Thioctic acid does not restore glutathione levels or protect against the potentiation of 6-hydroxydopamine toxicity induced by glutathione depletion in rat brain.
Decreased reduced glutathione (GSH) levels are an early marker of nigral cell death in Parkinson's disease. Depletion of rat brain GSH by intracerebroventricular administration of buthionine sulphoximine (BSO) potentiates the toxicity of 6-hydroxydopamine (6-OHDA) to the nigrostriatal pathway. We have investigated whether thioctic acid can replenish brain GSH levels following BSO-induced depletion and/or prevent 6-OHDA induced toxicity. Administration of BSO (2 x 1.6 mg i.c.v.) to rats depleted striatal GSH levels by upto 75%. BSO treatment potentiated 6-OHDA (75 micrograms i.c.v.) toxicity as judged by striatal dopamine content and the number of tyrosine hydroxylase immunoreactive cells in substantia nigra. Repeated treatment with thioctic acid (50 or 100 mg/kg i.p.) over 48h had no effect on the 6-OHDA induced loss of dopamine in striatum or nigral tyrosine hydroxylase positive cells in substantia nigra. Also thioctic acid treatment did not reverse the BSO induced depletion of GSH or prevent the potentiation of 6-OHDA neurotoxicity produced by BSO. Thioctic acid (50 mg or 100 mg/kg i.p.) alone or in combination with BSO did not alter striatal dopamine levels but increased dopamine turnover. Striatal 5-HT content was not altered by thioctic acid but 5-HIAA levels were increased. Under conditions of inhibition of GSH synthesis, thioctic acid does not replenish brain GSH levels or protect against 6-OHDA toxicity. At last in this model of Parkinson's disease, thioctic acid does not appear to have a neuroprotective effect.
Seaton
T A
TA
Neurodegenerative Disease Research Centre, King's College, London, United Kingdom.
Jenner
P
P
Marsden
C D
CD
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000033:anatomy & histology / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects*; D019328:Buthionine Sulfoximine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013565:Sympatholytics / Q000633:toxicity*; D008063:Thioctic Acid / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000963:Antimetabolites; D015306:Biogenic Monoamines; D013565:Sympatholytics; D019328:Buthionine Sulfoximine; D008063:Thioctic Acid; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D005978:Glutathione