Oral Administration of the Food-Derived Hydrophilic Antioxidant Ergothioneine Enhances Object Recognition Memory in Mice

Abstract

Background: The enhancement of learning and memory through food-derived ingredients is of great interest to healthy individuals as well as those with diseases. Ergothioneine (ERGO) is a hydrophilic antioxidant highly contained in edible golden oyster mushrooms (Pleurotus cornucopiae var. citrinopileatus), and systemically absorbed by its specific transporter, carnitine/organic cation transporter OCTN1/SLC22A4. Objective: This study aims to examine the possible enhancement of object recognition memory by oral administration of ERGO in normal mice. Method: Novel object recognition test, spatial recognition test, LC-MS/MS, Golgi staining, neuronal culture, western blotting, immunocytochemistry, and quantitative RT-PCR were utilized. Result: After oral administration of ERGO (at a dose of 1–50 mg/kg) three times per week for two weeks in ICR mice, the novel object recognition test revealed a longer exploration time for the novel object than for the familiar object. Oral administration of ERGO also revealed a longer exploration time for the moved object in the spatial recognition test in mice fed ERGO-free diet. The discrimination index was significantly higher in the ERGO-treated group than the control in both behavioral tests. ERGO administration led to an increase in its concentration in the plasma and hippocampus. The systemic concentration reached was relevant to those found in humans after oral ERGO administration. Golgi staining revealed that ERGO administration increased the number of matured spines in the hippocampus. Exposure of cultured hippocampal neurons to ERGO elevated the expression of the synapse formation marker, synapsin I. This elevation of synapsin I was inhibited by the tropomyosin receptor kinase inhibitor, K252a. Treatment with ERGO also increased the expression of neurotrophin-3 and -5, and phosphorylated mammalian target of rapamycin in hippocampal neurons. Conclusion: Oral intake of ERGO which provides its plasma concentration achievable in humans may enhance object recognition memory, and this enhancement effect could occur, at least in part, through the promotion of neuronal maturation in the hippocampus.

Could Ergothioneine Aid in the Treatment of Coronavirus Patients?

“…ET has a wide range of unique properties, conferring a variety of cytoprotective capabilities which, amongst others, includes the ability to scavenge reactive oxygen and reactive nitrogen species (ROS/RNS) such as hydroxyl radicals ( • OH) [ 33 ], hypochlorous acid (HOCl) [ 33 ], singlet oxygen ( 1 O 2 ) [ 34 , 35 ], and peroxynitrite (ONOO − ) [ 36 ]. However, a wide range of other studies have demonstrated that ET can, amongst other things, modulate inflammation [ 37 , 38 , 39 ], chelate divalent metal cations such as iron and copper (thereby decreasing the ability of these metal ions to stimulate oxidative damage) [ 33 , 40 , 41 , 42 ], protect against UV radiation-induced damage [ 43 , 44 ], inhibit expression of vascular adhesion proteins [ 45 , 46 ], inhibit myeloperoxidase activity [ 47 ], protect against the phagocyte respiratory burst [ 48 , 49 ], induce the expression of heat shock protein-70 [ 39 , 50 ], promote neuronal differentiation [ 51 , 52 , 53 ], and prevent lung [ 54 ] and liver [ 55 , 56 ] fibrosis. These features of ET and their application against various pathological aspects of COVID-19 will be discussed in greater detail throughout this review to demonstrate the multifunctional capabilities of ET as a potential therapeutic for coronavirus infection.…”

“…ET has been suggested to play a role in neuronal differentiation and maturation, which may be involved in repair following brain injury [ 51 , 52 , 53 ]. Studies have demonstrated that exposure of cultured hippocampal neurons to ET elevated the expression of the synapse formation marker synapsin-1 and neurotrophin-3 and -5, and ET supplementation in mice was shown to enhance learning and memory (object recognition test) and increase the number of mature spines in the hippocampus [ 51 ]. This ability may be useful following viral infiltration and damage to neurons in the brain.…”

“… Summary of possible mechanisms of action of ET: ( A ) An overview of the possible direct and indirect mechanisms by which ET can reduce the severity of symptoms in COVID-19 patients and thereby reduce mortality [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 43 , 45 , 46 , 47 , 48 , 50 , 51 , 52 , 53 , 55 , 56 , 57 , 58 , 61 , 62 , 63 , 68 , 96 , 97 , 98 , 99 , 100 , 104 , 119 , 131 , 132 , 133 , 152 , 153 , 184 , 185 , 186 , 203 ]. ( B ) Population studies have shown that lower blood levels of ET are associated with a wide range of disorders and frailty, suggesting that supplementation may assist or reduce the risk of these conditions.…”

“… Summary of tissue protection by ET [ 24 , 32 , 38 , 45 , 46 , 47 , 48 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 62 , 63 , 64 , 68 , 74 , 98 , 101 , 104 , 105 , 131 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 227 , 228 , 236 , 242 ]. There is evidence to suggest that ET can accumulate in most (if not all tissues) in the body, especially those shown below.…”

Ergothioneine, recent developments

“…Indeed, ET is present in human breast milk [ 47 ] and is also present in cow [ 53 ] and goat milk [ 47 ]. Nakamichi et al [ 54 ] and Ishimoto et al [ 55 ] demonstrated that ET promotes neurogenesis in mice, which may enhance memory [ 56 ], or alleviate symptoms of neuropsychiatric disorders [ 54 ]. It may therefore be plausible that ET plays a role in neuronal differentiation during growth and maturation of the brain in the developing child.…”