PROINFLAMMATORY CYTOKINE INHIBITORS FOR THE TREATMENT OF NEURODEGENERATIVE DISORDERS

Nigel H. Greig

Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA

Abstract

Clinical/preclinical studies indicate that basal inflammatory status increases as a function of normal aging, and development of a mild pro-inflammatory state closely associates with major degenerative diseases in the elderly. Accordingly, levels of brain pro-inflammatory cytokines bedcome elevated with age in rodents and humans, and several regulatory molecules and anti-inflammatory cytokines reduced. Microglia, as a source of these pro- and anti-inflammatory molecules, are thereby implicated as the major culprit of this neuroinflammation. Correcting the overproduction of pro-inflammatory cytokines by microglia may mitigate a broad number of neurodegenerative disorders prevalent in the elderly. Engaging an appropriate drug target to effectively achieve this has proved difficult, and accounts for the numerous failures of clinical trials of anti-inflammatory agents in neurodegenerative disorders. TNF-α, a vital pro-inflammatory cytokine, is generated by microglial during their activated M1 state. If not appropriately time-dependently reduced by microglial transition to a M2 phase, dysregulated TNF-α synthesis initiates a self-propagating cycle of unchecked inflammation. Pharmacologically inhibiting this cycle may benefit disorders with a neuroinflammatory component. Our generation of TNF-α synthesis inhibitors is providing pharmacological probes to understand the role of TNF-α in disease processes and drug candidates to treat them.