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Neurochem Res. 2016 Apr;41(4):844-54. doi: 10.1007/s11064-015-1761-4. Epub 2015 Nov 11.

Neuroprotective Effects of Etidronate and 2,3,3-Trisphosphonate Against Glutamate-Induced Toxicity in PC12 Cells.

Author information

1
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.
2
Science and Technology Research Institute, University of Hertfordshire, Hatfield, Herts, AL10 9AB, UK.
3
College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
4
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.

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.

KEYWORDS:

2,3,3-Trisphosphonate; Etidronate; Glutamate; Neuroprotection; PC12 cells

PMID:
26559687
DOI:
10.1007/s11064-015-1761-4
[Indexed for MEDLINE]

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