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>
Metabolic And Transmitter Changes In Core And Penumbra After Middle Cerebral Artery Occlusion In Mice
acetylcholine; Choline; focal ischemia; Glucose; glutamate; glutamate; Glycerol; hippocampus; hippocampus; intracerebral microdialysis; Microdialysis; mutant mice; neurodegenerative disorders; Neurosciences & Neurology; rat; release; reperfusion; Striatum; stroke
Middle cerebral artery occlusion (MCAO) is a popular model in experimental stroke research and causes prominent ischemic damage in the forebrain. To characterize metabolic changes induced by MCAO, we have induced permanent MCAO in mice that were implanted with a microdialysis probe in either striatum or hippocampus. Immediately after the onset of ischemia, glucose levels dropped to <10% of basal values in the striatum while they dropped to 50%, and recovered thereafter, in hippocampus. Extracellular levels of glutamate rose 80-fold in the striatum but only 10-fold, and in a transient fashion, in hippocampus. In striatum, release of acetylcholine briefly increased, then dropped to very low values. Both glycerol and choline levels increased strongly during ischemia in the striatum reflecting membrane breakdown. In hippocampus, glycerol increased transiently while the increase of choline levels was moderate. Taken together, these observations delineate metabolic changes in ischemic mouse brain with the striatum representing the core area of ischemia. In comparison, the dorsal hippocampus was identified as a brain area suitable for monitoring metabolic responses in the penumbra region. (C) 2009 Elsevier B.V. All rights reserved.
Kiewert C; Mdzinarishvili A; Hartmann J; Bickel U; Klein J
Brain Research
2010
2010-02
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.brainres.2009.11.068" target="_blank" rel="noreferrer noopener">10.1016/j.brainres.2009.11.068</a>
MULTIMODAL DRUGS AND THEIR FUTURE FOR ALZHEIMER'S AND PARKINSON'S DISEASE
designed multiple ligands; gamma agonist; inflammatory response; ischemia-reperfusion injury; mitochondrial-membrane protein; monoamine-oxidase-b; multifunctional drugs; neurodegenerative disorders; pioglitazone; ppar-gamma; receptor antagonist
This chapter discusses the rationale for developing multimodal or multifunctional drugs (also called designed multiple ligands or DMLs) aimed at disease-modifying treatment strategies for the most common neurodegenerative diseases Alzheimer's and Parkinson's disease (AD and PD). Both the prevalence and incidence of AD and PD have seen consistent and dramatic increases, a disconcerting phenomenon which, ironically, has been attributed to extended life expectancy brought about by better health care globally. In spite of these statistics, the development and introduction to the clinic of new therapies proven to prevent or delay the onset of AD and PD have been disappointing. Evidence has accumulated to suggest that the etiopathology of these diseases is extremely complex, with an array of potential drug targets located within a number of deleterious biochemical pathways. Therefore, in these diseases, it is unlikely that the complex pathoetiological cascade leading to disease initiation or progression will be mitigated by any one drug acting on a single pathway or target. The pursuit of novel DMLs may offer far better outcomes. Although certainly not the only, and perhaps not even the best, approach but farthest along the drug development pipeline in the DML paradigm are drugs that combine inhibition of monoamine oxidase with associated etiological targets unique to either AD or PD. These compounds will constitute the major focus of this chapter, which will also explore radically new paradigms that seek to combine cognitive enhancers with proneurogenesis compounds.
Van der Schyf C J; Geldenhuys W J
Monoamine Oxidases and Their Inhibitors
2011
2011
Book Section
<a href="http://doi.org/10.1016/b978-0-12-386467-3.00006-6" target="_blank" rel="noreferrer noopener">10.1016/b978-0-12-386467-3.00006-6</a>