Ngp1-01, A Multi-targeted Polycyclic Cage Amine, Attenuates Brain Endothelial Cell Death In Iron Overload Conditions
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
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.
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
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.brainres.2012.10.029" target="_blank" rel="noreferrer noopener">10.1016/j.brainres.2012.10.029</a>
Differential Effect Of Nimodipine In Attenuating Iron-induced Toxicity In Brain- And Blood-brain Barrier-associated Cell Types
Astrocytes; Biochemistry & Molecular Biology; central-nervous-system; cerebrospinal-fluid; cultured astrocytes; intracerebral hemorrhage; Iron in brain; Metal toxicity; Neurodegenerative diseases; neurodegenerative disorders; neurons; Neurosciences & Neurology; Nimodipine; oxidative; parkinsons-disease; redox-active iron; stress; substantia-nigra; transferrin receptor; 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 < 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 > 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.
Lockman J A; Geldenhuys W J; Bohn K A; DeSilva S F; Allen D D; Van der Schyf C J
Neurochemical Research
2012
2012-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1007/s11064-011-0591-2" target="_blank" rel="noreferrer noopener">10.1007/s11064-011-0591-2</a>
Voltage-gated Calcium Channels Provide An Alternate Route For Iron Uptake In Neuronal Cell Cultures
alzheimer-disease; alzheimers-disease; Biochemistry & Molecular Biology; fpl-64176; iron-overload toxicity; metabolism; mouse-brain; nerve growth-factor; neuroblastoma-cells; neurodegeneration; Neurosciences & Neurology; nimodipine; parkinsons-disease; parkinsons-disease; redox-active iron; substantia nigra; transferrin receptor; voltage-gated calcium channels
Gaasch J A; Geldenhuys W J; Lockman P R; Allen D D; Van der Schyf C J
Neurochemical Research
2007
2007-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1007/s11064-007-9313-1" target="_blank" rel="noreferrer noopener">10.1007/s11064-007-9313-1</a>