1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, induces dopaminergic cell death through apoptosis.
Endogenous MPTP-like neurotoxins such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) have been suspected in the etiology of Parkinson's disease (PD). 1BnTIQ was found in a concentration three times higher in cerebrospinal fluid of PD brains than control subjects [J. Neurochem. 65 (6) (1995) 2633]. In the present study, we have evaluated the mechanisms of 1BnTIQ toxicity in human dopaminergic SH-SY5Y cells and tested the neuroprotective action of SKF-38393, a dopamine receptor (D(1)) agonist. 1BnTIQ dose dependently decreased cell viability in dopaminergic SH-SY5Y cells and the extent of cell death was more pronounced when compared to MPP(+). Similar to MPP(+), 1BnTIQ significantly decreased [3H]dopamine uptake. 1BnTIQ significantly increased lipid peroxidation, Bax expression, and active caspase-3 formation. Furthermore, it decreased the expression of Bcl-xL, an anti-apoptotic protein, in these cells. SKF-38393, a dopamine receptor (D(1)) agonist (1 and 10 microM) completely prevented the cell death and significantly increased cell viability. These results strongly suggest that 1BnTIQ induces dopaminergic cell death by apoptosis and dopamine receptor agonists may be useful neuroprotective agents against 1BnTIQ toxicity.
Shavali
Shaik
S
Department of Pharmacology, School of Medicine and Health Sciences, University of North Dakota, 501 North Columbia Road, 58202, Grand Forks, ND, USA.
Ebadi
Manuchair
M
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism / Q000633:toxicity*; D044005:Tetrahydroisoquinolines; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D004298:Dopamine; C084924:1,2,3,4-tetrahydro-1-(phenylmethyl)isoquinoline