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Ikeda H.,Tokyo Institute of Technology | Ikuta N.,Kobe University | Nakata D.,CycloChem Bio Co. | Ishida Y.,CycloChem Bio Co. | Terao K.,CycloChem Bio Co.
Bulletin of the Chemical Society of Japan | Year: 2015

The structures of inclusion complexes of (R)-α-lipoic acid with α-, β-, and γ-cyclodextrin (CD) were constructed using restraints derived from ROESY spectra and MMFF94 molecular mechanics calculations. (R)-α-lipoic acid and α-CD generate a single stable inclusion complex, in which the 1,2-dithiolane ring of the (R)-α-lipoic acid is oriented toward the secondary hydroxy side of the α-CD. NMR data suggests that β-CD produces two kinds of inclusion complexes with α-lipoic acid. Finally, γ-CD yields 1:1 and 1:2 host/guest complexes with (R)-α-lipoic acid. The estimated structure of the 1:1 γ-CD inclusion complex has the 1,2-dithiolane ring oriented toward the primary hydroxy side of the γ-CD. © 2015 The Chemical Society of Japan. Source


Naito Y.,Kyoto Pharmaceutical University | Ikuta N.,Kobe University | Okano A.,Kyoto Pharmaceutical University | Okamoto H.,CycloChem Bio Co. | And 7 more authors.
Life Sciences | Year: 2015

Abstract Aims: Previous studies reported the anti-diabetic effects of α-lipoic acid (αLA) isomers: racemic-αLA, R-αLA, or S-αLA. Previously, we examined the anti-diabetic effects of αLA administered as a food additive, but were unable to demonstrate the differences among different isomers. In this study, αLAs were complexed with γ-cyclodextrin (γCD) for the stability. We then investigated the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs in KKAy mice. Main methods: Male type 2 diabetic KKAy mice were divided into 5 groups, and fed either a high-fat-diet (HFD),HFD supplemented with γCD, or HFD supplemented with racemic-αLA/γCD, R-αLA/γCD, or S-αLA/γCD for 4 weeks. At the end of the feeding period, HbA1c and adiponectin levels were measured, PPARγ2 mRNA expression levels were assessed in adipose tissues using real-time PCR, and AMP-activated protein kinase (AMPK) phosphorylation levels were evaluated in the liver by Western blotting. Key findings: The anti-diabetic effects of αLA; the isomeric compounds racemic-, R-, and S-αLA/γCD were investigated using amale type 2 diabetic KKAy mouse model. Significant differences were observed in HbA1c and plasma adiponectin levels between R-αLA/γCD-treated mice and control mice. PPARγ2 mRNA expression levels were slightly higher in racemic- and R-αLA/γCD-treated mice. Moreover, AMPK phosphorylation levels were elevated in racemic-αLA/γCD- and R-αLA/γCD-treated mice, but remained unchanged in S-αLA/γCD-treated mice. Significance: These results suggested that the stereoisomerism mediates a difference in the anti-diabetic effects of racemic-, R-, and S-αLA/γCDs. Furthermore, the anti-diabetic mechanism of αLA/γCD action may be attributed to the activation of AMPK in the liver. © 2015 Elsevier Inc. Source


Uchida R.,Tokyo University of Science | Okamoto H.,CycloChem Bio Co. | Okamoto H.,Kobe University | Ikuta N.,Kobe University | And 3 more authors.
International Journal of Molecular Sciences | Year: 2016

α-Lipoc acid (LA) contains a chiral carbon and exists as two enantiomers (R-α-lipoic acid (RLA) and S-α-lipoic acid (SLA)). We previously demonstrated that oral bioavailability of RLA is better than that of SLA. This difference arose from the fraction absorbed multiplied by gastrointestinal availability (Fa x Fg) and hepatic availability (Fh) in the absorption phase. However, it remains unclear whether Fa and/or Fg are involved in enantioselectivity. In this study, Caco-2 cells and Madin–Darby canine kidney strain II cells were used to assess the enantioselectivity of membrane permeability. LA was actively transported from the apical side to basal side, regardless of the differences in its steric structure. Permeability rates were proportionally increased in the range of 10–250 μg LA/mL, and the permeability coefficient did not differ significantly between enantiomers. Hence, we conclude that enantioselective pharmacokinetics arose from the metabolism (Fh or Fg x Fh), and definitely not from the membrane permeation (Fa) in the absorption phase. © 2016 by the authors; licensee MDPI, Basel, Switzerland. Source


Uchida R.,Tokyo University of Science | Okamoto H.,CycloChem Bio Co. | Okamoto H.,Kobe University | Ikuta N.,Kobe University | And 3 more authors.
International Journal of Molecular Sciences | Year: 2015

α-Lipoic acid (LA) is widely used for nutritional supplements as a racemic mixture, even though the R enantiomer is biologically active. After oral administration of the racemic mixture (R-α-lipoic acid (RLA) and S-α-lipoic acid (SLA) mixed at the ratio of 50:50) to rats, RLA showed higher plasma concentration than SLA, and its area under the plasma concentration-time curve from time zero to the last (AUC) was significantly about 1.26 times higher than that of SLA. However, after intravenous administration of the racemic mixture, the pharmacokinetic profiles, initial concentration (C0), AUC, and half-life (T1/2) of the enantiomers were not significantly different. After oral and intraduodenal administration of the racemic mixture to pyrolus-ligated rats, the AUCs of RLA were significantly about 1.24 and 1.32 times higher than that of SLA, respectively. In addition, after intraportal administration the AUC of RLA was significantly 1.16 times higher than that of SLA. In conclusion, the enantioselective pharmacokinetics of LA in rats arose from the fraction absorbed multiplied by gastrointestinal availability (FaFg) and hepatic availability (Fh), and not from the total clearance. © 2015 by the authors; licensee MDPI, Basel, Switzerland. Source


Naito Y.,Kyoto Pharmaceutical University | Ikuta N.,Kobe University | Nakata D.,CycloChem Bio Co. | Terao K.,Kobe University | And 7 more authors.
Journal of Clinical Biochemistry and Nutrition | Year: 2014

In recent years the number of patients suffering from diabetes mellitus has been increasing worldwide. In particular, type 2 diabetes mellitus, a lifestyle-related disease, is recognized as a serious disease with various complications. Many types of pharmaceutics or specific health foods have been used for the management of diabetes mellitus. At the same time, the relationship between diabetes mellitus and α-lipoic acid has been recognized for many years. In this study, we found that the α-lipoic acid γ-cyclodextrin complex exhibited an HbA1c lowering effect for treating type 2 diabetes mellitus in animal models. Moreover, in this study, we investigated the activation of phosphorylation of AMP-activated protein kinase, which plays a role in cellular energy homeostasis, in the liver of KKAy mice by using α-lipoic acid and the α-lipoic acid γ-cyclodextrin complex. Our results show that the α-lipoic acid γ-cyclodextrin complex strongly induced the phosphorylation of AMP-activated protein kinase. Thus, we concluded that intake of the α-lipoic acid γ-cyclodextrin complex exerted an antidiabetic effect by suppressing the elevation of postprandial hyperglycemia as well as doing exercise. © 2014 JCBN. Source

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