Thiol redox state and oxidative stress in midbrain and striatum of weaver mutant mice, a genetic model of nigrostriatal dopamine deficiency

In this study we measured thiol redox state (TRS) and the oxidative stress indicator lipid peroxidation in midbrain and striatum of adult (4 months old) male control (+/+) and weaver (wv/wv) mice in order to relate them with oxidative stress in conditions of progressive and severe (∼70%) nigrostriatal dopaminergic neurodegeneration. Specifically, we measured the specific TRS components glutathione (GSH), glutathione disulfide (GSSG), cysteine (CSH), and the general classes of TRS components. The latter are the protein thiols (PSH) and the disulfides between (a) protein (P) and protein thiols (PSSP), (b) protein and non-protein (NP/R) thiols (PSSR, PSSC) and (c) non-protein and non-protein thiols (NPSSR, NPSSC). In addition, the main product of lipid peroxidation malonyl dialdehyde (MDA) was estimated. In the midbrain of wv/wv, GSH and NPSSC levels are decreased (44% and 64%, respectively) and GSSG, NPSSR, CSH, PSH, PSSP, PSSR and MDA levels are increased (23%, 660%, 110%, 51%, 68%, 18% and 44%, respectively). In the striatum of male wv/wv, protein and non-protein thiol/disulfide and MDA levels do not change, possibly due to the high decrease in striatal dopamine level versus midbrain. Our data show that the high degeneration of the dopaminergic nigrostriatal neurons in male adult wv/wv mice is accompanied by significant changes in TRS and an increase in lipid peroxidation in the midbrain, suggesting involvement of oxidative stress in the degeneration of dopaminergic neurons. They also strengthen the possible use of thiol antioxidants for the development of new neuroprotective therapeutic strategies for neurodegenerative diseases, such as Parkinson's disease.