P2‐373: The anti‐rheumatic gold drug auranofin could be beneficial in Alzheimer's disease by inhibiting astrocyte‐mediated neuroinflammation

Abstract

Alzheimer's disease (AD) is characterized by chronic inflammation in brain areas affected by the disease process, which may contribute to the neuronal loss characteristic of AD. It is thought that by reducing this inflammation, the neuronal loss observed in AD could be decreased. Astrocytes support neurons by regulating their external chemical environment, but when activated by pathogenic stimuli, these cells can secrete pro-inflammatory and neurotoxic substances that contribute to neuroinflammation and neuronal death. There are currently no effective therapeutic agents directed at astrocyte neurotoxicity or neuroinflammation in general. Auranofin is a potent anti-inflammatory drug which has been used in the treatment of rheumatoid arthritis for many years and has been shown to inhibit several inflammatory pathways such as those involving p38 mitogen activated protein kinases and thioredoxin reductase. However, a potential for auranofin to reduce neuroinflammatory reactions has not been reported. Therefore, the effectiveness of auranofin and several other gold-containing compounds as inhibitors of astrocyte pro-inflammatory functions was investigated. Effects of gold compounds on the following activation parameters of interferon (IFN)-γ stimulated human U373-MG and U118-MG astrocytoma cells as well as primary human astrocytes were studied: i) mRNA expression (RT-qPCR) of several inflammatory markers including interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1 and heme oxygenase (HOX)-1; ii) pro-inflammatory cytokine secretion (ELISA); and iii) toxicity towards SH-SY5Y neuroblastoma cells (MTT and LDH cell viability assays). In the low micromolar range (0.1-5 m M), auranofin inhibited toxicity of stimulated astrocytoma and human primary astrocytes towards SH-SY5Y neuroblastoma cells. Treating SH-SY5Y cells directly with 1 m M auranofin protected neuronal cells from toxicity induced by supernatants from stimulated astrocytes. 1 mM auranofin upregulated expression of HOX-1 in both stimulated and unstimulated astrocytes. It also affected the secretion of pro-inflammatory cytokines. Several other gold-based drugs and a gold salt had no effect in the above assays. Auranofin may decrease toxicity of stimulated astrocytes towards neurons by up-regulating expression of the protective enzyme HOX-1. As an effective inhibitor of neuroinflammatory reactions, auranofin should be tested in animal models and clinically for its potential to slow neurodegeneration observed in AD.