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Differential Effect of Nimodipine in Attenuating Iron-Induced Toxicity in Brain- and Blood–Brain Barrier-Associated Cell Types

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Abstract

Metal homeostasis is increasingly being evaluated as a therapeutic target in stroke and neurodegenerative diseases. Metal dysregulation has been shown to lead to protein aggregation, plaque formation and neuronal death. In 2007, we first reported that voltage-gated calcium channels act as a facile conduit for the entry of free ferrous (Fe2+) ions into neurons. Herein, we evaluate differential iron toxicity to central nervous system cells and assess the ability of the typical L-type voltage-gated calcium channel blocker nimodipine to attenuate iron-induced toxicity. The data demonstrate that iron sulfate induces a dose-dependent decrease in cell viability in rat brain endothelial cells (RBE4; LC50 = 150 μM), neuronal cells (Neuro-2α neuroblastoma; LC50 = 400 μM), and in astrocytes (DI TNC1; LC50 = 1.1 mM). Pre-treatment with nimodipine prior to iron sulfate exposure provided a significant (P < 0.05) increase in viable cell numbers for RBE4 (2.5-fold), Neuro2-α (~2-fold), and nearly abolished toxicity in primary neurons. Astrocytes were highly resistant to iron toxicity compared to the other cell types tested and nimodipine had no (P > 0.05) protective effect in these cells. The data demonstrate variable susceptibility to iron overload conditions in different cell types of the brain and suggest that typical L-type voltage-gated calcium channel blockers (here represented by nimodipine), may serve as protective agents in conditions involving iron overload, particularly in cell types highly susceptible to iron toxicity.

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Authors and Affiliations

  1. Department of Life, Earth, and Environmental Sciences, West Texas A&M University, 2403 Russell Long Blvd., Canyon, TX, 79016, USA

    J. A. Lockman & S. F. DeSilva

  2. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), 1300 S. Coulter St., Amarillo, TX, 79106, USA

    J. A. Lockman & K. A. Bohn

  3. Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University (NEOMED), 4209 State Route 44, Rootstown, OH, 44272, USA

    W. J. Geldenhuys, D. D. Allen & C. J. Van der Schyf

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  1. J. A. Lockman
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  2. W. J. Geldenhuys
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  3. K. A. Bohn
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  4. S. F. DeSilva
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  5. D. D. Allen
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  6. C. J. Van der Schyf
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Correspondence to J. A. Lockman or C. J. Van der Schyf.

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Lockman, J.A., Geldenhuys, W.J., Bohn, K.A. et al. Differential Effect of Nimodipine in Attenuating Iron-Induced Toxicity in Brain- and Blood–Brain Barrier-Associated Cell Types. Neurochem Res 37, 134–142 (2012). https://doi.org/10.1007/s11064-011-0591-2

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  • DOI: https://doi.org/10.1007/s11064-011-0591-2

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