A common pathophysiology progression theme among dementia and related neurogenerative diseases is synaptic dysfunction. Synaptic dysfunction is thought to underlie the subtle amnesic changes that can occur prior to the development of histopathologic hallmarks of disease, such as amyloid plaques, neurofibrillary tangles (NFTs) and neuronal death in Alzheimer’s disease (AD). Deteriorated synaptic strength and synaptic plasticity and the emergence of cognitive dysfunction are associated with remodeling of various homeostasis systems such as neurotransmitters and innate immunity. Dysregulated production of proinflammatory cytokines is a component of innate immunity. A link between synaptic dysfunction and cytokine dysregulation is the activation of p38MAPK mediated signaling cascades in both neurons and glia. For example, p38αMAPK is activated in neurons, microglia, and astrocytes. In neurons, this directly induces abnormal synaptic plasticity associated with mitochondrial dysfunction, tau phosphorylation and, eventually, cell death. In microglia and astrocytes, p38αMAPK activation induces increased production of proinflammatory cytokines which trigger inflammation cascades, which in turn, add to the further activation of neuronal p38αMAPK. CNS p38αMAPK as a potential therapeutic target offers an unusual pharmacological strategy where the same inhibitor might attenuate stressor induced pathophysiological responses in two interacting cell types, glia and neurons, that are integral components of the synaptic structure. Targeting such a localized neuropathophysiology axis could offer an enhanced potential for efficacy in a complex disease progression mechanism.<br/><br/>As recently reviewed (Roy et al, 2019), our discovery platform has delivered MW150, a selective and safe p38αMAPK candidate, to first-in-human clinical trials. MW150 is especially interesting as a pleiotropic drug working via a single target in a complex pathophysiology progression mechanism involving synaptic dysfunction and neuroinflammation. Overall, MW150 provides a unique opportunity to test new therapeutic approaches as there are no other p38αMAPK candidates with MW150’s combination of molecular recognition, pharmacology and safety in preclinical and clinical studies.

Targeting the neuroinflammation-synaptic dysfunction axis in pathophysiology progression of CNS disorders: Case study of a clinical deliverable from an integrated CNS pharmacology-pathophysiology discovery platform

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.