2-Iodo-4'-Methoxychalcone Attenuates Methylglyoxal-Induced Neurotoxicity by Activation of GLP-1 Receptor and Enhancement of Neurotrophic Signal, Antioxidant Defense and Glyoxalase Pathway

• Published in: Molecules (Basel, Switzerland) Switzerland), 2019-06, Vol.24 (12), p.2249
• Main Authors: Tseng, Yu-Ting, Tsai, Yi-Hong, Fülöp, Ferenc, Chang, Fang-Rong, Lo, Yi-Ching
• Format: Article
• Language: English
• Subjects: AKT protein; antioxidant defense; Antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; Apoptosis; Attenuation; Brain-derived neurotrophic factor; Cell Line; Cell Survival - drug effects; Chalcones - chemistry; Chalcones - pharmacology; Chemical reactions; Cyclic AMP response element-binding protein; Defense; Diabetes; Dopamine; Dopamine receptors; Down-regulation; Drug development; Flavonoids; Glucagon; Glucagon-like peptide 1; Glycogen; Glycogen synthase kinase 3; Glycogens; glyoxalase pathway; halogen-containing chalcones; Hippocampus; Homeostasis; Humans; Kinases; methylglyoxal; Neurons; neuroprotection; Neurotoxicity; Neurotoxicity Syndromes - drug therapy; Neurotoxicity Syndromes - etiology; Neurotoxicity Syndromes - pathology; neurotrophic effect; Organic chemistry; Oxidation; Oxidative Stress - drug effects; Parkinson's disease; Pharmacology; Phosphorylation; Protein-tyrosine kinase; Proteins; Pyruvaldehyde; Pyruvaldehyde - toxicity; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Studies; TrkB receptors; Tyrosine
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24122249

Methylglyoxal (MG) acts as a reactive precursor of advanced glycation end products (AGEs). This compound is often connected with pathologies such as diabetes, neurodegenerative processes and diseases of aging. 2-iodo-4'-methoxychalcone (CHA79), a synthetic halogen-containing chalcone derivative, has been reported its anti-diabetic activity. This study aims to investigate the potential protective capability of CHA79 against MG-mediated neurotoxicity in SH-SY5Y cells. Results indicated CHA79 increased viability of cells and attenuated the rate of apoptosis in MG-exposed SH-SY5Y. CHA79 up-regulated expression of anti-apoptotic protein (Bcl-2) and down-regulated apoptotic proteins (Bax, cytochrome , caspase-3, caspase-9). Moreover, CHA79 significantly up-regulated expression of neurotrophic factors, including glucagon-like peptide-1 receptor (GLP-1R), brain derived neurotrophic factor (BDNF), p75NTR, p-TrkB, p-Akt, p-GK-3β and p-CREB. CHA79 attenuated MG-induced ROS production and enhanced the antioxidant defense including nuclear factor erythroid 2-related factor 2 (Nrf2), HO-1, SOD and GSH. Furthermore, CHA79 attenuated MG-induced reduction of glyoxalase-1 (GLO-1), a vital enzyme on removing AGE precursors. In conclusion, CHA79 is the first novel synthetic chalcone possessing the GLP-1R and GLO-1 activating properties. CHA 79 also exhibits neuroprotective effects against MG toxicity by enhancing neurotrophic signal, antioxidant defense and anti-apoptosis pathway.