In vitro and in vivo neuroprotection by gamma-glutamylcysteine ethyl ester against MPTP: relevance to the role of glutathione in Parkinson's disease.
Glutathione is an abundant intracellular thiol antioxidant whose levels are reduced both in Parkinson's disease itself and in a widely used animal model of the disorder, systemic MPTP administration. Previous in vitro work from our laboratory has suggested that glutathione depletion may be directly responsible for mitochondrial dysfunction, which ultimately leads to dopaminergic cell death associated with the disease. Here, we demonstrate the ability of gamma-glutamylcysteine ethyl ester, a lipid permeable derivative of the major substrate for scavenger glutathione synthesis, to counteract glutathione loss and neurodegeneration associated with in vitro and in vivo administration of MPTP or its derivatives. This data suggests that prevention of glutathione depletion is a likely therapeutic target for the disease.
Chinta
Shankar J
SJ
Buck Institute for Age Research, 8001 Redwood Blvd, Novato, CA 94945, United States.
Rajagopalan
Subramanian
S
Butterfield
D Allan
DA
Andersen
Julie K
JK
D000704:Analysis of Variance; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004151:Dipeptides / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D066298:In Vitro Techniques; D020267:MPTP Poisoning / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D004151:Dipeptides; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; C067744:N-gamma-glutamylcysteine ethyl ester; D019328:Buthionine Sulfoximine; D014446:Tyrosine 3-Monooxygenase; D005978:Glutathione