Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reversal of the Na(+)/Ca(2+) exchanger (NCX) occurs during ischemia-reperfusion injury as a result of changes in intracellular pH and sodium concentration. Inhibition of NCXs has been shown to be neuroprotective in vitro. In this study, we evaluated the effects of KB-R7943 (50 microM), a specific inhibitor of the reverse mode of NCX, applied topically onto rat cerebral cortex prior to and during ischemia. Amino acid and free fatty acid levels in cortical superfusates, withdrawn at 10-min intervals from bilateral cortical windows, were analyzed by high-performance liquid chromatography. During a 20-min period of ischemia in control animals, there were significant increases in all amino acids and in all FFAs. Following reperfusion, all FFAs remained significantly elevated. Application of KB-R7943 (50 microM) significantly inhibited effluxes of phosphoethanolamine, but had no effect on glutamate, aspartate, taurine or GABA levels. KB-R7943 also resulted in significant reductions in levels of myristic, docosahexaenoic and arachidonic acid during ischemia and in reperfusion levels of arachidonic and docosahexaenoic acids. These data indicate that inhibition of Na(+)/Ca(2+) exchange likely prevented the activation of phospholipases that usually occurs following an ischemic insult as evidenced by its attenuation of phosphoethanolamine and free fatty acid efflux. The inhibition of phospholipases may be an essential component of the neuroprotective benefits of Na(+)/Ca(2+) exchange inhibitors in ischemia-reperfusion injury and may provide a basis for their possible use in therapeutic strategies for stroke.
 ...
PMID:Inhibition of Na(+)/Ca(2+) exchange by KB-R7943, a novel selective antagonist, attenuates phosphoethanolamine and free fatty acid efflux in rat cerebral cortex during ischemia-reperfusion injury. 1159 6

Excessive activation of neuronal glutamate receptors has been implicated in the pathophysiology of stroke, epilepsy, and traumatic brain injury. Previously, it has been demonstrated that excitotoxic glutamate exposure results in the induction of an extended neuronal depolarization (END), as well as protracted elevations in free intracellular calcium ([Ca(2+)](i)). Both END and the prolonged [Ca(2+)](i) elevations were shown to correlate with subsequent neuronal death. In the current study, we used whole-cell current-clamp electrophysiology and fura-ff Ca(2+) imaging to determine the electrophysiological basis of END. We found that removal of extracellular Ca(2+) but not Na(+) in the post-glutamate period resulted in complete reversal of END, allowing neurons to rapidly repolarize to their initial resting membrane potential (RMP). In addition, removal of extracellular Ca(2+) was sufficient to eliminate the protracted [Ca(2+)](i) elevations induced by excitotoxic glutamate exposure. To investigate the mechanism through which extracellular Ca(2+) was effecting these changes, pharmacological antagonists of well-characterized routes of Ca(2+) entry were tested for their effects on END. Antagonists of glutamate receptors and voltage-gated Ca(2+) channels (VGCCs) had no significant effect on the membrane potential of neurons in END. Likewise, inhibitors of the Na(+)/Ca(2+) exchange (NCX) were ineffective. In contrast, addition of 500 microM ZnCl(2) or 100 microM GdCl(3) to control extracellular medium (containing normal levels of extracellular Ca(2+)) in the post-glutamate period resulted in rapid and complete reversal of END. Addition of 1mM CdCl(2) to control medium had only modest effects on END. These data provide the first direct evidence that END induced by excitotoxic glutamate exposure is caused by an influx of extracellular Ca(2+) and demonstrate that the previously irreversible condition of END can be reversed by removing extracellular Ca(2+). In addition, understanding the electrophysiological basis of this novel Ca(2+)-induced extended depolarization may provide an insight into the pathophysiology of stroke, traumatic brain injury, and other forms of neuronal injury.
 ...
PMID:Calcium influx constitutes the ionic basis for the maintenance of glutamate-induced extended neuronal depolarization associated with hippocampal neuronal death. 1253 Nov 83

Aspirin is increasingly being used for long-term prophylaxis of myocardial infarction and stroke, but its use is limited by toxicity in the gastrointestinal tract. Even very low doses of aspirin can markedly increase the risk of gastrointestinal bleeding and ulceration. While proven effective in prophylaxis of stroke and myocardial infarction, the efficacy of aspirin is limited. Addition of a nitric oxide-releasing moiety to several non-steroidal anti-inflammatory drugs results in a profound reduction in their toxicity in the gastrointestinal tract and kidney. A similar derivatization of aspirin has recently been shown to result in a more potent, gastrointestinal-sparing antithrombotic drug. Two such compounds (NCX-4215 and NCX-4016; NicOx SA) have undergone detailed evaluation thus far. In each case, the NO-aspirin has shown improved anti-aggregatory activity while not inducing detectable gastric damage. The compounds have also been shown to exert protective effects in the gastrointestinal tract exposed to other injurious agents. The NO-aspirin derivatives significantly inhibit leukocyte adherence to the vascular endothelium, which may contribute to their anti-thrombotic activity. NO-releasing derivatives of aspirin and naproxen also exhibit beneficial effects in experimental hypertension, which would also contribute to improved anti-thrombotic activity. NO-releasing derivatives of NSAIDs offer great potential as gastrointestinal-sparing anti-thrombotic drugs.
 ...
PMID:Nitric oxide-releasing NSAIDs: GI-safe antithrombotics. 1615 51

Hypertension is the most common chronic disease and is the leading risk factor for death caused by stroke, myocardial infarction, and end-stage renal failure. The critical importance of excess salt intake in the pathogenesis of hypertension is widely recognized. However, the molecular mechanisms underlying salt-sensitive hypertension remain obscure. Recent studies using selective Na(+)/Ca(2+) exchanger (NCX) inhibitors and genetically engineered mice provide compelling evidence that salt-sensitive hypertension is triggered by Ca(2+) entry through NCX type 1 (NCX1) in arterial smooth muscle. Cardiotonic steroids, such as endogenous ouabain, which may contribute to the pathogenesis of salt-sensitive hypertension, seem to be necessary for NCX1-mediated hypertension. These findings have enabled us to explain how high salt intake leads to hypertension and further to describe the potential of vascular NCX1 as a new therapeutic or diagnostic target for salt-sensitive hypertension.
 ...
PMID:Salt-sensitive hypertension, Na+/Ca2+ exchanger, and vascular smooth muscle. 1629 63

Cardiac fibrillation, a form of cardiac arrhythmia, is the most common cause of embolic stroke and death associated with heart failure. The molecular mechanisms underlying cardiac fibrillation are largely unknown. Here we report a zebrafish model for cardiac fibrillation. The hearts of zebrafish tremblor (tre) mutants exhibit chaotic movements and fail to develop synchronized contractions. Calcium imaging showed that normal calcium transients are absent in tre cardiomyocytes, and molecular cloning of the tre mutation revealed that the tre locus encodes the zebrafish cardiac-specific sodium-calcium exchanger (NCX) 1, NCX1h. Forced expression of NCX1h or other calcium-handling molecules restored synchronized heartbeats in tre mutant embryos in a dosage-dependent manner, demonstrating the critical role of calcium homeostasis in maintaining embryonic cardiac function. By creating mosaic zebrafish embryos, we showed that sporadic NCX1h-null cells were not sufficient to disrupt normal cardiac function, but clustered wild-type cardiomyocytes contract in unison in tre mutant hearts. These data signify the essential role of calcium homeostasis and NCX1h in establishing rhythmic contraction in the embryonic zebrafish heart.
 ...
PMID:Mutation in sodium-calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish. 1631 83

Although Ca(2+) signals are necessary for cell communication and survival, abnormal cellular Ca(2+) load can trigger different cell death programs. Ca(2+) mediates cell death by activating proteases (ie, calpains), by reinforcing signals leading to caspase activation or by triggering other catabolic processes mediated by lipases and nucleases. Failure in the clearance of excitatory amino acid is a critical determinant of neuronal loss in the ischemic brain. Glutamate activates glutamate-ionotropic receptors at synaptic and extra-synaptic sites, causing prolonged neuronal depolarization and triggering deregulation of cellular ion homeostasis, mainly intracellular calcium and sodium. The mechanisms leading to the sustained calcium deregulation in excitotoxic conditions are only in part elucidated. Recently, we have shown that calpains mediate the inhibition of calcium efflux in primary dissociated neurons challenged with excitotoxic glutamate concentrations. Calpains cleave the sodium-calcium exchanger (NCX) and inhibit its capability to remove calcium accumulated as a consequence of the excitotoxic stimulus. Our findings highlight the link between calcium-dependent proteases, calcium overload and neuronal degeneration after an excitotoxic insult.
Stroke 2007 Feb
PMID:Ca2+ signals and neuronal death in brain ischemia. 1726 13

The Na(+)/Ca(2+) exchanger (NCX) is a bi-directional membrane ion transporter. Under normal conditions, the exchanger transports one calcium ion out of the cell and three sodium ions into the cell. This is known as the calcium exit, or "forward" mode. Under certain conditions, however, the exchanger can reverse and transport calcium ions into the cell (calcium entry mode). Because dysregulation of sodium and calcium homeostasis is an integral feature of ischaemic brain injury, the role of the NCX in neurons following ischaemia has been investigated using a number of in vitro and in vivo models. Studies using in vitro ischaemia-related models (hypoxia, glutamate) have produced conflicting results, with some showing that NCX activity is neuroprotective while others indicate that it is neurodamaging. The majority of in vivo studies using the focal cerebral ischaemia model indicate that blocking NCX activity is neurodamaging while increasing NCX activity is neuroprotective. We have reviewed the major in vitro and in vivo neuronal ischaemia-related NCX studies in an attempt to clarify the reason for the conflicting findings. The use of different ischaemia models and doubts as to the specificity of pharmacological NCX inhibitors and stimulators has contributed to the confusion over the role of the NCX in ischaemic brain injury. The development of NCX transgenic animals may help our understanding of the role of this ion exchanger in neurons following ischaemia and aid the development of an effective stroke treatment.
 ...
PMID:The role of the Na(+)/Ca(2+) exchanger (NCX) in neurons following ischaemia. 1743 Jul 74

Within the first 2 min of global brain ischemia, extracellular [K+] ([K+]o) increases above 60 mM and [Na+](o) drops to about 50 mM, indicating a massive K+ efflux and Na+ influx, a phenomenon known as anoxic depolarization (AD). Similar ionic shifts take place during repetitive peri-infarct depolarizations (PID) in the area penumbra in focal brain ischemia. The size of ischemic infarct is determined by the duration of AD and PID. However, the mechanism of cytosolic [Ca2+] ([Ca2+]c) elevation during AD or PID is poorly understood. Our data show that the exposure of cultured rat hippocampal CA1 neurons to AD-like conditions promptly elevates [Ca2+]c to about 30 microM. These high [Ca2+]c elevations depend on external Ca2+ and can be prevented by removing Na+ or by simultaneously inhibiting NMDA and AMPA/kainate receptors. These data indicate that [Ca2+]c elevations during AD result from Na+ influx via either NMDA or AMPA/kainate channels. The mechanism of the Na-dependent [Ca2+]c elevations may involve a reversal of plasmalemmal Na+/Ca2+ (NCX) and/or Na+/Ca2+ + K+ (NCKX) exchangers. KB-R7943, an NCX inhibitor, suppresses a fraction of the Na-dependent Ca2+ influx during AD. Therefore, Ca2+ influx via NCX and a KB-R7943-resistant pathway (possibly NCKX) is involved. Inhibition of the Na-dependent Ca2+ influx is likely to decrease ischemic brain damage. No drugs are known that are able to inhibit the KB-R7943-resistant component of Na-dependent Ca2+ influx during AD. The present data encourage development of such agents as potential therapeutic means to limit ischemic brain damage after stroke or heart attack.
 ...
PMID:NCX and NCKX operation in ischemic neurons. 1744 79

Sodium ion transporters in sarcolemma are involved in numerous vital cell functions, such as excitability, excitation-contraction coupling, energy metabolism, pH and volume regulation, development and growth. In a number of cardiac pathologies, the intracellular sodium concentration ([Na+]i) is elevated. Since [Na+]i and intracellular Ca2+ concentration ([Ca2+]i are coupled through the Na+/Ca(2+)-exchanger, these cardiac pathologies display disturbed calcium handling. For instance, [Na+]i is increased in heart failure (HF) leading to Na+/Ca(2+)-exchanger mediated increase in [Ca2+]i, reduced contractility and increased propensity to arrhythmias. Several studies support the contention that an increase in [Na+]i and [Ca2+]i transduces a signal the nucleus, that triggers development of cardiac remodelling and hypertrophy. Pharmacological intervention, which favourably interferes with [Na+]i and [Ca2+]i homeostasis, might prevent hypertrophy, cardiac remodelling, arrhythmias and HF. The most important sodium transport mechanisms that may underlie increased [Na+]i are: Na+/H(+)-exchanger (NHE-1), Na+-HCO(3)(-) co-transporter (NBC), Na(+)-K(+)-Cl(-) co-transporter (NKCC), Na(+)-channel, Na+/K(+)-ATPase and Na+/Ca(2+)-exchanger (NCX). Preclinical studies showed that pharmacological interventions, targeted against sarcolemmal sodium ion transporters, proved effective in ameliorating heart failure. In this respect: 1) NHE-1 inhibition reduces cardiac remodelling, hypertrophy and HF, although, in the patients following coronary artery bypass graft surgery, it was associated with an increase of stroke. 2) The activity of NBC is up-regulated, during the development of hypertrophy and may be a therapeutic strategy to prevent the development of hypertrophy and HF. 3) NKCC is increased in post-infarction HF, and the inhibition of NKCC attenuated post-infarction remodelling. 4) Inactivation of sodium channels is impaired in HF, which may result, in increased Na+ influx and prolongation of the action potential. 5) Blockade of NCX may be useful as a part of a combined therapeutic approach. Inhibition of reversed mode, or activation of forward mode NCX reduce Ca2+ overload. 6) Inhibition of Na+/K(+)-ATPase (digoxin), is used to increase contractility, however, it enhances progression of HF. Oppositely, new drugs which increase activity of Na+/K(+)-ATPase may prevent the development of cardiac remodelling hypertrophy and HF.
 ...
PMID:Sodium ion transporters as new therapeutic targets in heart failure. 1885 35

Delayed calcium deregulation (DCD) plays an essential role in glutamate excitotoxicity, a major detrimental factor in stroke, traumatic brain injury, and various neurodegenerations. In the present study, we examined the role of calpain activation and Na(+)/Ca(2+) exchanger (NCX) degradation in DCD and excitotoxic cell death in cultured hippocampal neurons. Exposure of neurons to glutamate caused DCD accompanied by secondary mitochondrial depolarization. Activation of calpain was evidenced by detecting NCX isoform 3 (NCX3) degradation products. Degradation of NCX isoform 1 (NCX1) was below the detection limit of Western blotting. Degradation of NCX3 was detected only after 1 hr of incubation with glutamate, whereas DCD occurred on average within 15 min after glutamate application. Calpeptin, an inhibitor of calpain, significantly attenuated NCX3 degradation but failed to inhibit DCD and excitotoxic neuronal death. Calpain inhibitors I, III, and VI also failed to influence DCD and glutamate-induced neuronal death. On the other hand, MK801, an inhibitor of the NMDA subtype of glutamate receptors, added shortly after the initial glutamate-induced jump in cytosolic Ca(2+), completely prevented DCD and activation of calpain and strongly protected neurons against excitotoxicity. Taken together, our results suggest that, in glutamate-treated hippocampal neurons, the initial increase in cytosolic Ca(2+) that precedes DCD is insufficient for sustained calpain activation, which most likely occurs downstream of DCD.
 ...
PMID:Calpain activation and Na+/Ca2+ exchanger degradation occur downstream of calcium deregulation in hippocampal neurons exposed to excitotoxic glutamate. 1993 13


1 2 3 Next >>