Salsolinol, an Endogenous Neurotoxin, Activates JNK and NF-κB Signaling Pathways in Human Neuroblastoma Cells

Wanpen, Sawitri; Kooncumchoo, Patcharee; Shaik, Shavali; Govitrapong, Piyarat; Ebadi, Manuchair

doi:10.1007/s11064-006-9246-0

Cited by 20 publications

(11 citation statements)

References 44 publications

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“…Glycolysis is a crucial process in DM and the most extensively investigated metabolic pathway (22). MG is an important byproduct in this pathway and its production is increased due to hyperglycemia.…”

Section: Discussionmentioning

confidence: 99%

Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycemia and a rat model of diabetes

Song

Xin

Xie

et al. 2013

International Journal of Molecular Medicine

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Abstract. There are statistical data indicating that diabetes is a risk factor for Parkinson's disease (PD). Methylglyoxal (MG), a biologically reactive byproduct of glucose metabolism, the levels of which have been shown to be increase in diabetes, reacts with dopamine to form 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (ADTIQ); this formation may provide further insight into the connection between PD and diabetes. In this study, we investigated the role of ADTIQ in these two diseases to determine in an aim to enhance our understanding of the link between PD and diabetes. To this end, a cell model of hyperglycemia and a rat model of diabetes were established. In the cell model of hyperglycemia, compared with the control group, the elevated glucose levels promoted free hydroxyl radical formation (p<0.01). An ADTIQ assay was successfully developed and ADTIQ levels were detected and quantified. The levels of its precursors, MG and dopamine (DA), were determined in both the cell model of hyperglycemia and the rat model of diabetes. The proteins related to glucose metabolism were also assayed. Compared with the control group, ADTIQ and MG levels were significantly elevated not only in the cell model of hyperglycemia, but also in the brains of rats with diabetes (p<0.01). Seven key enzymes from the glycolytic pathway were found to be significantly more abundant in the brains of rats with diabetes. Moreover, it was found that adenosine triphosphate (ATP) synthase and superoxide dismutase (SOD) expression levels were markedly decreased in the rats with diabetes compared with the control group. Therefore, ADTIQ expression levels were found to be elevated under hyperglycemic conditions. The results reported herein demonstrate that ADTIQ, which is derived from MG, the levels of which areincreased in diabetes, may serve as a neurotoxin to dopaminergic neurons, eventually leading to PD. IntroductionDiabetes mellitus (DM), as a state of chronic hyperglycemia, and Parkinson's disease (PD) are diseases which consist a global health threat. In recent years, there have been increasing data indicating that hyperglycemia is associated with an increased risk of developing PD (1,2). However, the mechanisms underlying the association between hyperglycemia and PD have not yet been elucidated.Deng and Rajput (6) were the first to report, in 2001, that 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (ADTIQ), a salsolinol-like compound, is found at highly concentrated levels in the brains of patients who suffer from PD (3). When the brains of deceased patients with PD were compared to those of normal subjects, it was found that patients with PD presented elevated levels of ADTIQ in all the examined brain areas. This finding indicated that elevated ADTIQ expression levels may be one of the mechanisms involved in the increased risk patients with diabetes have of developing PD (4).Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycem...

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Section: Discussionmentioning

confidence: 99%

Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycemia and a rat model of diabetes

Song

Xin

Xie

et al. 2013

International Journal of Molecular Medicine

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“…ROS were increased and glutathione levels were decreased when SH-SY5Y cells were treated with racemic salsolinol, especially at concentrations near to 500 μM (Wanpen et al 2004). The treatment also decreased the levels of an anti-apoptotic protein bcl-2 and increased a pro-apoptotic protein bax (Shukla et al 2013;Wanpen et al 2007). Storch et al (2000) concluded that (RS)-salsolinol was toxic to human dopaminergic neuroblastoma SH-SY5Y cells by blocking the cellular energy supply via the inhibition of mitochondrial complex II activity but not complex I.…”

Section: Discussionmentioning

confidence: 97%

Salsolinol—neurotoxic or Neuroprotective?

et al. 2019

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Salsolinol (6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline), widely available in many edibles, is considered to alter the function of dopaminergic neurons in the central nervous system and thus, multiple hypotheses on its either physiological and/or pathophysiological role have emerged. The aim of our work was to revisit its potentially neurotoxic and/or neuroprotective role through a series of both in vitro and in vivo experiments. Salsolinol in the concentration range 10-250 μM did not show any significant release of lactate dehydrogenase from necrotic SH-SY5Y cells and was able in the concentration of 50 and 100 μM to rescue SH-SY5Y cells from death induced by H 2 O 2. Its neuroprotective effect against neurotoxin 6-hydroxydopamine was also determined. Salsolinol was found to decrease significantly the reactive oxygen species level in SH-SY5Y cells treated by 500 μM H 2 O 2 and the caspase activity induced by 300 μM of H 2 O 2 or 100 μM of 6-hydroxydopamine. Serum levels of TNFα and CRP of salsolinol-treated rats were not significantly different from control animals. Both TNFα and CRP served as indirect markers of neurotoxicity and/or neuroprotection. Although the neurotoxic properties of salsolinol have numerously been emphasized, its neuroprotective properties should not be neglected and need greater consideration.

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“…Oxidation of N -methylated derivatives into N -methylisoquinolinium ion augmented the potency to inhibit mitochondrial respiration and complex I (Morikawa et al 1998 ). Wanpen et al ( 2007 ) confirmed that mitochondrial complex I activity was significantly decreased, and reactive oxygen species were increased when SH-SY5Y cells were treated with racemic salsolinol. The treatment decreased the levels of the anti-apoptotic protein bcl-2 and increased pro-apoptotic protein bax, while enhancing the release of cytochrome c from mitochondria (Wanpen et al 2007 ).…”

Section: Salsolinol In Experimental Modelsmentioning

confidence: 97%

“…Wanpen et al ( 2007 ) confirmed that mitochondrial complex I activity was significantly decreased, and reactive oxygen species were increased when SH-SY5Y cells were treated with racemic salsolinol. The treatment decreased the levels of the anti-apoptotic protein bcl-2 and increased pro-apoptotic protein bax, while enhancing the release of cytochrome c from mitochondria (Wanpen et al 2007 ). Storch et al ( 2000 ) concluded that salsolinol was toxic to human dopaminergic neuroblastoma SH-SY5Y cells by blocking the cellular energy supply via the inhibition of mitochondrial complex II activity (succinate-Q reductase) but not that of complex I.…”

Section: Salsolinol In Experimental Modelsmentioning

confidence: 97%

Salsolinol: an Unintelligible and Double-Faced Molecule—Lessons Learned from In Vivo and In Vitro Experiments

et al. 2017

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Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is a tetrahydroisoquinoline derivative whose presence in humans was first detected in the urine of Parkinsonian patients on l-DOPA (l-dihydroxyphenylalanine) medication. Thus far, multiple hypotheses regarding its physiological/pathophysiological roles have been proposed, especially related to Parkinson’s disease or alcohol addiction. The aim of this review was to outline studies related to salsolinol, with special focus on in vivo and in vitro experimental models. To begin with, the chemical structure of salsolinol together with its biochemical implications and the role in neurotransmission are discussed. Numerous experimental studies are summarized in tables and the most relevant ones are stressed. Finally, the ability of salsolinol to cross the blood–brain barrier and its possible double-faced neurobiological potential are reviewed.

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Salsolinol, an Endogenous Neurotoxin, Activates JNK and NF-κB Signaling Pathways in Human Neuroblastoma Cells

Cited by 20 publications

References 44 publications

Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycemia and a rat model of diabetes

Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycemia and a rat model of diabetes

Salsolinol—neurotoxic or Neuroprotective?

Salsolinol: an Unintelligible and Double-Faced Molecule—Lessons Learned from In Vivo and In Vitro Experiments

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