salubrinal and Alzheimer-Disease

Neuronal loss characterizes many of the most intractable nervous system diseases that deprive our ageing population of their quality of life. Neuroprotective pharmacological modalities are urgently needed to address this burgeoning population. Small ubiquitin-like modifier (SUMO) conjugation has been established as an endogenous neuroprotective response, and we have discovered several classes of small molecules that enhance SUMO conjugation. Herein we describe the hit to lead campaign that enabled the discovery of 3 diverse classes of drug-like SUMOylation activators. Optimized compounds were ultimately validated in cell-based models of neuronal loss and provide a foundation for establishing systemically active SUMO activators to treat degenerative diseases such as Parkinson's disease, Alzheimer's disease, and stroke.

Topics: Alzheimer Disease; Benzothiazoles; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Molecular Structure; Neuroprotective Agents; Parkinson Disease; Quinolines; Small Molecule Libraries; Small Ubiquitin-Related Modifier Proteins; Stroke; Structure-Activity Relationship; Sumoylation; Thiazoles

Alzheimer's disease (AD) is characterized by the deposition of β-amyloid (Aβ) peptides in the brain, inducing neuronal cell death and microglial activation. Endoplasmic reticulum (ER) stress has been proposed to be a mediator of Aβ neurotoxicity. In this study, we test whether salubrinal, an ER stress inhibitor, can protect against Aβ-mediated neurotoxicity. We show in rat primary cortical neurons and mouse microglial BV-2 cells that short-term treatment with salubrinal attenuates Aβ-induced neuronal death and microglial activation. Remarkably, our results show that salubrinal's neuroprotective effects are not due to inhibition of ER stress. Rather, we demonstrate that salubrinal exerts its effects through the inhibition of IκB kinase (IKK) activation, IκB degradation, and the subsequent nuclear factor-kappa B (NF-κB) activation. These results elucidate inhibition of the NF-κB pathway as a new mechanism responsible for the protective effects of salubrinal against Aβ neurotoxicity. This study also suggests that modulation of Aβ-induced NF-κB activation could be a potential therapeutic strategy for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Death; Cell Line; Cinnamates; Mice; Microglia; Nerve Degeneration; Neurons; Neuroprotective Agents; NF-kappa B; Primary Cell Culture; Rats; Thiourea