Cytotoxicity of 17 tetrahydroisoquinoline derivatives in SH-SY5Y human neuroblastoma cells is related to mitochondrial NADH–ubiquinone oxidoreductase inhibition

Kotake, Yaichiro; Sekiya, Yoko; Okuda, Kunio; Ohta, Shigeru

doi:10.1016/j.neuro.2006.06.002

Cited by 17 publications

(11 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2a and b). The benzyl moiety of 1BnTIQ might be important for neurotoxicity, because TIQs, which have the benzyl moiety, are toxic to neuronal cells (Kotake et al. 2007).…”

Section: Discussionmentioning

confidence: 99%

1‐Benzyl‐1,2,3,4‐tetrahydroisoquinoline binds with tubulin β, a substrate of parkin, and reduces its polyubiquitination

Kohta¹,

Kotake²,

Hosoya³

et al. 2010

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and the appearance of Lewy bodies in the substantia nigra, leading to clinical symptoms of rigidity, resting tremor, and bradykinesia. A few percent of PD is of genetic origin, and over ten genes have been identified as causes of familial PD so Received October 9, 2009; revised manuscript received November 27, 2009; accepted December 1, 2009. Address correspondence and reprint requests to Dr Y. Kotake, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. E-mail: yaichiro@hiroshima-u.ac.jp Abbreviations used: 1BnTIQ, 1-Benzyl-1,2,3,4-tetrahydroisoquinoline; 1DAzBnTIQ, 1-(3-azido-5-azidomethylbenzyl)-1,2,3,4-tetrahydroisoquinoline; 1MeTIQ, 1-methyl-1,2,3,4-tetrahydroisoquinoline; 3¢,4¢ DHBnTIQ, 1-(3,4-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline; AR-JP, autosomal recessive juvenile parkinsonism; BSA, bovine serum albumin; CBB, Coomassie Brilliant Blue; GST, glutathione-S-transferase; IP, immunoprecipitation; N-Boc, N-tert-butoxycarbonyl; Pael-R, parkinassociated endothelin receptor-like receptor; PBS, phosphate-buffered saline; PD, Parkinson's disease; PVDF, polyvinylidene difluoride; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TIQ, 1,2,3,4-tetrahydroisoquinoline; TNE, tris-NaCl-EDTA; TOF, time of flight; Tris, tris(hydroxymethyl)aminomethane; TTBS, Tween 20-containing tris-buffered saline; WB, western blotting. AbstractSubstances that mimic the actions of causative gene products of familial Parkinson's disease (PD) are candidate as causative agents of idiopathic PD. 1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, is present at three times higher levels in CSF of PD patients than in CSF of control subjects. However, the mechanism of 1BnTIQ's neurotoxicity is unclear. In this study, we tried to identify 1BnTIQ-binding proteins by using a diazido-functionalized 1BnTIQ analog, 1-(3-azido-5-azidomethylbenzyl)-1,2,3,4-tetrahydroisoquinoline, designed and synthesized as a probe for radioisotope-free photoaffinity labeling. One major photolabeled protein identified using this probe was tubulin b, which has been reported to be a substrate of parkin, a ubiquitin E3 ligase and a causative gene product of familial PD. Loss of function mutation of parkin is reported to result in loss of tubulin b ubiquitination. Therefore, we examined the effect of 1BnTIQ on ubiquitination of tubulin b. The polyubiquitinated tubulin b level in human neuroblastoma SH-SY5Y cells was reduced in the presence of 1BnTIQ, even at concentrations as low as those detected in parkinsonian CSF. In vitro ubiquitination assay gave similar results. It is suggested that 1BnTIQ has the same effect on tubulin ubiquitination as does mutant parkin in familial PD. Taken together, substances which reduce polyubiquitination of tubulin such as 1BnTIQ are supposed to be candidates of etiological factors of PD.

show abstract

“…2a and b). The benzyl moiety of 1BnTIQ might be important for neurotoxicity, because TIQs, which have the benzyl moiety, are toxic to neuronal cells (Kotake et al. 2007).…”

Section: Discussionmentioning

confidence: 99%

1‐Benzyl‐1,2,3,4‐tetrahydroisoquinoline binds with tubulin β, a substrate of parkin, and reduces its polyubiquitination

Kohta¹,

Kotake²,

Hosoya³

et al. 2010

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Deeply, according to the information above, the mitochondrial dysfunction exists both in α-syn overexpression models and in CTIQs treated models [25,38,46,47,49,50,65,66,78,82,[137][138][139][140]. Therefore, the contribution of α-syn and CTIQs to the pathogenesis of PD could both ascribe to the damaged mitochondria, which further verified the interrelation between CTIQs and α-syn.…”

Section: Ctiqs and α-Syn Aggregationmentioning

confidence: 77%

“…However, the neurotoxic effect of 1BnTIQ is dependent on its concentration:1BnTIQ in a low concentration(50 μM) played a neuroprotective role, whereas in 10 times higher concentration (500 μM) it played a neurotoxic role by increasing apoptosis markers [81]. Recently, Kotake et al detected a novel metabolite of 1BnTIQ, 1-benzyl-3,4-dihydroisoquinoline (1BnDIQ) in rat liver S9 and demonstrated that 1BnDIQ is more toxic than 1BnTIQ [82,83]. In addition, the analog of 1BnTIQ, 1-(3' ,4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3' ,4'DHBn TIQ) also exerted the DA neurotoxic effect and reduced cell viability as a potential endogenous parkinsonism inducer [84].…”

Section: Tiqs-like Candidates Of Endogenous Neurotoxinsmentioning

confidence: 99%

“…In addition, the analog of 1BnTIQ, 1-(3' ,4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3' ,4'DHBn TIQ) also exerted the DA neurotoxic effect and reduced cell viability as a potential endogenous parkinsonism inducer [84]. Importantly, the mechanism of these TIQ derivatives induced neurotoxicity may be related to the inhibition of mitochondrial function [82].…”

Section: Tiqs-like Candidates Of Endogenous Neurotoxinsmentioning

confidence: 99%

See 1 more Smart Citation

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

Chen¹,

Lu²,

Duan³

et al. 2017

J Alzheimers Dis Parkinsonism

View full text Add to dashboard Cite

“…12) 1BnTIQ at lower concentrations was reported to increase alpha-synuclein expression. 13) In addition to MPTP and its analogues, rotenone has been noted as another PD-related environmental factor. Rotenone is a potent complex I inhibitor.…”

Section: Pd-related Tiq Derivativesmentioning

confidence: 99%

Neurotoxicity Induced by Environmental Low-molecular-weight Substances

Kotake

2007

JOURNAL OF HEALTH SCIENCE

Self Cite

View full text Add to dashboard Cite

The neurotoxicity of Parkinson's disease (PD)-related tetrahydroisoquinolines (TIQs) and organotins is reviewed. PD is one of the most common neurodegenerative diseases among aged people and characteristized by the selective death of nigrostriatal dopaminergic neurons, but its pathological mechanism remains unknown. 1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous brain amine, was proposed as a possible PD-inducing neurotoxin, and its characteristics relevant to PD were evaluated. 1BnTIQ was detected in the mouse brain and human cerebrospinal fluid (CSF), and 1BnTIQ content was found to increase in the patients with PD. Repeated administration of 1BnTIQ induced PD-like symptoms in monkey and mice. 1BnTIQ induced dopaminergic cell death and subsequent dopamine decreases in organotypic slice co-culture, an in vitro culture system similar to the in vivo physiological environment. 1BnTIQ treatment also inhibited NADH-ubiquinone oxidoreductase in the mitochondrial respiratory chain. Thus, 1BnTIQ might a causative factor for PD, although the concentration required for neurotoxicity is higher than that found in the parkinsonian cerebrospinal fluid. We propose that tributyltin is another neurotoxin that acts through the glutamatergic pathway. Glutamate is one of the most abundant neurotransmitters in the central nervous system (CNS), but excessive release of glutamate causes prolonged stimulation of NMDA receptors, inducing calcium overload and neuronal death that is collectively referred to as excitotoxicity. Glutamate-mediated toxicity is selective for the CNS because only the CNS possesses this system. We clarified that tributyltin induces extracellular glutamate release and that tributyltin-induced neuronal death is mediated by glutamate excitotoxicity in cultured rat cortical neurons.

show abstract

Cytotoxicity of 17 tetrahydroisoquinoline derivatives in SH-SY5Y human neuroblastoma cells is related to mitochondrial NADH–ubiquinone oxidoreductase inhibition

Cited by 17 publications

References 32 publications

1‐Benzyl‐1,2,3,4‐tetrahydroisoquinoline binds with tubulin β, a substrate of parkin, and reduces its polyubiquitination

1‐Benzyl‐1,2,3,4‐tetrahydroisoquinoline binds with tubulin β, a substrate of parkin, and reduces its polyubiquitination

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

Neurotoxicity Induced by Environmental Low-molecular-weight Substances

Contact Info

Product

Resources

About