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Updated: Jan 31, 2026
Induction and Diverse Assessment Indicators of Experimental Autoimmune Encephalomyelitis
Published on: September 9, 2022
The Mixed-Lineage Kinase Inhibitor URMC-099 Protects Hippocampal Synapses in Experimental Autoimmune
Matthew J Bellizzi1,2,3, Jennetta W Hammond1, Herman Li1
1Center for Neurotherapeutics Discovery, University of Rochester Medical Center, Rochester, NY 14642.
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.
Insights
A novel drug, URMC-099, shows promise for treating multiple sclerosis (MS) by protecting brain synapses and reducing inflammation. Broad-spectrum inhibition of mixed-lineage kinases (MLKs) proved more effective than targeting a single kinase.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Gray matter degeneration causes progressive disability in multiple sclerosis (MS).
- Mixed-lineage kinases (MLKs) contribute to microglial activation and neuronal damage in MS.
- Existing treatments lack efficacy in preventing gray matter neurodegeneration.
Purpose of the Study:
- To investigate the neuroprotective potential of inhibiting MLKs in a mouse model of MS.
- To evaluate the efficacy of a broad-spectrum MLK inhibitor (URMC-099) versus a selective MLK3 inhibitor.
Main Methods:
- Experimental autoimmune encephalomyelitis (EAE) mouse model to mimic MS-related synaptic injury.
- Administration of URMC-099 (broad-spectrum MLK inhibitor) and a selective MLK3 inhibitor post-symptom onset.
- Assessment of synaptic integrity (PSD95), microglial phenotype, and cognitive function (contextual fear conditioning).
- In vitro neuronal cultures to model MLK-driven degeneration.
Main Results:
- URMC-099 prevented synaptic loss and reduced microglial inflammatory markers in EAE mice.
- URMC-099 administration reversed cognitive deficits in EAE mice.
- A selective MLK3 inhibitor failed to protect synapses or rescue cultured neurons, indicating broad-spectrum inhibition is key.
Conclusions:
- URMC-099 demonstrates significant neuroprotective effects in an MS model, suggesting potential as a therapeutic agent.
- Broad-spectrum inhibition of MLKs and related kinases is more effective for neuroinflammation than targeting single kinases.
- Targeting MLK pathways offers a promising strategy for preventing MS-related gray matter degeneration and disability.
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