, and 9,181,247, and international patents/applications to H.A.G.; References: PMCID: PMC3682381; PMC4032177). CLFB-1134 is the proprietary asset of Califia Bio, Inc. with US Patent 9,370,515 to V. S. Goodfellow and H.A.G. H.A.G. has no commercial interest in URMC-099 or CLFB-1134. All other authors declare no competing financial interests.
This work was supported by PO1 MH64570 (to H.A.G.), R44 NS092137 (to H.A.G.), TDFs from URMC (to H.A.G.) and by the National Multiple Sclerosis Society RG-1607-25423 (to M.J.B.).
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