The novel Na+/Ca2+ exchange inhibitor KB-R7943 protects CA1 neurons in rat hippocampal slices against hypoxic/hypoglycemic injury

Schröder, Ulrich H.; Breder, Jörg; Sabelhaus, Clemens F; Reymann, Klaus G.

doi:10.1016/s0028-3908(98)00198-1

Cited by 77 publications

(56 citation statements)

References 7 publications

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“…We suggest that the somatic elevation of [Na ϩ ] i, which we observed by SBFI fluorescence, and the concomitant cellular depolarization reverse the driving force of the Na ϩ /Ca 2ϩ exchanger and contribute to degeneration. In line with this explanation, our laboratory and others have already shown that the inhibition of the exchanger generates neuroprotection in vivo and in vitro (Breder et al, 2000;Matsuda et al, 2001;Schroder et al, 1999;Stys, 1996).…”

Section: Discussion Energy Deficiency and Loss Of Intracellular Ion Hmentioning

confidence: 59%

“…This electrogenic exchanger can, however, reverse its mode of operation under certain pathological conditions and aggravate ischemic intracellular Ca 2ϩ accumulation (Blaustein and Lederer, 1999). Blockade of this ionic pathway has clear neuroprotective effects in different models of ischemia (Breder et al, 2000;Matsuda et al, 2001;Schroder et al, 1999). This complex scenario is further complicated by the contribution of intracellular stores to the cytosolic Ca 2ϩ elevation.…”

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confidence: 99%

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Na+ and Ca2+ homeostasis pathways, cell death and protection after oxygen–glucose-deprivation in organotypic hippocampal slice cultures

et al. 2004

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elevation during OGD was due to Na ؉ influx through voltagedependent Na ؉ channels. In hippocampal slices, cellular degeneration occurring 24 h after OGD, selectively affected the pyramidal cell population through apoptotic and non-apoptotic cell death. OGD-induced cell loss was mediated by activation of ionotropic glutamate receptors, voltage-dependent Na ؉ channels, and both plasma membrane and mitochondrial Na ؉ /Ca 2؉ exchangers. Thus, we show that neuroprotection induced by blockade of NMDA receptors and plasma membrane Na ؉ /Ca 2؉ exchangers is mediated by reduction of Ca 2؉ entry into neuronal soma, whereas neuroprotection induced by blockade of AMPA/kainate receptors and mitochondrial Na ؉ /Ca 2؉ exchangers might result from reduced Na ؉ entry at dendrites level.

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Section: Discussion Energy Deficiency and Loss Of Intracellular Ion Hmentioning

confidence: 59%

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confidence: 99%

Na+ and Ca2+ homeostasis pathways, cell death and protection after oxygen–glucose-deprivation in organotypic hippocampal slice cultures

et al. 2004

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“…High cytosolic Ca 2ϩ causes mitochondrial fragmentation, permeability transition, and degradation by mitophagy (for review, see Rodriguez-Enriquez et al, 2004). Drugs that selectively inhibit the reverse mode of the NCX (Ca 2ϩ influx) are neuroprotective in models of I/R injury in vitro and in vivo (Schröder et al, 1999;Matsuda et al, 2001;Iwamoto and Kita, 2006). We found that two structurally distinct inhibitors of the reverse-mode of the NCX, KB-R7943 (15 M) or YM-244769 (1 M), attenuated the loss of DAPI staining in stratum pyramidale (Fig.…”

Section: % Occupancymentioning

confidence: 99%

Transient Oxygen/Glucose Deprivation Causes a Delayed Loss of Mitochondria and Increases Spontaneous Calcium Signaling in Astrocytic Processes

O‘Donnell

Jackson

Robinson

2016

Journal of Neuroscience

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Recently, mitochondria have been localized to astrocytic processes where they shape Ca 2ϩ signaling; this relationship has not been examined in models of ischemia/reperfusion. We biolistically transfected astrocytes in rat hippocampal slice cultures to facilitate fluorescent confocal microscopy, and subjected these slices to transient oxygen/glucose deprivation (OGD) that causes delayed excitotoxic death of CA1 pyramidal neurons. This insult caused a delayed loss of mitochondria from astrocytic processes and increased colocalization of mitochondria with the autophagosome marker LC3B. The losses of neurons in area CA1 and mitochondria in astrocytic processes were blocked by ionotropic glutamate receptor ( (1) in the cytoplasm surrounding mitochondria (mitochondrially centered) and (2) traversing the space between mitochondria (extramitochondrial). The spatial spread, kinetics, and frequency of these events were different. The amplitude of both types was doubled and the spread of both types changed by ϳ2-fold 24 h after OGD. Together, these data suggest that pathologic activation of glutamate transport and increased astrocytic Ca 2ϩ through reversed Na ϩ /Ca 2ϩ exchange triggers mitochondrial loss and dramatic increases in Ca 2ϩ signaling in astrocytic processes.

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“…Several groups reported that NCX blockers rescue both neurons and glia from hypoxia/reoxygenation or glutamate-induced injury [112][113][114]. However, the others found increased cell death upon NCX inhibition [115,116].…”

Section: Pathological Roles For Na + /H + Exchange: Impact On [Na + ]mentioning

confidence: 99%

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Mongin

2007

Pathophysiology

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The mechanisms of brain tissue damage in stroke are strongly linked to the phenomenon of excitotoxicity, which is defined as damage or death of neural cells due to excessive activation of receptors for the excitatory neurotransmitters glutamate and aspartate. Under physiological conditions, ionotropic glutamate receptors mediate the processes of excitatory neurotransmission and synaptic plasticity. In ischemia, sustained pathological release of glutamate from neurons and glial cells causes prolonged activation of these receptors, resulting in massive depolarization and cytoplasmic Ca 2+ overload. The NMDA subtype of glutamate receptors is particularly important as it represents the main initial route for the Ca 2+ influx. High cytoplasmic levels of Ca 2+ activate many degradative processes that, depending on the metabolic status, cause immediate or delayed death of neural cells. This traditional view has been expanded by a number of observations that implicate Cl − channels and several types of non-channel transporter proteins, such as the Na + ,K + ,2Cl − cotransporter, Na + /H + exchanger, and Na + /Ca 2+ exchanger, in the development of glutamate toxicity. Some of these ion transporters increase tissue damage by promoting pathological cell swelling and necrotic cell death, while others contribute to a long term accumulation of cytoplasmic Ca 2+ . This brief review is aimed at illustrating how the dysregulation of various ion transport processes combine in a 'perfect storm' that disrupts neural ionic homeostasis and culminates in the irreversible damage and death of neural cells. The clinical relevance of individual transporters as targets for therapeutic intervention in stroke is also briefly discussed.

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The novel Na+/Ca2+ exchange inhibitor KB-R7943 protects CA1 neurons in rat hippocampal slices against hypoxic/hypoglycemic injury

Cited by 77 publications

References 7 publications

Na+ and Ca2+ homeostasis pathways, cell death and protection after oxygen–glucose-deprivation in organotypic hippocampal slice cultures

Na+ and Ca2+ homeostasis pathways, cell death and protection after oxygen–glucose-deprivation in organotypic hippocampal slice cultures

Transient Oxygen/Glucose Deprivation Causes a Delayed Loss of Mitochondria and Increases Spontaneous Calcium Signaling in Astrocytic Processes

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

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