The effect and the mechanism of glutathione isopropyl ester on experimental parkinson's model

Pakinson?s disease (PD) is a neurodegenerative disorder characterized by progressive motor decline and loss of dopaminergic neurons from the substantia nigra (SN). One of the earliest biochemical changes seen in PD is a reduction in the levels of total glutathione (GSH), a key cellular antioxidant. Treatments that lead to enhanced synthesis of GSH or that inhibit its degredation may result in a slowing of disease progression. The aim of this study was to investigate the protective effect and the metabolism of N-(N-r-L-glutamyl-L-cysteinyl) glycine l-isopropyl ester sulfate monohydrate (YM737), a GSH analog which penetrates blood-brain barrier and provides protection againts cerebral ischemia in rats by inhibiting lipid peroxidation.Three month old Wistar male rats were randomly divided into 4 groups as follows; control (C), YM737-treated (Y), experimental Parkinson induced (P), experimental Parkinson induced + YM737-treated (PY). Experimental model of PD was created by unilateral infusion of a neurotoxin, 6-hydroxydopamine (6-OHDA) (3x4?g/?l, 1?l/min), into the medial forebrain bundle (MFB). YM737 was administered i.p. (300mg/kg), in a volume of 0,1ml/100g. Motor activity of rats was evaluated via catalepsy, locomotor activity, and rotation tests. Apoptosis in SN was detected by enzymatic labeling of DNA strand breaks using Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method. B-cell lymphoma-2 (Bcl-2) and apoptosis signal regulating kinase 1 (ASK1) protein expression were evaluated by immunohistochemistry. Nigral GSH, 4-hydroxynoneal (4-HNE) and cytochrome-c (cyt-c) levels were determined by spectrophotometric assays.Animals in P group exhibited catalepsy, decreased locomotor activity and rotation. Decreased nigral TH-positive neuron number and decreased Bcl-2 protein density were detected in this group compared to control group. TUNEL-positive cells were detected in experimental Parkinson group. No change was observed between groups in ASK1 immunoreactivity. Additionally, P group exhibited lower concentration of GSH, higher levels of 4-HNE and unchanged levels of cyt-c compared to conrol. However there was no difference in PY group versus P group with respect to the all these parameters. Y group exhibited decreased GSH and increased 4-HNE levels compared to control group. Moreover, nigral TUNEL-positive cells were detected in Y group.In conclusion, we did not observe any protective effect of YM737, a GSH analogue, on behavioral, histological and biochemical alterations which were detect in 6-OHDA Parkinson model. However YM737 exerts some toxic effect on non-lesioned animals.