Abstract

Glutathione (GSH) has been reported to be closely related to various diseases of the central nervous system, yet its authentic active ingredients and action sites remain unclear. In the present study, oral exogenous GSH significantly alleviated ischemic brain injury, but this result was inconsistent with its low bioavailability and blood-brain barrier (BBB) permeability. To ascertain 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 not only increases the GSH and CYS levels in rat striatum and cortex, but it also can decrease the rise of intracerebral Glu concentration caused by ischemia/reperfusion surgery. Then the influence of GSH on the BBB was investigated via measuring IgG leakage, intracerebral endotoxin, and tight-junction proteins. All indicators showed that GSH dosing can repair the destroyed BBB. 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 link between brain injury and gastrointestinal dysfunction. Our findings further suggest that oral GSH significantly improves intestinal inflammatory damage and barrier disruptions. 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, and γ-GC and improving intestinal barrier disruptions.