The Cellular Mechanisms of Neuronal Swelling Underlying Cytotoxic Edema

Rungta, Ravi L.; Choi, Hyun B.; Tyson, John R.; Malik, Aqsa; Dissing-Olesen, Lasse; Lin, Paulo J.C.; Cain, Stuart M.; Cullis, Pieter R.; Snutch, Terrance P.; MacVicar, Brian A.

doi:10.1016/j.cell.2015.03.029

Cited by 206 publications

(243 citation statements)

References 65 publications

(64 reference statements)

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“…Cellular swelling occurs after cerebral trauma, stroke, spreading depression and epilepsy (Rungta et al, 2015; Stokum et al, 2016). There is a pressing need for pharmacological interventions that limit swelling and prevent the damage resulting from cells being damaged while expanding into the closed volume of the cranium.…”

Section: Discussionmentioning

confidence: 99%

How Cells Can Control Their Size by Pumping Ions

Kay

2017

Front. Cell Dev. Biol.

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The ability of all cells to set and regulate their size is a fundamental aspect of cellular physiology. It has been known for sometime but not widely so, that size stability in animal cells is dependent upon the operation of the sodium pump, through the so-called pump-leak mechanism (Tosteson and Hoffman, 1960). Impermeant molecules in cells establish an unstable osmotic condition, the Donnan effect, which is counteracted by the operation of the sodium pump, creating an asymmetry in the distribution of Na+ and K+ staving off water inundation. In this paper, which is in part a tutorial, I show how to model quantitatively the ion and water fluxes in a cell that determine the cell volume and membrane potential. The movement of water and ions is constrained by both osmotic and charge balance, and is driven by ion and voltage gradients and active ion transport. Transforming these constraints and forces into a set of coupled differential equations allows us to model how the ion distributions, volume and voltage change with time. I introduce an analytical solution to these equations that clarifies the influence of ion conductances, pump rates and water permeability in this multidimensional system. I show that the number of impermeant ions (x) and their average charge have a powerful influence on the distribution of ions and voltage in a cell. Moreover, I demonstrate that in a cell where the operation of active ion transport eliminates an osmotic gradient, the size of the cell is directly proportional to x. In addition, I use graphics to reveal how the physico-chemical constraints and chemical forces interact with one another in apportioning ions inside the cell. The form of model used here is applicable to all membrane systems, including mitochondria and bacteria, and I show how pumps other than the sodium pump can be used to stabilize cells. Cell biologists may think of electrophysiology as the exclusive domain of neuroscience, however the electrical effects of ion fluxes need to become an intimate part of cell biology if we are to understand a fundamental process like cell size regulation.

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Section: Discussionmentioning

confidence: 99%

How Cells Can Control Their Size by Pumping Ions

Kay

2017

Front. Cell Dev. Biol.

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“…1) leads to energy-dependent ion channel failure and intracellular sodium and water retention. Rungta et al established that the Na + Cl − receptor SLC26A11 is a critical modulator of intracellular transport of chloride and subsequent cerebral edema after ischemia [46]. The authors showed that blockade of this receptor attenuated cytotoxic cerebral edema [46] after HIBI.…”

Section: Secondary Injurymentioning

confidence: 99%

“…Rungta et al established that the Na + Cl − receptor SLC26A11 is a critical modulator of intracellular transport of chloride and subsequent cerebral edema after ischemia [46]. The authors showed that blockade of this receptor attenuated cytotoxic cerebral edema [46] after HIBI. The role of Na + Cl − receptor antagonism after HIBI is yet to be clarified but represents a future therapeutic target.…”

Section: Secondary Injurymentioning

confidence: 99%

Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two-hit” model

2017

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Hypoxic ischemic brain injury (HIBI) after cardiac arrest (CA) is a leading cause of mortality and long-term neurologic disability in survivors. The pathophysiology of HIBI encompasses a heterogeneous cascade that culminates in secondary brain injury and neuronal cell death. This begins with primary injury to the brain caused by the immediate cessation of cerebral blood flow following CA. Thereafter, the secondary injury of HIBI takes place in the hours and days following the initial CA and reperfusion. Among factors that may be implicated in this secondary injury include reperfusion injury, microcirculatory dysfunction, impaired cerebral autoregulation, hypoxemia, hyperoxia, hyperthermia, fluctuations in arterial carbon dioxide, and concomitant anemia.Clarifying the underlying pathophysiology of HIBI is imperative and has been the focus of considerable research to identify therapeutic targets. Most notably, targeted temperature management has been studied rigorously in preventing secondary injury after HIBI and is associated with improved outcome compared with hyperthermia. Recent advances point to important roles of anemia, carbon dioxide perturbations, hypoxemia, hyperoxia, and cerebral edema as contributing to secondary injury after HIBI and adverse outcomes. Furthermore, breakthroughs in the individualization of perfusion targets for patients with HIBI using cerebral autoregulation monitoring represent an attractive area of future work with therapeutic implications.We provide an in-depth review of the pathophysiology of HIBI to critically evaluate current approaches for the early treatment of HIBI secondary to CA. Potential therapeutic targets and future research directions are summarized.

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“…Such reduction in size happened in the ONC/SHAM group and is a hallmark of RGC degeneration 18 . In contrast, with our repeated in vivo imaging we were able to demonstrate that the surviving neurons were slightly but significantly increased in size (17%) after ONC/rtACS compared to baseline, but this moderate swelling was clearly smaller than the characteristic swelling of an acute toxic oedema 55, 56 . Therefore we suggest that this moderate swelling is a sign of long-term survival or neuronal plasticity 51, 57 and not an indicator of future cell death.…”

Section: Discussionmentioning

confidence: 59%

Electrical brain stimulation induces dendritic stripping but improves survival of silent neurons after optic nerve damage

Henrich‐Noack

Sergeeva

Eber

et al. 2017

Sci Rep

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Repetitive transorbital alternating current stimulation (rtACS) improves vision in patients with chronic visual impairments and an acute treatment increased survival of retinal neurons after optic nerve crush (ONC) in rodent models of visual system injury. However, despite this protection no functional recovery could be detected in rats, which was interpreted as evidence of “silent survivor” cells. We now analysed the mechanisms underlying this “silent survival” effect. Using in vivo microscopy of the retina we investigated the survival and morphology of fluorescent neurons before and after ONC in animals receiving rtACS or sham treatment. One week after the crush, more neurons survived in the rtACS-treated group compared to sham-treated controls. In vivo imaging further revealed that in the initial post-ONC period, rtACS induced dendritic pruning in surviving neurons. In contrast, dendrites in untreated retinae degenerated slowly after the axonal trauma and neurons died. The complete loss of visual evoked potentials supports the hypothesis that cell signalling is abolished in the surviving neurons. Despite this evidence of “silencing”, intracellular free calcium imaging showed that the cells were still viable. We propose that early after trauma, complete dendritic stripping following rtACS protects neurons from excitotoxic cell death by silencing them.

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The Cellular Mechanisms of Neuronal Swelling Underlying Cytotoxic Edema

Cited by 206 publications

References 65 publications

How Cells Can Control Their Size by Pumping Ions

How Cells Can Control Their Size by Pumping Ions

Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two-hit” model

Electrical brain stimulation induces dendritic stripping but improves survival of silent neurons after optic nerve damage

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