Ngp1-01, A Multi-targeted Polycyclic Cage Amine, Attenuates Brain Endothelial Cell Death In Iron Overload Conditions

Ngp1-01, A Multi-targeted Polycyclic Cage Amine, Attenuates Brain Endothelial Cell Death In Iron Overload Conditions

Lockman J A; Geldenhuys W J; Jones-Higgins M R; Patrick J D; Allen D D; Van der Schyf C J

Brain Research

2012

2012-12

Development and progression of neurodegenerative disorders have, amongst other potential causes, been attributed to a disruption of iron regulatory mechanisms and iron accumulation. Excess extracellular iron may enter cells via nontraditional routes such as voltage-gated calcium channels and N-methyl-D-aspartate (NMDA) receptors leading to intracellular oxidative damage and ultimately mitochondrial failure. Nimodipine, an L-type calcium channel blocker has been shown to reduce iron-induced toxicity in neuronal and brain endothelial cells. Our current study investigates NGP1-01, a multimodal drug acting as an antagonist at both the NMDA receptor and the L-type calcium channel. Our previous studies support NGP1-01. as a promising neuroprotective agent in diseases involving calcium-related excitotoxicity. We demonstrate here that NGP1-01 (1 and 10 mu M) pretreatment abrogates the effects of iron overload in brain endothelial cells protecting cellular viability. Both concentrations of NGP1-01 were found to attenuate iron-induced reduction in cellular viability to a similar extent, and were statistically significant. To further verify the mechanism, the L-type calcium channel agonist FPL 64176 was administered to promote iron uptake. Addition of NGP1-01 dose-dependently reduced FPL 64176 stimulated uptake of iron. These data support further evaluation of NGP1-01 as a neuroprotective agent, not only in diseases associated with excitotoxicity, but also in those of iron overload. (C) 2012 Elsevier B.V. All rights reserved.

activator; barrier; calcium channels; channels provide; intracerebral hemorrhage; Iron-overload; neurodegeneration; neurodegenerative disorders; neuroprotection; Neurosciences & Neurology; Nimodipine; parkinsons-disease; permeability; rat-brain; toxicity; transport; Vascular endothelial cells; Voltage-gated calcium channel

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