title: NGP1-01, a multi-targeted polycyclic cage amine, attenuates brain endothelial cell death in iron overload conditions.
abstract: 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 10μM) 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.
authors.affiliation: Department of Life, Earth, and Environmental Sciences, 2403 Russell Long Blvd., West Texas A&M University, 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: M R
authors.initials: MR
authors.lastname: Jones-Higgins
authors.forename: J D
authors.initials: JD
authors.lastname: Patrick
authors.forename: D D
authors.initials: DD
authors.lastname: Allen
authors.forename: C J
authors.initials: CJ
authors.lastname: Van der Schyf
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D029681:Arabidopsis Proteins / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019190:Iron Overload / Q000188:drug therapy* / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D000588:Amines; D029681:Arabidopsis Proteins; D001952:Bridged-Ring Compounds; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins; C507154:NIMIN1 protein, Arabidopsis; D018696:Neuroprotective Agents; D011758:Pyrroles; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; C071658:FPL 64176; C049649:NGP 1-01