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

Center for Neuropharmacology and Neuroscience, Albany Medical College, 47 New Scotland Avenue (MC-136), Albany, NY 12208, USA.
Pathophysiology 01/2008; 14(3-4):183-93. DOI: 10.1016/j.pathophys.2007.09.009
Source: PubMed


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. 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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Available from: Alexander A Mongin, Oct 13, 2014
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    • "To test this hypothesis we examined the direct effects of both compounds on glutamate release in primary astrocyte cultures. The focus on glia is based on the prevailing idea that glial cells represent a major source of excitatory amino acid release in stroke [7] [59] [60]. In cerebral ischemia, glia, primarily astrocytes, may release glutamate via several transport pathways: (i) reversal of the glia-specific glutamate transporter GLT-1; (ii) activation of glutamate-permeable VRAC channels; (iii) opening of connexin hemichannels, which in astrocytes are constituted by Cx43; and (iv) enhanced activity of xCT [61] [62] [63] [64]. "
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    ABSTRACT: The contribution of oxidative stress to ischemic brain damage is well established. Nevertheless, for unknown reasons, several clinically tested antioxidant therapies failed to show benefits in human stroke. Based on our previous in vitro work, we hypothesized that the neuroprotective potency of antioxidants is related to their ability to limit release of the excitotoxic amino acids, glutamate and aspartate. We explored the effects of two antioxidants, tempol and edaravone, on amino acid release in the brain cortex, in a rat model of transient occlusion of the middle cerebral artery (MCAo). Amino acid levels were quantified using a microdialysis approach, with the probe positioned in the ischemic penumbra as verified by a laser Doppler technique. Two-hour MCAo triggered a dramatic increase in the levels of glutamate, aspartate, taurine and alanine. Microdialysate delivery of 10mM tempol reduced the amino acid release by 60-80%, while matching levels of edaravone had no effect. In line with these latter data, an intracerebroventricular injection of tempol but not edaravone (500 nmols each, 15 minutes prior to MCAo) reduced infarction volumes by ~50% and improved neurobehavioral outcomes. In vitro assays showed that tempol was superior in removing superoxide anion, whereas edaravone was more potent in scavenging hydrogen peroxide, hydroxyl radical, and peroxynitrite. Overall, our data suggests that the neuroprotective properties of tempol are likely related to its ability to reduce tissue levels of the superoxide anion and pathological glutamate release, and, in such a way, limit progression of brain infarction within ischemic penumbra. These new findings may be instrumental in developing new antioxidant therapies for treatment of stroke.
    Free Radical Biology and Medicine 09/2014; 77. DOI:10.1016/j.freeradbiomed.2014.08.029 · 5.74 Impact Factor
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    • "The disruption of ionic and excitatory amino acid (EAA) homeostasis that occurs during cerebral ischemia results in enhanced glutamate/K+ uptake by astrocytic transporters, leading to marked volume changes in astrocytes during ischemia [1]. In order to determine whether these transporters underlie the differences in volume changes between HR-/LR-astrocytes, we tested the effect of DL-TBOA, an inhibitor of the excitatory amino acid transporters EAAT1 and EAAT2, bumetanide, an inhibitor of Na+-K+-Cl− co-transporters (NKCCs), and DIOA, an inhibitor of K+-Cl− co-transporters (KCCs), on the astrocyte swelling evoked by OGD (for concentrations see Table 1). "
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    ABSTRACT: Recently, we have identified two astrocytic subpopulations in the cortex of GFAP-EGFP mice, in which the astrocytes are visualized by the enhanced green-fluorescent protein (EGFP) under the control of the human glial fibrillary acidic protein (GFAP) promotor. These astrocytic subpopulations, termed high response- (HR-) and low response- (LR-) astrocytes, differed in the extent of their swelling during oxygen-glucose deprivation (OGD). In the present study we focused on identifying the ion channels or transporters that might underlie the different capabilities of these two astrocytic subpopulations to regulate their volume during OGD. Using three-dimensional confocal morphometry, which enables quantification of the total astrocytic volume, the effects of selected inhibitors of K⁺ and Cl⁻ channels/transporters or glutamate transporters on astrocyte volume changes were determined during 20 minute-OGD in situ. The inhibition of volume regulated anion channels (VRACs) and two-pore domain potassium channels (K(2P)) highlighted their distinct contributions to volume regulation in HR-/LR-astrocytes. While the inhibition of VRACs or K(2P) channels revealed their contribution to the swelling of HR-astrocytes, in LR-astrocytes they were both involved in anion/K⁺ effluxes. Additionally, the inhibition of Na⁺-K⁺-Cl⁻ co-transporters in HR-astrocytes led to a reduction of cell swelling, but it had no effect on LR-astrocyte volume. Moreover, employing real-time single-cell quantitative polymerase chain reaction (PCR), we characterized the expression profiles of EGFP-positive astrocytes with a focus on those ion channels and transporters participating in astrocyte swelling and volume regulation. The PCR data revealed the existence of two astrocytic subpopulations markedly differing in their gene expression levels for inwardly rectifying K⁺ channels (Kir4.1), K(2P) channels (TREK-1 and TWIK-1) and Cl⁻ channels (ClC2). Thus, we propose that the diverse volume changes displayed by cortical astrocytes during OGD mainly result from their distinct expression patterns of ClC2 and K(2P) channels.
    PLoS ONE 01/2012; 7(1):e29725. DOI:10.1371/journal.pone.0029725 · 3.23 Impact Factor
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    • "Within the cell, glutamate supports several metabolic cascades, including energy production and antioxidant (glutathione) functions . The brain damage that results from ischemia is mediated to an important degree by excessive glutamate release from neurons and glial cells (see review by Mongin, 2007), resulting in excessive depolarization and accumulation of cytoplasmic Ca 2+ . In addition to glutamate and calcium toxicity, other factors contributing to neuronal damage and death in ischemia include free radical and nitric oxide accumulations and dysfunction of mitochondria and endoplasmic reticulum (Guo et al., 2009). "
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    ABSTRACT: The pathophysiology of brain damage that is common to ischemia-reperfusion injury and brain trauma include disodered neuronal and glial cell energetics, intracellular acidosis, calcium toxicity, extracellular excitotoxic glutamate accumulation, and dysfunction of the cytoskeleton and endoplasmic reticulum. The principal thyroid hormones, 3,5,3'-triiodo-l-thyronine (T(3)) and l-thyroxine (T(4)), have non-genomic and genomic actions that are relevant to repair of certain features of the pathophysiology of brain damage. The hormone can non-genomically repair intracellular H(+) accumulation by stimulation of the Na(+)/H(+) exchanger and can support desirably low [Ca(2+)](i.c.) by activation of plasma membrane Ca(2+)-ATPase. Thyroid hormone non-genomically stimulates astrocyte glutamate uptake, an action that protects both glial cells and neurons. The hormone supports the integrity of the microfilament cytoskeleton by its effect on actin. Several proteins linked to thyroid hormone action are also neuroprotective. For example, the hormone stimulates expression of the seladin-1 gene whose gene product is anti-apoptotic and is potentially protective in the setting of neurodegeneration. Transthyretin (TTR) is a serum transport protein for T(4) that is important to blood-brain barrier transfer of the hormone and TTR also has been found to be neuroprotective in the setting of ischemia. Finally, the interesting thyronamine derivatives of T(4) have been shown to protect against ischemic brain damage through their ability to induce hypothermia in the intact organism. Thus, thyroid hormone or hormone derivatives have experimental promise as neuroprotective agents.
    Frontiers in Molecular Neuroscience 10/2011; 4:29. DOI:10.3389/fnmol.2011.00029 · 4.08 Impact Factor
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