Investigating the Efficacy of Ergothioneine to Delay Cognitive Decline

Ergothioneine (ET) is a naturally occurring thiol/thione obtained in humans solely through diet. It is able to accumulate in specific cells and tissues (including the brain), via a specific transporter, OCTN1, at high levels. Although the exact physiological function(s) of ET have yet to be elucidated, numerous reports have demonstrated that this compound can scavenge reactive oxygen species (such as hydroxyl radicals, hypochlorous acid, and peroxynitrite), modulate inflammation, and chelate divalent metal ions. These processes are all implicated in the pathology of dementia. Various studies in cell and animal models have also highlighted the potential neuroprotective capabilities of ET following insult by various neurotoxic agents such as cisplatin and amyloid beta peptide.

Studies demonstrated that ET dose-dependently protected PC12 cells against beta amyloid-induced apoptotic death, and later was shown to protect against neuronal injury caused by direct administration of amyloid beta into the mouse hippocampus, thereby increasing scores in active avoidance and water maze tests. ET also dose-dependently extend lifespan of a transgenic Caenorhabditis elegans model of AD by reducing amyloid oligomer formation. Other studies also demonstrated that ET is also able to attenuate oxidative stress and prevents cognitive deficits in a D-galactose-induced dementia mouse model; protect against N-methyl-D-aspartate-induced cytotoxicity in rat retinal neurons; and prevent cisplatin-induced neuronal damage in cell cultures and mice.

To date no studies have evaluated the therapeutic ability of ET, clinically, to delay or halt cognitive decline. Prior studies administering pure ET to humans provide insights into the pharmacokinetics and demonstrate the safety of this compound, laying the foundations for this clinical study. The present proposal will shed light onto a relatively lesser known natural compound and the therapeutic capabilities it possesses, which has the potential to significantly impact the economic and societal burdens of dementia.