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.

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Oral administration of the food-derived antioxidant amino acid ergothioneine (ERGO) results in its efficient distribution in the brain and enhanced cognitive function. However, the effect of ERGO deficiency on cognitive impairment and the underlying mechanisms remain unknown. We revealed that cognitive function and hippocampal neurogenesis were lower in mice fed an ERGO-free diet than in those fed the control diet. Furthermore, ERGO supplementation to achieve the control diet ERGO levels reversed these effects and restored ERGO concentrations in the plasma and hippocampus. The ERGO-induced recovery of cognitive function and hippocampal neurogenesis was blocked by TrkB inhibition, with a concomitant reduction in hippocampal phosphorylated TrkB, suggesting the involvement of TrkB activation in these events. Phosphorylated TrkB was also detected in extracellular vesicles (EVs) derived from serum samples of volunteers who had been orally administered ERGO-containing tablets (5 mg/day for 12 weeks). Importantly, the ratio of serum EV-derived phosphorylated TrkB was significantly higher in the ERGO-treated group than in the placebo-treated group and was positively correlated with both serum ERGO concentrations and several cognitive domain scores from Cognitrax. Altogether, TrkB phosphorylation is involved in ERGO-induced cognitive enhancement, and TrkB phosphorylation levels in serum EVs may quantitatively represent ERGO-induced cognitive enhancement in humans.

Salmon milt extract is known to improve impaired brain function in animal models with brain disease and contains high levels of nucleic acids. The purpose of the present study is to clarify the effect of hydrolyzed salmon milt extract (HSME) and its nucleic acid fraction (NAF) on brain function in normal mice. A diet containing 2.5% HSME or NAF, but not normal diet, induced normal mice to devote more time in exploring novel and moved objects than in exploring familiar and unmoved objects, as observed during novel object recognition and spatial recognition tests, respectively, suggesting that nucleic acids in HSME may enhance brain function. Quantitative PCR analysis revealed that expression of marker genes for neural stem cells (NSCs) and glial cells, followed by those of neurons, was upregulated after start of the ingestion. Exposure of primary cultured NSCs to HSME, NAF, and oligonucleotides significantly increased MTT reduction activity and cellular ATP level, suggesting that nucleic acids directly promote proliferation in NSCs. Thus, oral ingestion of nucleic acids enhances brain function in normal mice, and this effect may be at least partially provoked by increase in proliferation of NSCs.

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