Previous research demonstrated that the progressive accumulation of iron in the substantia nigra pars compacta (SNpc) may contribute to dopaminergic (DA) neurons selective degeneration in Parkinson's disease (PD). However, the etiology and mechanism underlying iron-induced neurotoxicity processes are as yet unresolved. It has been reported that L-type calcium channels (LTCCs) may mediate iron influx into neuronal cells and can compete with calcium for common routes to enter primary neurons. The present study, we found that isradipine can alleviate iron-induced toxicity caused by raising intracellular calcium in MES23.5 cells. Analysis of experimental results revealed that an increase in extracellular free CaCl2 (500 µmol/L) is sufficient to promote FeSO4 (100 µmol/L) entry by activating L-type Ca2+ channels (LTCCs) significantly. The enhancement of calcium and/or iron influx was accompanied by a corresponding decrease of cell viability and higher susceptibility of toxicity, such as decrease of mitochondrial membrane potential (ΔΨm) and increase of nucleus pyknosis ratio and cleaved caspase-3 protein expression in MPP+ (5 µmol/L) treatment MES23.5 cells. Pre-treatment with isradipine (10 µmol/L), a LTCCs blocker, for 15 min, can antagonize calcium and/or iron-induced neurotoxicity. These results suggest that application of isradipine may be a potential method for the treatment of the neurodegenerative disease induced by calcium and/or iron dysmetabolism.
Iron, Mitochondria, Neurotoxicity, L-Type Ca2+ Channel
- Follett, J., Darlow, B., Wong, M. B., Goodwin, J. & Pountney, D. L. Potassium depolarization and raised calcium induces alpha-synuclein aggregates. Neurotoxicity research 23, 378-392, doi:10.1007/s12640-012-9366-z (2013).
- Dragicevic, E. et al. Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons. Brain : a journal of neurology 137, 2287-2302, doi:10.1093/brain/awu131 (2014).
- Bostanci, M. O. & Bagirici, F. Blocking of L-type calcium channels protects hippocampal and nigral neurons against iron neurotoxicity. The role of L-type calcium channels in iron-induced neurotoxicity. The International journal of neuroscience 123, 876-882, doi:10.3109/00207454.2013.813510 (2013).
- Singh, N. et al. Brain iron homeostasis: from molecular mechanisms to clinical significance and therapeutic opportunities. Antioxidants & redox signaling 20, 1324-1363, doi:10.1089/ars.2012.4931 (2014).
- Tsushima, R. G. et al. Modulation of Iron Uptake in Heart by L-Type Ca2+Channel Modifiers. Circulation Research 84, 1302-1309, doi:10.1161/01.res.84.11.1302 (1999).
- Yu, X. et al. Isradipine prevents rotenone-induced intracellular calcium rise that accelerates senescence in human neuroblastoma SH-SY5Y cells. Neuroscience 246, 243-253, doi:10.1016/j.neuroscience.2013.04.062 (2013).
- Wang, R., Ma, Z., Wang, J. & Xie, J. L-type Cav1.2 calcium channel is involved in 6-hydroxydopamine-induced neurotoxicity in rats. Neurotoxicity research 21, 266-270, doi:10.1007/s12640-011-9271-x (2012).
- Surmeier, D. J., Guzman, J. N. & Sanchez-Padilla, J. Calcium, cellular aging, and selective neuronal vulnerability in Parkinson's disease. Cell calcium 47, 175-182, doi:10.1016/j.ceca.2009.12.003 (2010).
- Parkinson Study, G. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson's disease (STEADY-PD). Movement disorders : official journal of the Movement Disorder Society 28, 1823-1831, doi:10.1002/mds.25639 (2013).
- Ortner, N. J. et al. Lower Affinity of Isradipine for L-Type Ca(2+) Channels during Substantia Nigra Dopamine Neuron-Like Activity: Implications for Neuroprotection in Parkinson's Disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 37, 6761-6777, doi:10.1523/JNEUROSCI.2946-16.2017 (2017).
- Puopolo, M., Raviola, E. & Bean, B. P. Roles of subthreshold calcium current and sodium current in spontaneous firing of mouse midbrain dopamine neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 645-656, doi:10.1523/JNEUROSCI.4341-06.2007 (2007).
- Zhu, Z. J., Wu, K. C., Yung, W. H., Qian, Z. M. & Ke, Y. Differential interaction between iron and mutant alpha-synuclein causes distinctive Parkinsonian phenotypes in Drosophila. Biochimica et biophysica acta 1862, 518-525, doi:10.1016/j.bbadis.2016.01.002 (2016).
- Pelizzoni, I. et al. Iron handling in hippocampal neurons: activity-dependent iron entry and mitochondria-mediated neurotoxicity. Aging cell 10, 172-183, doi:10.1111/j.1474-9726.2010.00652.x (2011).
- Striessnig, J., Bolz, H. J. & Koschak, A. Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels. Pflugers Archiv : European journal of physiology 460, 361-374, doi:10.1007/s00424-010-0800-x (2010).
- Striessnig, J., Pinggera, A., Kaur, G., Bock, G. & Tuluc, P. L-type Ca(2+) channels in heart and brain. Wiley interdisciplinary reviews. Membrane transport and signaling 3, 15-38, doi:10.1002/wmts.102 (2014).
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