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

作者：Lockman J A^*; Geldenhuys W J; Bohn K A; DeSilva S F; Allen D D; Van der Schyf C J

来源：Neurochemical Research, 2012, 37(1): 134-142.

DOI：10.1007/s11064-011-0591-2

• Nimodipine
• Neurodegenerative diseases
• Iron in brain
• Metal toxicity
• Neurons
• Astrocytes
• Vascular endothelial cells

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 mu M), neuronal cells (Neuro-2 alpha neuroblastoma; LC50 = 400 mu M), and in astrocytes (DI TNC1; LC50 = 1.1 mM). Pre-treatment with nimodipine prior to iron sulfate exposure provided a significant (P %26lt; 0.05) increase in viable cell numbers for RBE4 (2.5-fold), Neuro2-alpha (similar to 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 %26gt; 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.

• 出版日期2012-1