SLC22A4, also known as carnitine/organic cation transporter OCTN1 is ubiquitously expressed in the body. OCTN1 is functionally expressed in neurons, microglia, and neural stem cells in the brain, and ...may play a protective role in pathophysiological conditions via its in vivo substrate ergothioneine, a food-derived antioxidant. On the other hand, we have recently noticed that pentylenetetrazole-induced seizure was limitedly observed in octn1 gene knockout (octn1-/-) mice, and this may not be explained by the absence of this antioxidant. To find new OCTN1 substrates in the brain, we here conducted untargeted metabolome analysis using LC-TOF-MS. Hippocampus, cerebral cortex, and plasma of wild-type and octn1-/- mice were subjected to metabolomics, and 2,599, 2,676, and 1,697 ion peaks, respectively, were observed. Among them, five ion peaks with m/z 455, 426, 158, 154, and 144 exhibited at least two times difference between the two strains, only m/z 158 being found to be commonly lower in octn1-/- in all the samples. Time-dependent and saturable transport of chemically synthesized compound corresponding to this peak was observed in HEK293/OCTN1 cells. In addition, systemic elimination of this compound in octn1-/- mice was more rapid compared with wild-type. Thus, we have newly identified OCTN1 substrate in the brain.
The aim of the present study was to examine enhancement of learning and memory by oral administration of ergothioneine (ERGO), which is a hydrophilic antioxidant highly contained in golden oyster ...mushrooms and other foods, and systemically absorbed by its specific transporter OCTN1/SLC22A4 in daily life, with an aim to clarify its possible role as a neurotropic compound. After oral administration of ERGO in normal mice, the novel object test revealed a longer exploration time for the novel object than for the familiar object. Similar result was also confirmed in mice ingested with ERGO-free diet. Dietary-derived ERGO is present in the body without the administration, but the ERGO administration led to modest (3～4 times) increase in its concentration in plasma and hippocampus. Exposure of cultured hippocampal neurons to ERGO elevated the expression of the synapse formation marker, synapsin I, and neurotrophin-3 and -5. The elevation of synapsin I was inhibited by tropomyosin receptor kinase inhibitor K252a. Thus, oral intake of ERGO may enhance object recognition memory, and this could occur at least partially through promotion of neuronal maturation in the hippocampus.
Hydrophilic antioxidant ergothioneine (ERGO) is not synthesized in mammals, but ingested from daily life in humans. Oral administration of ERGO exhibits several beneficial effects in the brain in ...experimental animals. ERGO promotes neuronal differentiation of neural progenitor cells in primary culture, and involvement of the activation of mTOR pathway has been proposed (Cell Signal 53, 269, 2018), although its directly interacting proteins have not yet been clarified. The aim of the present study is to perform comprehensive study to clarify the pathways involved in the pharmacological activity of ERGO. After repeated oral dose of ERGO or vehicle alone in normal mice, hippocampal dentate which is important in neurogenesis was isolated, and membrane proteome analysis using LC-MS/MS was conducted. Accordingly, 3,337 proteins were identified, and we found change in expression of proteins associated with mitochondria and synapse formation. Mouse neural stem cells were primarily cultured for 6 days, followed by incubation with ERGO. Gene product of neuronal marker b-III tubulin was increased by ERGO, confirming neuronal differentiation. Effect of ERGO on mitochondrial proteins is now under investigation.
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 up-regulated 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.
PDF
