RT Journal Article
SR Electronic
T1 Insights into the authentic active ingredients and action sites of oral exogenous glutathione in the treatment of ischemic brain injury based on pharmacokinetic-pharmacodynamic studies
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.089458
DO 10.1124/dmd.119.089458
A1 Chong Chen
A1 Qingqing Ding
A1 Boyu Shen
A1 Tengjie Yu
A1 He Wang
A1 Yangfan Xu
A1 Huimin Guo
A1 Kangrui Hu
A1 Lin Xie
A1 Guangji Wang
A1 Yan Liang
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/11/08/dmd.119.089458.abstract
AB Glutathione (GSH) has been reported to be closely related to various diseases of central nervous system (CNS), yet its authentic active ingredients and action sites are still unclear. In the present study, oral exogenous GSH was first proved to significantly alleviate ischemic brain injury, but it was inconsistent with its low bioavailability and blood-brain barrier (BBB) permeability. In order to find out the exposure of GSH-derived ingredients, including GSH, cysteine (CYS), glutamate (Glu), glycine (GLY), CYS-GLY and γ-Glutamylcysteine (γ-GC) were systematically studied both in vitro and in vivo. The outcomes demonstrated that oral GSH could not only increases the GSH and CYS levels in rat striatum and cortex, but also can decrease the rise of intracerebral Glu concentration caused by ischemia/reperfusion (I/R) surgery. Then the influence of GSH on BBB was investigated via measuring IgG leakage, intracerebral endotoxin and tight junction proteins. All indicators showed that GSH-dosing can repair the destroyed BBB. This should be noted that oral GSH greatly enhances the exposure of GSH, CYS, CYS-GLY and γ-GC in rat duodenum, jejunum, ileum and colon. Accumulating evidence reveals a close linkage of brain injury and gastrointestinal dysfunction. Our findings further suggested that oral GSH significantly improves intestinal inflammatory damage and barrier disruption. In conclusion, oral GSH can have a direct therapeutic role in brain injury by stabilizing intracerebral levels of GSH, CYS and Glu. It can also play an indirect therapeutic role by enhancing the intestinal exposure of GSH, CYS, CYS-GLY, γ-GC and improving intestinal barrier disruptions.SIGNIFICANCE STATEMENT The authentic active ingredients and action sites of exogenous GSH in the treatment of ischemic brain injury are still unclear. We uncovered that oral exogenous GSH not only stabilizes intracerebral levels of GSH, CYS and Glu to act on brain injury directly, but also can exert an indirect therapeutic role by improving intestinal barrier disruptions. These findings have great significance for revealing the therapeutic effect of GSH on ischemic brain injury and promoting its further development and clinical application.