New model of glutathione deficit during development: Effect on lipid peroxidation in the rat brain.
Glutathione is a major regulator of the redox equilibrium, so its deficit weakens tissue resistance to oxidants. The nervous system is particularly susceptible to oxidative insults and is therefore very dependent on its glutathione content, especially during development, when brain metabolism and growth are maximal. In addition, various pathologies affecting the nervous system involve oxidative stress, possibly associated with a diminution of glutathione concentrations. To study the involvement of glutathione in brain redox homeostasis, we set up an experimental model of chronic glutathione deficit. Developing rats were treated daily with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione synthesis, and their brain levels of glutathione and lipid peroxidation products (TBARS) were measured. BSO induced a 40-50% glutathione deficit in the cortex, diencephalon, and pons/medulla. Despite the glutathione deficit induced by BSO, we did not observe any signs of oxidative stress. Because it is known that rats compensate for a glutathione deficit by enhancing their synthesis and tissue levels of ascorbic acid (AA), we performed the same experiment in osteogenic-disorder Shionogi (ODS) rats, a mutant strain that cannot synthetize AA. Although BSO induced a glutathione deficit of comparable intensity in the two strains of rats, it elevated TBARS levels in the diencephalon and pons/medulla only in ODS and not in nonmutant rats. These results suggest that ODS rats, which closely mimic the human redox regulation, will allow study of the long-term consequences of chronic glutathione deficit observed in various clinical situations.
Rougemont
Michaël
M
Centre de Recherche en Neurosciences Psychiatriques, Hôpital Psychiatrique Universitaire de Cery, Prilly-Lausanne, Switzerland.
Do
Kim Quang
KQ
Castagné
Vincent
V
D000818:Animals; D001206:Ascorbic Acid Deficiency / Q000235:genetics; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D001923:Brain Chemistry / Q000235:genetics; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis / Q000172:deficiency* / Q000187:drug effects* / Q000235:genetics; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D023421:Models, Animal; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011922:Rats, Mutant Strains; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D017392:Thiobarbituric Acid Reactive Substances; D019328:Buthionine Sulfoximine; C043425:vanoxerine; D005978:Glutathione