Alteration of Sweet and Bitter Taste Sensitivity with Development of Glucose Intolerance in Non-insulin-Dependent Diabetes Mellitus Model OLETF Rats.

Patients with diabetes exhibit altered taste sensitivity, but its details have not been clarified yet. Here, we examined alteration of sweet taste sensitivity with development of glucose intolerance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats as a model of non-insulin-dependent diabetes mellitus. Compared to the cases of Long Evans Tokushima Otsuka (LETO) rats as a control, glucose tolerance of OLETF rats decreased with aging, resulting in development of diabetes at 36-weeks-old. In brief-access tests with a mixture of sucrose and quinine hydrochloride, OLETF rats at 25 or more-weeks-old seemed to exhibit lower sweet taste sensitivity than age-matched LETO ones, but the lick ratios of LETO, but not OLETF, rats for the mixture and quinine hydrochloride solutions decreased and increased, respectively, aging-dependently. Expression of sweet taste receptors, T1R2 and T1R3, in circumvallate papillae (CP) was almost the same in LETO and OLETF rats at 10- and 40-weeks-old, while expression levels of a bitter taste receptor, T2R16, were greater in 40-weeks-old rats than in 10-weeks-old ones in both strains. There was no apparent morphological alteration in taste buds in CP between 10- and 40-weeks-old LETO and OLETF rats. Metagenomic analysis of gut microbiota revealed strain- and aging-dependent alteration of mucus layer-regulatory microbiota. Collectively, we concluded that the apparent higher sweet taste sensitivity in 25 or more-weeks-old OLETF rats than in age-matched LETO rats was due to the aging-dependent increase of bitter taste sensitivity in LETO rats with alteration of the gut microbiota.

Suppressive Effects of Neuromedin U Receptor 2-Selective Peptide Agonists on Appetite and Prolactin Secretion in Mice.

Neuromedin U receptor 2 (NMUR2), which is expressed in the central nervous system (CNS) including the hypothalamus, has been noted as a therapeutic target against obesity. We previously reported that intranasal administration of CPN-219, a NMUR2-selective hexapeptide agonist, suppresses body weight gain in mice; however, there is no detailed information regarding its CNS effects. Recently, in addition to appetite suppression, stress responses and regulation of prolactin (PRL) secretion have also attracted attention. NMUR2 expressed in the hypothalamic tuberoinfundibular dopaminergic neurons has emerged as an alternative target for treating hyperprolactinemia. Here, CPN-219 decreased food intake up to 24 h after administration at a dose of 200 nmol, resulting in body weight gain suppression, although grooming and anxiety-like behaviors were transiently induced. Interestingly, the restraint stress-induced increase in plasma PRL levels was significantly suppressed at a lower dose of 20 nmol, indicating the potential for drug development as an anti-PRL agent of NMUR2-selective agonists.

Sub-chronic and mild social defeat stress exposure to C57BL/6J mice increases visceral fat mass and causes accumulation of cholesterol and bile acids in the liver.

Major depressive disorder is accompanied by a high metabolic illness comorbidity and patients with atypical depression are a subgroup with particularly high risk of obesity, dyslipidemia, and metabolic syndrome; however, the underlying mechanisms have not been fully elucidated. In this study, we examined visceral fat deposition, lipid profiles in the liver, and gut microbiota in sub-chronic and mild social defeat stress (sCSDS)-exposed C57BL/6J mice, which exhibit atypical depression-like phenotypes, i.e., increased body weight and food and water intake. We found that visceral fat mass and levels of hepatic cholesterol and bile acids in sCSDS-exposed mice were significantly increased compared to those in controls. The expression of hepatic small heterodimer partner, a negative regulator of cholesterol metabolism, was significantly elevated in sCSDS-exposed mice. We also found that gut microbial diversity and composition including lower relative abundance of Bacteroides spp. and Bifidobacterium spp. in sCSDS-exposed mice were different from those in controls. In addition, relative abundance of Bacteroides spp. and Bifidobacterium spp. was significantly and negatively correlated with body weight, visceral fat mass, and hepatic cholesterol and bile acids levels. These results indicate that sCSDS-exposure induces dysbiosis, and thereby contributes to metabolic disorder development.

Delayed blink R1 latency in a patient with trigeminal neuralgia due to a contralateral vestibular schwannoma: An illustrative case.

Background: Although the blink reflex (BR) is effective in objectively evaluating trigeminal neuropathy, few studies have demonstrated its effect on trigeminal neuralgia (TN). The authors report a patient with TN due to contralateral vestibular schwannoma (VS) functionally diagnosed by delayed R1 latency of the BR. Case Description: A 36-year-old man presented with left-sided deafness and paroxysmal facial pain in the right V1-3 area. Magnetic resonance imaging (MRI) showed a solid cystic mass compressing the right pons and left brainstem at the left cerebellopontine angle. Although preoperative BR evoked by right supraorbital nerve stimulation-induced delayed ipsilateral R1 latency and normal ipsilateral and contralateral R2 responses, the BR latency evoked by left supraorbital nerve stimulation was normal, indicating deficits in the principal nucleus of the trigeminal nerve in the right pons. The symptoms of TN disappeared after the removal of the VS. Postoperative MRI showed subtotal removal of the tumor and sufficient decompression of the pons and cerebellopontine cistern. The R1 latency returned to normal 50 days after surgery. Conclusion: The perioperative BR test was not only useful for objective evaluation of the localization of trigeminal neuropathy but also correlated with the symptoms of TN.

Transient Receptor Potential Ankyrin 1 in Taste Nerve Contributes to the Sense of Sweet Taste in Mice.

Transient receptor potential (TRP) channels play a significant role in taste perception. TRP ankyrin 1 (TRPA1) is present in the afferent sensory neurons and is activated by food-derived ingredients, such as Japanese horseradish, cinnamon, and garlic. The present study aimed to investigate the expression of TRPA1 in taste buds, and determine its functional roles in taste perception using TRPA1-deficient mice. In circumvallate papillae, TRPA1 immunoreactivity colocalised with P2X2 receptor-positive taste nerves but not with type II or III taste cell markers. Behavioural studies showed that TRPA1 deficiency significantly reduced sensitivity to sweet and umami tastes, but not to salty, bitter, and sour tastes, compared to that in wild-type animals. Furthermore, administration of the TRPA1 antagonist HC030031 significantly decreased taste preference to sucrose solution compared to that in the vehicle-treated group in the two-bottle preference tests. TRPA1 deficiency did not affect the structure of circumvallate papillae or the expression of type II or III taste cell and taste nerve markers. Adenosine 5'-O-(3-thio)triphosphate evoked inward currents did not differ between P2X2- and P2X2/TRPA1-expressing human embryonic kidney 293T cells. TRPA1-deficient mice had significantly decreased c-fos expression in the nucleus of the solitary tract in the brain stem following sucrose stimulation than wild-type mice. Taken together, the current study suggested that TRPA1 in the taste nerve contributes to the sense of sweet taste in mice.

Perceptual Translucency in 3D Printing Using Surface Texture.

We propose a method of reproducing perceptual translucency in three-dimensional printing. In contrast to most conventional methods, which reproduce the physical properties of translucency, we focus on the perceptual aspects of translucency. Humans are known to rely on simple cues to perceive translucency, and we develop a method of reproducing these cues using the gradation of surface textures. Textures are designed to reproduce the intensity distribution of the shading and thus provide a cue for the perception of translucency. In creating textures, we adopt computer graphics to develop an image-based optimization method. We validate the effectiveness of the method through subjective evaluation experiments using three-dimensionally printed objects. The results of the validation suggest that the proposed method using texture may increase perceptual translucency under specific conditions. As a method for translucent 3D printing, our method has the limitation that it depends on the observation conditions; however, it provides knowledge to the field of perception that the human visual system can be cheated by only surface textures.

Expression profile of the zinc transporter ZnT3 in taste cells of rat circumvallate papillae and its role in zinc release, a potential mechanism for taste stimulation.

Zinc is an essential trace element, and its deficiency causes taste dysfunction. Zinc accumulates in zinc transporter (ZnT)3-expressing presynaptic vesicles in hippocampal neurons and acts as a neurotransmitter in the central nervous system. However, the distribution of zinc and its role as a signal transmitter in taste buds remain unknown. Therefore, we examined the distribution of zinc and expression profiles of ZnT3 in taste cells and evaluated zinc release from isolated taste cells upon taste stimuli. Taste cells with a spindle or pyriform morphology were revealed by staining with the fluorescent zinc dye ZnAF-2DA and autometallography in the taste buds of rat circumvallate papillae. Znt3 mRNA levels were detected in isolated taste buds. ZnT3-immunoreactivity was found in phospholipase-ß2-immunopositive type II taste cells and aromatic amino acid decarboxylase-immunopositive type III cells but not in nucleoside triphosphate diphosphohydrolase 2-immunopositive type I cells. Moreover, we examined zinc release from taste cells using human transient receptor potential A1-overexpressing HEK293 as zinc-sensor cells. These cells exhibited a clear response to isolated taste cells exposed to taste stimuli. However, pretreatment with magnesium-ethylenediaminetetraacetic acid, an extracellular zinc chelator - but not with zinc-ethylenediaminetetraacetic acid, used as a negative control - significantly decreased the response ratio of zinc-sensor cells. These findings suggest that taste cells release zinc to the intercellular area in response to taste stimuli and that zinc may affect signaling within taste buds.

Prophylactic Administration of Magnesium Oxide Prevents Dextran Sulfate Sodium-Induced Colonic Injury in Mice.

We previously demonstrated that per os administration and ad libitum ingestion of a magnesium chloride (MgCl2) solution had a prophylactic effect on dextran sulfate sodium (DSS)-induced colitis in mice, magnesium being considered to play a role in this preferable action. Magnesium oxide (MgO) is a commercially available magnesium formulation, but whether or not it prevents development of colitis is unknown. In this study, we investigated the effect of MgO administration on development of colitis in DSS-treated male C57BL/6J mice. Experimental colitis was induced by ad libitum ingestion of 1% (w/v) DSS, and the colitis severity was evaluated by disease activity index (DAI) scores, histological assessment and colonic expression of inflammatory cytokines. A 1 mg/mL MgO solution was administered to mice through ad libitum ingestion from a day before DSS treatment to the end of the experimental period of 12 d. In addition, the effects of DSS, MgO and their combination on the gut microbiota were investigated by 16S ribosomal RNA metagenome analysis. DSS-induced elevation of DAI scores was partially but significantly decreased by MgO administration, while MgO administration had no apparent effect on the shortened colonic length, elevated mRNA expression of colonic interleukin-1ß and tumor necrosis factor-α, increased accumulation of colonic mast cells, or altered features of the gut microbiota in DSS-treated mice. Overall, we demonstrated that MgO had a prophylactic effect on the development of colitis in DSS-treated mice by preventing histological colonic damage, but not colonic inflammation or alteration of the gut microbiota.

Alteration of sweet taste receptor expression in circumvallate papillae of mice with decreased sweet taste preference induced by social defeat stress.

Anhedonia is a key diagnostic symptom and central feature of depression symptomatology, but the underlying mechanism remains unknown. In this study, we investigated whether the decrease of sweet taste preference, anhedonia-like behavior in experimental animals, was accompanied by alteration of sweet taste receptor expression in circumvallate papillae (CP) of social defeat stress (SDS)-subjected mice. By subjecting to 10-d SDS, male BALB/c and C57BL/6J mice with decreased sociability in a social interaction test were defined as SDS-susceptible ones, and they exhibited a depressive-like behavior in a forced swim test. In SDS-susceptible BALB/c mice, a two-bottle choice test with a sucrose solution revealed a reduction of sweet taste preference, while expression of sweet taste receptors, T1R2 and T1R3, in their CP was elevated, and the morphology of taste buds and numbers of type II-taste cells were not changed. In CP of SDS-susceptible C57BL/6J mice without a decrease of sweet taste preference, in contrast, there was no alteration of sweet taste receptor expression. Together with the finding that the body weight gain of SDS-susceptible BALB/c mice was apparently less than that of control ones, differing from the case of SDS-susceptible C57BL/6J ones, it is suggested that expression of sweet taste receptors in CP of SDS-susceptible BALB/c mice with decreased sweet taste preference might be upregulated to compensate for the stress-induced increase of energy expenditure.

Fabrication of a Human Skin Mockup with a Multilayered Concentration Map of Pigment Components Using a UV Printer.

In this paper, we propose a pipeline that reproduces human skin mockups using a UV printer by obtaining the spatial concentration map of pigments from an RGB image of human skin. The pigment concentration distributions were obtained by a separating method of skin pigment components with independent component analysis from the skin image. This method can extract the concentration of melanin and hemoglobin components, which are the main pigments that make up skin tone. Based on this concentration, we developed a procedure to reproduce a skin mockup with a multi-layered structure that is determined by mapping the absorbance of melanin and hemoglobin to CMYK (Cyan, Magenta, Yellow, Black) subtractive color mixing. In our proposed method, the multi-layered structure with different pigments in each layer contributes greatly to the accurate reproduction of skin tones. We use a UV printer because the printer is capable of layered fabrication by using UV-curable inks. As the result, subjective evaluation showed that the artificial skin reproduced by our method has a more skin-like appearance than that produced using conventional printing.

Texture Management for Glossy Objects Using Tone Mapping.

In this paper, we proposed a method for matching the color and glossiness of an object between different displays by using tone mapping. Since displays have their own characteristics, such as maximum luminance and gamma characteristics, the color and glossiness of an object when displayed differs from one display to another. The color can be corrected by conventional color matching methods, but the glossiness, which greatly changes the impression of an object, needs to be corrected. Our practical challenge was to use tone mapping to correct the high-luminance part, also referred to as the glossy part, which cannot be fully corrected by color matching. Therefore, we performed color matching and tone mapping using high dynamic range images, which can record a wider range of luminance information as input. In addition, we varied the parameters of the tone-mapping function and the threshold at which the function was applied to study the effect on the object's appearance. We conducted a subjective evaluation experiment using the series category method on glossy-corrected images generated by applying various functions to each display. As a result, we found that the differences in glossiness between displays could be corrected by selecting the optimal function for each display.

Development of telemedicine tools with an emphasis on visual observation.

We developed a system to improve the quality of telemedicine, and the test results obtained have been presented in this paper, along with the technical details of the system. The spread of COVID-19 has accelerated the need for telemedicine to effectively prevent infections. However, in traditional Japanese medicine (Kampo), where color is essential, an accurate diagnosis cannot be made without color reproduction. Because commercial smartphones cannot reproduce colors with the level of fidelity required for medical treatments, we created a color chart that includes the human skin and tongue colors to help doctors identify their colors accurately during a telemedicine examination. Further, we developed a telemedicine system that allows for automatic color correction using a mobile device, with a color chart and non-contact heart rate measurements.

Dextran sulfate sodium-induced colitis in C57BL/6J mice increases their susceptibility to chronic unpredictable mild stress that induces depressive-like behavior.

AIMS: In patients with colitis, the high comorbidity of depressive disorders is well-known, but the detailed mechanisms remain unresolved. In this study, we examined whether colitis induced by dextran sulfate sodium (DSS) increased the susceptibility to chronic unpredictable mild stress (CUMS) in C57BL/6J mice with resilience to CUMS. MAIN METHODS: To induce experimental colitis and depressive-like behaviors, male 7-weeks old C57BL/6J mice were administered ad libitum 1% DSS solution for 11 days, and subjected to various mild stressors in a chronic, inevitable and unpredictable way according to a random schedule for 21 days, respectively. KEY FINDINGS: In naïve mice exposed to CUMS, their immobility times in a forced swim (FS) test were almost equal to those in control mice. The DSS administration to naïve mice induced colitis without depressive-like behavior, and at 18 days after termination of the DSS administration, the colitis had recovered to control levels, while altered diversity and composition of bacterial genera such as Bacteroides spp., Alistipes spp., etc., were found in the gut microbiota. Exposure of mice with DSS-induced colitis to CUMS (DSS + CUMS) significantly increased the immobility times in the FS test. In the gut microbiota of DSS + CUMS mice, the alteration profile of the relative abundance of bacterial genera differed from in the DSS ones. SIGNIFICANCE: These findings indicate that mice with colitis exhibit increased susceptibility to psychological stress, resulting in induction of depressive-like behavior, and this might be due, at least in part, to altered characteristics of the gut microbiota.

Reproducible induction of depressive-like behavior in C57BL/6J mice exposed to chronic social defeat stress with a modified sensory contact protocol.

AIMS: C57BL/6J mice are well-known to exhibit resilience to chronic social defeat stress (CSDS) for induction of depressive-like behavior. Establishment of protocols for reproducible induction of depressive-like behavior in C57BL/6J mice would be useful to elucidate the underlying molecular mechanisms using target gene-knock-in and -out mice whose background is generally C57BL/6J. Here, we developed a modified CSDS protocol for reproducible induction of depressive-like behavior in C57BL/6J mice, and compared the profile of their gut microbiota with that with the standard CSDS protocol. MAIN METHODS: To prevent acclimation of defeated C57BL/6J mice to aggressive ICR mice, the sensory contact following a daily 10 min-defeat episode was performed by housing an individual defeated mouse in a cage set next to a cage for the aggressor one. KEY FINDINGS: The number of attacks by ICR mice on C57BL/6J ones was significantly increased with the modified CSDS protocol, and the susceptible mice exhibited greater hippocampal inflammation and an increased immobility time in the forced swim test, compared in the case of the standard CSDS protocol, and the reproducibility was confirmed in another set of experiments. Both the standard and modified CSDS protocols changed the diversity and relative composition of gut microbiota in the susceptible mice, but there was no apparent difference in them between the standard and modified CSDS-susceptible mice. SIGNIFICANCE: We established a CSDS protocol for reproducible induction of depressive-like behavior in C57BL/6J mice, and the features of the gut microbiota were similar in the susceptible mice with and without the depressive-like behavior.

Liposomalization of Oxaliplatin Exacerbates the Non-Liposomal Formulation-Induced Decrease of Sweet Taste Sensitivity in Rats.

Here, we investigated whether or not the characteristics of the oxaliplatin-induced sweet taste sensitivity were altered by PEGylated liposomalization of oxaliplatin (liposomal oxaliplatin), which enhances its anticancer efficacy. Liposomal oxaliplatin and oxaliplatin were intravenously and intraperitoneally, respectively, administered to male Sprague-Dawley rats at the total dose of 8 mg/kg. A brief-access test for evaluation of sweet taste sensitivity on day 7 revealed that both liposomal oxaliplatin and oxaliplatin decreased the sensitivity of rats, the degree with the former being greater than in the case of the latter. Liposomalization of oxaliplatin increased the accumulation of platinum in lingual non-epithelial tissues, through which taste nerves passed. The lingual platinum accumulation induced by not only liposomal oxaliplatin but also oxaliplatin was decreased on cooling of the tongue during the administration. In the current study, we revealed that liposomalization of oxaliplatin exacerbated the oxaliplatin-induced decrease of sweet taste sensitivity by increasing the accumulation of platinum/oxaliplatin in lingual non-epithelial tissues. These findings may suggest that reduction of liposomal oxaliplatin distribution to the tongue on cooling during the administration prevents exacerbation of the decrease of sweet taste sensitivity, maintaining the quality of life and chemotherapeutic outcome in patients.

Elevation of the Blood Glucose Level is Involved in an Increase in Expression of Sweet Taste Receptors in Taste Buds of Rat Circumvallate Papillae.

The gustation system for sweeteners is well-known to be regulated by nutritional and metabolic conditions, but there is no or little information on the underlying mechanism. Here, we examined whether elevation of the blood glucose level was involved in alteration of the expression of sweet taste receptors in circumvallate papillae (CP) and sweet taste sensitivity in male Sprague-Dawley rats. Rats under 4 h-fed conditions following 18 h-fasting exhibited elevated blood glucose levels and decreased pancreatic T1R3 expression, compared to rats after 18 h-fasting treatment, and they exhibited increased protein expression of sweet taste receptors T1R2 and T1R3 in CP. Under streptozotocin (STZ)-induced diabetes mellites (DM) conditions, the protein expression levels of T1R2 and T1R3 in CP were higher than those under control conditions, and these DM rats exhibited increased lick ratios in a low sucrose concentration range in a brief access test with a mixture of sucrose and quinine hydrochloride (QHCl). These findings indicate that the elevation of blood glucose level is a regulator for an increase in sweet taste receptor protein expression in rat CP, and such alteration in STZ-induced DM rats is involved in enhancement of their sweet taste sensitivity.

Intracellular labile zinc is a determinant of vulnerability of cultured astrocytes to oxidative stress.

Recently, we found that treatment of cultured mouse astrocytes of ddY-strain mice (ddY-astrocytes) with 400 µM H2O2 for 24 h increased the intracellular labile zinc level without cell toxicity. In contrast, 170 µM H2O2 for 12 h is reported to kill mouse astrocytes obtained from C57BL/6-strain mice (C57BL/6-astrocytes) with an increase in intracellular labile zinc. To clarify this discrepancy, we compared the intracellular zinc levels and cell toxicity in H2O2-treated ddY- and C57BL/6-astrocytes. Exposure of C57BL/6-astrocytes to 170 or 400 µM H2O2 for 12 h dose-dependently decreased the cell viability and administration of plasma membrane-permeable zinc chelator TPEN prevented the 170 µM H2O2-induced astrocyte death, while neither concentration of H2O2 killed ddY-astrocytes. The intracellular zinc level in H2O2-treated C57BL/6-astrocytes was higher than that in H2O2-treated ddY-astrocytes, and this increase was suppressed by TPEN. There was no apparent difference in the expression levels of zinc transporters ZIPs and ZnTs between the two types of astrocytes, while expression of zinc releasable channel TRPM7 was found on the plasma membrane in ddY-astrocytes, but not in C57BL/6-astrocytes, although the total cellular expression levels were almost the same. In addition, a TRPM7 blocker, 2-aminoethoxydiphenyl borate, increased the intracellular zinc level in H2O2-treated ddY-, but not C57BL/6-astrocytes. Collectively, it is suggested that vulnerability of astrocytes to oxidative stress depends on an increased level of intracellular labile zinc, and TRPM7 localized on the plasma membrane contributes, at least in part, to ameliorate the cell injury by decreasing the zinc level.

Transient receptor potential vanilloid 4 mediates sour taste sensing via type III taste cell differentiation.

Taste buds are comprised of taste cells, which are classified into types I to IV. Transient receptor potential (TRP) channels play a significant role in taste perception. TRP vanilloid 4 (TRPV4) is a non-selective cation channel that responds to mechanical, thermal, and chemical stimuli. The present study aimed to define the function and expression of TRPV4 in taste buds using Trpv4-deficient mice. In circumvallate papillae, TRPV4 colocalized with a type IV cell and epithelial cell marker but not type I, II, or III markers. Behavioural studies showed that Trpv4 deficiency reduced sensitivity to sourness but not to sweet, umami, salty, and bitter tastes. Trpv4 deficiency significantly reduced the expression of type III cells compared with that in wild type (WT) mice in vivo and in taste bud organoid experiments. Trpv4 deficiency also significantly reduced Ki67-positive cells and ß-catenin expression compared with those in WT circumvallate papillae. Together, the present results suggest that TRPV4 contributes to sour taste sensing by regulating type III taste cell differentiation in mice.

Copper accumulation in the brain causes the elevation of oxidative stress and less anxious behavior in Ts1Cje mice, a model of Down syndrome.

Elevated oxidative stress (OS) is widely accepted to be involved in the pathogenesis of Down syndrome (DS). However, the mechanisms underlying the elevation of OS in DS are poorly understood. Biometals, in particular copper and iron, play roles in OS. We therefore focused on biometals in the brain with DS. In this study, we analyzed the profile of elements, including biometals, in the brain of Ts1Cje mice, a widely used genetic model of DS. An inductively coupled plasma-mass spectrometry (ICP-MS)-based comparative metallomic/elementomic analysis of Ts1Cje mouse brain revealed a higher level of copper in the hippocampus and cerebral cortex, but not in the striatum, in comparison to wild-type littermates. The expression of the copper transporter CTR1, which is involved in the transport of copper into cells, was decreased in the ependymal cells of Ts1Cje mice, suggesting a decrease in the CTR1-mediated transport of copper into the ependymal cells, which excrete copper into the cerebrospinal fluid. To evaluate the pathological significance of the accumulation of copper in the brain of Ts1Cje mice, we examined the effects of a diet with a low copper content (LoCD) on the elevated lipid peroxidation, the accumulation of hyperphosphorylated tau, and some behavioral anomalies. Reducing the copper concentration in the brain by an LoCD restored the enhanced lipid peroxidation and phosphorylation of tau in the brain and reduced anxiety-like behavior, but not hyperactivity or impaired spatial leaning, in Ts1Cje mice. The findings highlight the reduction of accumulation of copper in the brain may be a novel therapeutic strategy for DS.

Ergothioneine ameliorates oxaliplatin-induced peripheral neuropathy in rats.

AIMS: Oxaliplatin (l-OHP) is a key drug in therapeutic regimens for metastatic or advanced-stage colorectal cancer, but causes peripheral neuropathy as a dose-limiting adverse effect. It is reported that this peripheral neuropathy results from l-OHP accumulation in dorsal root ganglion (DRG) neurons, and that one of the transporters responsible for the accumulation in DRG neurons is organic cation transporter novel (OCTN) 1. Here, we examined whether co-administration of ergothioneine, a substrate/inhibitor of OCTN1, with l-OHP could prevent this peripheral neuropathy. MAIN METHODS: l-OHP (4 mg/kg, i.p., twice/week, for 6 weeks) and ergothioneine or l-carnitine (1.5 or 15 mg/kg, i.v., twice per l-OHP administration) were administered to rats, and tissue/cellular platinum concentrations and peripheral neuropathy were determined. Expression of transporters in DRG neuronal cells was evaluated by real-time PCR and immunocytochemistry. KEY FINDINGS: On administration of l-OHP to rats, it accumulated in DRG neurons and their mitochondria, while negligible accumulation was found in Schwann cells. Expression of OCTN1 was observed in DRG neurons, especially in small- and medium-sized ones, which are responsible for the nociceptive response. In rats repeatedly administered l-OHP, co-administration of ergothioneine (15 mg/kg), but not l-carnitine, a substrate/inhibitor of OCTN2, decreased l-OHP accumulation in DRGs and development of the mechanical allodynia. SIGNIFICANCE: These results indicated that l-OHP-induced peripheral neuropathy was ameliorated by co-administration of ergothioneine, at least in part, via a decrease in its accumulation in DRG neurons. Plant diets contain ergothioneine, and thus their consumption might offer relief to patients suffering from l-OHP-induced peripheral neuropathy.