Novel protective properties of auranofin: inhibition of human astrocyte cytotoxic secretions and direct neuroprotection.

ABSTRACT

AIMS: Steroidal and non-steroidal anti-inflammatory drugs are used for treatment of peripheral inflammation, but they are not effective in neurodegenerative disorders. Gold compounds are also used to treat peripheral inflammation, but their effects on neuroimmune reactions are unknown. This study investigated the effects of gold compounds on astrocytic cell functions and assessed in vivo distribution of auranofin after its oral administration in mice. MAIN METHODS: Auranofin and three other gold compounds were investigated for their ability to reduce the secretion of pro-inflammatory cytokines and cytotoxins produced by activated human astrocytic cells. Ability of the gold compounds to protect neuronal cells from glial cytotoxins and from oxidative damage induced by hydrogen peroxide was also studied. The in vivo distribution of auranofin was investigated using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). KEY FINDINGS: Auranofin (0.1-5 µM) inhibited the toxicity of stimulated primary human astrocytes and U-373 MG astrocytic cells towards human neuronal cells, but did not inhibit secretion of cytokines. Treatment of neuronal cells with high nanomolar to low micromolar concentrations of auranofin protected them from toxicity induced by hydrogen peroxide and supernatants of stimulated astrocytic cells through the upregulation of heme-oxygenase (HOX)-1. Aurothiomalate, aurothioglucose, and aurothiosulphate were ineffective in the assays used. Auranofin reached low micromolar concentrations in mouse brains following daily oral administration for one week. SIGNIFICANCE: Since auranofin may protect neurons by inhibiting astrocyte toxicity and is also directly neuroprotective, it could be useful in neurodegenerative diseases where activation of astrocytes contributes to the neuronal loss.