title: Differential effect of nimodipine in attenuating iron-induced toxicity in brain- and blood-brain barrier-associated cell types.
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 (Fe(2+)) 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; LC(50) = 150 μM), neuronal cells (Neuro-2α neuroblastoma; LC(50) = 400 μM), and in astrocytes (DI TNC1; LC(50) = 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.
authors.affiliation: Department of Life, Earth, and Environmental Sciences, West Texas A&M University, 2403 Russell Long Blvd., Canyon, TX 79016, USA. jlockman@wtamu.edu
authors.forename: J A
authors.initials: JA
authors.lastname: Lockman
authors.forename: W J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: K A
authors.initials: KA
authors.lastname: Bohn
authors.forename: S F
authors.initials: SF
authors.lastname: Desilva
authors.forename: D D
authors.initials: DD
authors.lastname: Allen
authors.forename: C J
authors.initials: CJ
authors.lastname: Van der Schyf
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D007501:Iron / Q000633:toxicity*; D008856:Microscopy, Fluorescence; D009553:Nimodipine / Q000494:pharmacology*; D051381:Rats
chemical_list: D002121:Calcium Channel Blockers; D009553:Nimodipine; D007501:Iron