Glutathione depletion in rat brain does not cause nigrostriatal pathway degeneration.
Nigral cell death in Parkinson's disease (PD) may involve oxidative stress and mitochondrial dysfunction initiated by a decrease in reduced glutathione (GSH) levels in substantia nigra. L-buthionine-(S,R)-sulphoximine (BSO; 4.8 and 9.6 mg/kg/day), an irreversible inhibitor of gamma-glutamyl cysteine synthetase, was chronically infused into the left lateral ventricle of rats over a period of 28 days and markedly reduced GSH concentrations in substantia nigra (approx. 59% and 65% in 4.8 and 9.6 mg/kg/d BSO respectively) and the striatum (approx. 63% and 80% in 4.8 and 9.6 mg/kg/d BSO respectively). However, the number of tyrosine hydroxylase (TH)-positive cells in substantia nigra was not altered by BSO-treatment compared to control animals. Similarly, there was no difference in specific [3H]-mazindol binding in the striatum and nucleus accumbens of BSO-treated rats compared to control rats. In conclusion, depletion of GSH following chronic administration of BSO in the rat brain does not cause damage to the nigrostriatal pathway and suggests that loss of GSH alone is not responsible for nigrostriatal damage in PD. Rather, GSH depletion may enhance the susceptibility of substantia nigra to destruction by endogenous or exogenous toxins.
Toffa
S
S
Neurodegenerative Disease Research Centre, King's College, London, United Kingdom.
Kunikowska
G M
GM
Zeng
B Y
BY
Jenner
P
P
Marsden
C D
CD
D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003342:Corpus Striatum / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D005978:Glutathione / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D008297:Male; D009410:Nerve Degeneration / Q000187:drug effects* / Q000502:physiology; D009434:Neural Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*
D019328:Buthionine Sulfoximine; D005978:Glutathione