Neuroprotective Effects of Etidronate and 2,3,3-Trisphosphonate Against Glutamate-Induced Toxicity in PC12 Cells
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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 Ca2+ channel operations. The mechanistic actions of BP, involving interactions and regulations of Ca2+, 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, Ca2+ 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.
KeywordsEtidronate 2,3,3-Trisphosphonate PC12 cells Glutamate Neuroprotection
This work was supported by grant from Tianjin Research Program of Application Foundation and Advanced Technology (14JCZDJC35000), the National Natural Science Foundation of China (81571804) and the UK Royal Academy of Engineering (RAEng. 1213RECI052).
- 4.Russell RGG, Xia Z, Dunford JE, Oppermann U, Kwaasi A, Hulley PA, Kavanagh KL, Triffitt JT, Lundy MW, Phipps RJ, Barnett BL, Coxon FP, Rogers MJ, Watts NB, Ebetino FH (2007) Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 1117:209–257CrossRefPubMedGoogle Scholar
- 18.Xu P, Xu J, Liu S, Ren G, Yang Z (2012) In vitro toxicity of nanosized copper particles in PC12 cells induced by oxidative stress. J Nanopart Res 14:1–9Google Scholar
- 27.Liu S-b, Zhang N, Guo Y-y, Zhao R, Shi T-y, Feng S-f, Wang S-q, Yang Q, Li X-q, Wu Y-m, Ma L, Hou Y, Xiong L-z, Zhang W, Zhao M-g (2012) G-Protein-coupled receptor 30 mediates rapid neuroprotective effects of estrogen via depression of NR2B-containing NMDA receptors. Journal of Neuroscience 32:4887–4900CrossRefPubMedGoogle Scholar
- 34.Dieli F, Vermijlen D, Fulfaro F, Caccamo N, Meraviglia S, Cicero G, Roberts A, Buccheri S, D’Asaro M, Gebbia N, Salerno A, Eberl M, Hayday AC (2007) Targeting human gamma delta T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res 67:7450–7457CrossRefPubMedPubMedCentralGoogle Scholar