Pulmonary delivery of D-methionine is associated with an increase in ALCAR and glutathione in cochlear fluids
Pulmonary delivery of D-methionine is associated with an increase in ALCAR and glutathione in cochlear fluids
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DOI：
10.1016/j.heares.2012.12.011
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发表时间：
2013-04-01
期刊：
影响因子：
2.8
通讯作者：
Rogers, Rick A.
中科院分区：
文献类型：
--
作者：
Grondin, Yohann;Cotanche, Douglas A.;Rogers, Rick A.
在动物中，D-蛋氨酸(D-MET)和乙酰化L肉碱(ALCAR)等抗氧化剂可减轻耳蜗机感受器细胞损伤所致的听力损失。这些化合物的全身给药途径，必然要通过耳蜗液，可能会影响耳蜗内的抗氧化剂水平，以及由此产生的保护耳朵的效果。在本研究中，我们分析了气管内(IT)、鼻腔(IN)和经口(OG)给药后[C-14]D-MET在耳蜗和其他四种组织中的药代动力学，并与静脉给药(IV)进行了比较。然后用液相色谱/质谱仪分析了D-MET和ALCAR给药后四种途径对耳蜗液中抗氧化剂含量的影响。结果表明，分别全身给药后，耳蜗液中蛋氨酸和ALCAR的浓度显著升高。有趣的是，D-MET管理也促进了ALCAR的增加。我们的结果还表明，不同的给药途径对[C-14]D-MET的生物利用度以及蛋氨酸、ALCAR的浓度和氧化/还原谷胱甘肽的比例都有不同的影响。总体而言，通过IT给药的肺部给药在耳蜗液中获得了较高浓度的蛋氨酸、ALCAR和氧化相关代谢物，在某些情况下超过了静脉给药，而IN途径的效果似乎最差。据我们所知，这是第一次直接测量耳蜗液中的抗氧化剂水平的报告后，他们全身给药。这份报告还证明了肺部给予抗氧化剂的有效性，并强调了D-MET和ALCAR的不同贡献，从而进一步研究了它们对耳蜗微环境中氧化应激的影响。(C)2013爱思唯尔B.V.保留所有权利。
In animals, hearing loss resulting from cochlear mechanosensory cell damage can be mitigated by antioxidants such as D-methionine (D-met) and acetyl-L-carnitine (ALCAR). The systemic routes of administration of these compounds, that must of necessity transit trough the cochlear fluids, may affect the antioxidant levels in the cochlea and the resulting oto-protective effect. In this study, we analyzed the pharmacokinetics of [C-14]D-met in the cochlea and four other tissues after intratracheal (IT), intranasal (IN), and oral by gavage (OG) administration and compared it to intravenous administration (IV). We then analyzed the effect of these four routes on the antioxidant content of the cochlear fluids after D-met or ALCAR administration, by liquid chromatography/mass spectrometry. Our results showed that the concentration of methionine and ALCAR in cochlear fluids significantly increased after their respective systemic administration. Interestingly, D-met administration also contributed to an increase of ALCAR. Our results also showed that the delivery routes differently affected the bioavailability of administered [C-14]D-met as well as the concentrations of methionine, ALCAR and the ratio of oxidized to reduced glutathione. Overall, pulmonary delivery via IT administration achieved high concentrations of methionine, ALCAR, and oxidative-related metabolites in cochlear fluids, in some cases surpassing IV administration, while IN route appeared to be the least efficacious. To our knowledge, this is the first report of the direct measurements of antioxidant levels in cochlear fluids after their systemic administration. This report also demonstrates the validity of the pulmonary administration of antioxidants and highlights the different contributions of D-met and ALCAR allowing to further investigate their impact on oxidative stress in the cochlear microenvironment. (C) 2013 Elsevier B.V. All rights reserved.