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

Abstract

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...

The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality

“…This active metabolite is present in human brain tissue, including the substantia nigra. ADTIQ levels are increased in PD patients (Deng et al, 2012), and the structure of ADTIQ resembles that of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) elucidated using hyperglycemic cell and rat models (Song et al, 2014). Interestingly, in a separate study, ADTIQ has been shown as an endogenous neurotoxin in SH-SY5Y neuroblastoma cells, and the levels of both MGO and ADTIQ are increased in the striatum of a streptozotocin-induced diabetic rat model (Xie et al, 2015).…”

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

“…MGO increased the levels of DA and Sal, contributing to neuronal cell death [76]. Moreover, the elevated levels of ADTIQ and MGO were observed in the cell model of hyperglycemia and the brains of rats with diabetes [77]. Figure 2 showed significantly increased levels of ADTIQ and MGO in the striatum of SD rats with type2 diabetes.…”

On the Relationship between Energy Metabolism, Proteostasis, Aging and Parkinson’s Disease: Possible Causative Role of Methylglyoxal and Alleviative Potential of Carnosine

“…ADTIQ not only accumulates in PD brains but also mimics the effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) whose effects on mitochondria resemble the changes associated with PD [69]. Further evidence supporting the proposed link between MG, dopamine and generation of the neurotoxin ADTIQ is shown by the increased levels of glycolytic enzymes, MG and ADTIQ in the brains of diabetic rats [70]. It may be relevant to note that another group of nigrostriatal neurotoxins, N-methylated-beta-carboline and 2,9-dimethyl beta-carboline, whose structures resembles MPTP, not only inhibit mitochondria respiration but are also potent inhibitors of triosephosphate isomerase (TPI) [71].…”

“…Furthermore, in the substantia nigra increased MG generation would (as previously mentioned) following reaction with dopamine, increase the likelihood of formation of ADTIQ, which has been detected in diabetic brains, which in turn will damage mitochondria etc. and further exacerbate the condition, to promote a self-reinforcing deleterious cycle of dysfunction [70,101]. …”