1-Benzyl-1,2,3,4-tetrahydroisoquinoline, a Parkinsonism-inducing endogenous toxin, increases alpha-synuclein expression and causes nuclear damage in human dopaminergic cells.
1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, is known to cause parkinsonism in rodents and nonhuman primates. The levels of 1BnTIQ in cerebrospinal fluid of patients with Parkinson's disease (PD) were reported to be three times higher than those in control subjects. In the present study, we have evaluated the effects of 1BnTIQ on alpha-synuclein (alpha-syn) expression together with biochemical and morphological changes in human dopaminergic SH-SY5Y cells in culture. 1BnTIQ at lower concentrations (1-50 microM) increased alpha-syn protein expression in a time- and dose-dependent manner in these cells. There was also up-regulation of alpha-syn mRNA by 1BnTIQ. Inhibition of complex I by rotenone and depletion of glutathione by L-buthionine sulfoxamine also correlated with an increase in alpha-syn expression, suggesting that oxidative stress may cause an increase in alpha-syn levels in dopaminergic cells. Furthermore, 1BnTIQ significantly depleted glutathione levels. 1BnTIQ at higher concentrations (500 microM) increased reactive oxygen species levels, decreased ATP levels, and caused nuclear damage in the cells. The 1BnTIQ-induced alpha-syn up-regulation was inhibited by cotreatment with the antioxidants selegiline, coenzyme Q(10), and N-acetylcystein and the caspase inhibitor DEVD-CHO. Taken together, these results suggest that alpha-syn up-regulation and oxidative stress are contributing factors in 1BnTIQ-induced neurotoxicity in dopaminergic neurons in PD.
Shavali
Shaik
S
Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58203, USA.
Carlson
Edward C
EC
Swinscoe
John C
JC
Ebadi
Manuchair
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000648:ultrastructure; D003067:Coenzymes; D015853:Cysteine Proteinase Inhibitors; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008854:Microscopy, Electron / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012642:Selegiline / Q000494:pharmacology; D051843:Synucleins; D044005:Tetrahydroisoquinolines / Q000633:toxicity*; D013997:Time Factors; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D051844:alpha-Synuclein
D000975:Antioxidants; D003067:Coenzymes; D015853:Cysteine Proteinase Inhibitors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009842:Oligopeptides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C497604:SNCA protein, human; D051843:Synucleins; D044005:Tetrahydroisoquinolines; D051844:alpha-Synuclein; C108637:aspartyl-glutamyl-valyl-aspartal; D014451:Ubiquinone; D012642:Selegiline; D000255:Adenosine Triphosphate; C024989:coenzyme Q10; D005978:Glutathione; D004298:Dopamine; C084924:1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline