Breast abscess: a rare presentation of typhoid.

Abstract

<h3>Abstract</h3> 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, 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 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 <i>in vitro</i> 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. <b>Significance Statement</b> Multiple sclerosis (MS) causes progressive neurologic decline that correlates with damage to gray matter in the brain, and is not stopped by current treatments. We used a mouse model of MS, in which gray matter injury is associated with inflammatory molecules produced by activated microglia, to test novel neuroprotective treatments. URMC-099, a mixed-lineage kinase (MLK) inhibitor that has anti-inflammatory and direct neuroprotective properties, prevented loss of hippocampal synapses and reversed deficits in learning and memory in a mouse model of MS. An MLK inhibitor with a narrower range of specificity was not effective, suggesting that combination kinase inhibition with URMC-099 may have potential as a neuroprotective treatment in MS.