In this study the authors test the hypothesis that drug interventions targeting dysregulated glial proinflammatory cytokine production might be effective as disease modifying therapeutics. To test the hypothesis the authors examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that selectively inhibits p38α MAPK , and attenuates proinflammatory cytokine production at low doses. MW-151 was tested in an APP/PS1 knock-in mouse model that exhibits increases in AD-relevant pathology progression with age, including increases in proinflammatory cytokine levels. The drug was administered during two distinct but overlapping therapeutic time windows of early stage pathology development. MW-151 treatment attenuated the increase in microglial and astrocyte activation and proinflammatory cytokine production in the cortex and yielded improvement in neurologic outcomes, such as protection against synaptic protein loss and synaptic plasticity impairment. MW-151 had no effect on amyloid plaque load or Aβ40 or Aβ42.Gene expression studies found that MW-151 is selective in its action and not a pan-suppressor of microglia and neuron responses.The results indicate that selective inhibition of increasing proinflammatory cytokine production early in disease progression is beneficial at maintaining synaptic function.
Pharmacokinetic and toxicology data can be found in supplementary material of the following: Hu W, Ralay Ranaivo H, Roy SM, Behanna HA, Wing LK, Munoz L, Guo L, Van Eldik LJ, Watterson DM. Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits. Bioorg Med Chem Lett. 2007;17:414–418.