title: Neuroprotective Effects of Etidronate and 2,3,3-Trisphosphonate Against Glutamate-Induced Toxicity in PC12 Cells.
abstract: Etidronate is one of the best known bisphosphonates (BP) derivatives. It is often used as a reference drug in research related to hypercalcaemia and other common bone diseases. 2,3,3-trisphosphonate (TrisPP) is brand new analogue of BP, that also contains a 'germinal bisphosphonate' unit with an additional phosphoryl group attached in proximity to the BP unit. It is known that BPs bind to calcium by chemisorptions to form Ca-BP complexes through (O)P-C-P(O) moiety and hydrogen coordinations, and so they suppress calcium flow by interfering with Ca(2+) channel operations. The mechanistic actions of BP, involving interactions and regulations of Ca(2+), are somewhat similar to the pathogenesis of well-known neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. To investigate if neuroprotective effects are exhibited by the compounds of interests, we used a rat adrenal pheochromocytoma cell line (PC12) as our in vitro model to observe any occurrence of neuron inter-reflection. We pre-treated these PC12 cells with etidronate and TrisPP before challenging the cells with a high concentration of the neurotoxin, glutamate. Our data showed that pre-treatment with 100 μM etidronate partially ameliorated the glutamate-induced decrease in cell viability (47 %), whereas pre-treating cells with 10-100 μM TrisPP showed remarkable cell protection (78-86 %). Moreover, pre-treatments of the cells with etidronate or TrisPP attenuated cell apoptosis, reactive oxygen species generation, Ca(2+) overloading and caspase-3 protein expression, which were associated with a remarkable increase in superoxide dismutase activity in our glutamate-injured PC12 cells. Therefore, this study supports the notion that etidronate and TrisPP may be promising neuroprotective agents.
authors.affiliation: School of Medicine, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Science and Technology Research Institute, University of Hertfordshire, Hatfield, Herts, AL10 9AB, UK.
authors.forename: Yuen-Ki
authors.initials: YK
authors.lastname: Cheong
authors.affiliation: College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Science and Technology Research Institute, University of Hertfordshire, Hatfield, Herts, AL10 9AB, UK.
authors.forename: Guogang
authors.initials: G
authors.lastname: Ren
authors.affiliation: School of Medicine, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University, 94 Weijin Road, Tianjin, 300071, China. zhuoyang@nankai.edu.cn.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D012968:Etidronic Acid / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity*; D042541:Intracellular Space / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D063065:Organophosphonates / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D063065:Organophosphonates; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D012968:Etidronic Acid; D002118:Calcium
keywords: 2,3,3-Trisphosphonate; Etidronate; Glutamate; Neuroprotection; PC12 cells