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1
Hoffmann, Ulrike, Inna Sukhotinsky, Katharina Eikermann-Haerter, and Cenk Ayata. "Glucose Modulation of Spreading Depression Susceptibility." Journal of Cerebral Blood Flow & Metabolism 33, no. 2 (September 12, 2012): 191–95. http://dx.doi.org/10.1038/jcbfm.2012.132.
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Spreading depression of Leão is an intense spreading depolarization (SD) wave associated with massive transmembrane ionic, water, and neurotransmitter shifts. Spreading depolarization underlies migraine aura, and occurs in brain injury, making it a potential therapeutic target. While susceptibility to SD can be modulated pharmacologically, much less is known about modulation by systemic physiological factors, such as the glycemic state. In this study, we systematically examined modulation of SD susceptibility by blood glucose in anesthetized rats under full physiological monitoring. Hyperglycemia and hypoglycemia were induced by insulin or dextrose infusion (blood glucose ~40 and 400 mg/dL, respectively). Spreading depolarizations were evoked by direct cortical electrical stimulation to determine the intensity threshold, or by continuous topical KCl application to determine SD frequency. Hyperglycemia elevated the electrical SD threshold and reduced the frequency of KCl-induced SDs, without significantly affecting other SD properties. In contrast, hypoglycemia significantly prolonged individual and cumulative SD durations, but did not alter the electrical SD threshold, or SD frequency, amplitude or propagation speed. These data show that increased cerebral glucose availability makes the tissue resistant to SD.
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Somjen, George G. "Mechanisms of Spreading Depression and Hypoxic Spreading Depression-Like Depolarization." Physiological Reviews 81, no. 3 (July 1, 2001): 1065–96. http://dx.doi.org/10.1152/physrev.2001.81.3.1065.
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Spreading depression (SD) and the related hypoxic SD-like depolarization (HSD) are characterized by rapid and nearly complete depolarization of a sizable population of brain cells with massive redistribution of ions between intracellular and extracellular compartments, that evolves as a regenerative, “all-or-none” type process, and propagates slowly as a wave in brain tissue. This article reviews the characteristics of SD and HSD and the main hypotheses that have been proposed to explain them. Both SD and HSD are composites of concurrent processes. Antagonists of N-methyl-d-aspartate (NMDA) channels or voltage-gated Na+ or certain types of Ca2+channels can postpone or mitigate SD or HSD, but it takes a combination of drugs blocking all known major inward currents to effectively prevent HSD. Recent computer simulation confirmed that SD can be produced by positive feedback achieved by increase of extracellular K+ concentration that activates persistent inward currents which then activate K+ channels and release more K+. Any slowly inactivating voltage and/or K+-dependent inward current could generate SD-like depolarization, but ordinarily, it is brought about by the cooperative action of the persistent Na+ current I Na,P plus NMDA receptor-controlled current. SD is ignited when the sum of persistent inward currents exceeds persistent outward currents so that total membrane current turns inward. The degree of depolarization is not determined by the number of channels available, but by the feedback that governs the SD process. Short bouts of SD and HSD are well tolerated, but prolonged depolarization results in lasting loss of neuron function. Irreversible damage can, however, be avoided if Ca2+ influx into neurons is prevented.
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Dreier, Jens P., Martin Fabricius, Cenk Ayata, Oliver W. Sakowitz, C. William Shuttleworth, Christian Dohmen, Rudolf Graf, et al. "Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group." Journal of Cerebral Blood Flow & Metabolism 37, no. 5 (July 20, 2016): 1595–625. http://dx.doi.org/10.1177/0271678x16654496.
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Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.
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Ayata, Cenk, and Martin Lauritzen. "Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature." Physiological Reviews 95, no. 3 (July 2015): 953–93. http://dx.doi.org/10.1152/physrev.00027.2014.
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Spreading depression (SD) is a transient wave of near-complete neuronal and glial depolarization associated with massive transmembrane ionic and water shifts. It is evolutionarily conserved in the central nervous systems of a wide variety of species from locust to human. The depolarization spreads slowly at a rate of only millimeters per minute by way of grey matter contiguity, irrespective of functional or vascular divisions, and lasts up to a minute in otherwise normal tissue. As such, SD is a radically different breed of electrophysiological activity compared with everyday neural activity, such as action potentials and synaptic transmission. Seventy years after its discovery by Leão, the mechanisms of SD and its profound metabolic and hemodynamic effects are still debated. What we did learn of consequence, however, is that SD plays a central role in the pathophysiology of a number of diseases including migraine, ischemic stroke, intracranial hemorrhage, and traumatic brain injury. An intriguing overlap among them is that they are all neurovascular disorders. Therefore, the interplay between neurons and vascular elements is critical for our understanding of the impact of this homeostatic breakdown in patients. The challenges of translating experimental data into human pathophysiology notwithstanding, this review provides a detailed account of bidirectional interactions between brain parenchyma and the cerebral vasculature during SD and puts this in the context of neurovascular diseases.
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Kager, H., W. J. Wadman, and G. G. Somjen. "Conditions for the Triggering of Spreading Depression Studied With Computer Simulations." Journal of Neurophysiology 88, no. 5 (November 1, 2002): 2700–2712. http://dx.doi.org/10.1152/jn.00237.2002.
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In spite of five decades of study, the biophysics of spreading depression (SD) is incompletely understood. Earlier we have modeled seizures and SD, and we have shown that currents through ion channels normally present in neuron membranes can generate SD-like depolarization. In the present study, we define the conditions for triggering SD and the parameters that influence its course in a model of a hippocampal pyramidal cell with more complete representation of ions and channels than the previous version. “Leak” conductances for Na+, K+, and Cl− and an ion pump were present in the membrane of the entire cell; fast inactivating voltage dependent conductances for sodium and potassium in the soma; “persistent” conductances in soma and apical dendrite, and K+- and voltage-dependent N-methyl-d-aspartate (NMDA)-controlled conductance in the apical dendrite. The neuron was surrounded by restricted interstitial space and by a “glia-endothelium” system of extracellular ion regulation bounded by a membrane having leak conductances and an ion pump. Ion fluxes and concentration changes were continuously computed as well as osmotic cell volume changes. As long as reuptake into the neuron and “buffering” by glia kept pace with K+ released from the neuron, stimulating current applied to the soma evoked repetitive firing that stopped when stimulation ceased. When glial uptake was reduced, K+ released from neurons could accumulate in the interstitium and keep the neuron depolarized so that strong depolarizing pulses injected into the soma were followed either by afterdischarge or SD. SD-like depolarization was ignited when depolarization spreading into the apical dendrite, activated persistent Na+ current and NMDA-controlled current. With membrane parameters constant, varying the injected stimulating current influenced SD onset but neither the depolarization nor the increase in extracellular K+. Glial “leak” conductance influenced SD duration and SD ignition point. Varying maximal conductances (representing channel density) also influenced SD onset time but not the amplitude of the depolarization. Hypoxia was simulated by turning off the Na-K exchange pump, and this resulted in SD-like depolarization. The results confirm that, once ignited, SD runs an all-or-none trajectory, the level of depolarization is governed by feedback involving ion shifts and glutamate acting on ion channels and not by the number of channels open, and SD is ignited if the net persistent membrane current in the apical dendrites turns inward.
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Spong, Kristin E., R. David Andrew, and R. Meldrum Robertson. "Mechanisms of spreading depolarization in vertebrate and insect central nervous systems." Journal of Neurophysiology 116, no. 3 (September 1, 2016): 1117–27. http://dx.doi.org/10.1152/jn.00352.2016.
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Spreading depolarization (SD) is generated in the central nervous systems of both vertebrates and invertebrates. SD manifests as a propagating wave of electrical depression caused by a massive redistribution of ions. Mammalian SD underlies a continuum of human pathologies from migraine to stroke damage, whereas insect SD is associated with environmental stress-induced neural shutdown. The general cellular mechanisms underlying SD seem to be evolutionarily conserved throughout the animal kingdom. In particular, SD in the central nervous system of Locusta migratoria and Drosophila melanogaster has all the hallmarks of mammalian SD. Locust SD is easily induced and monitored within the metathoracic ganglion (MTG) and can be modulated both pharmacologically and by preconditioning treatments. The finding that the fly brain supports repetitive waves of SD is relatively recent but noteworthy, since it provides a genetically tractable model system. Due to the human suffering caused by SD manifestations, elucidating control mechanisms that could ultimately attenuate brain susceptibility is essential. Here we review mechanisms of SD focusing on the similarities between mammalian and insect systems. Additionally we discuss advantages of using invertebrate model systems and propose insect SD as a valuable model for providing new insights to mammalian SD.
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Santos, Edgar, Renán Sánchez-Porras, Oliver W. Sakowitz, Jens P. Dreier, and Markus A. Dahlem. "Heterogeneous propagation of spreading depolarizations in the lissencephalic and gyrencephalic brain." Journal of Cerebral Blood Flow & Metabolism 37, no. 7 (January 25, 2017): 2639–43. http://dx.doi.org/10.1177/0271678x16689801.
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In the recently published article, “Heterogeneous incidence and propagation of spreading depolarizations,” it is shown, in vivo and in vitro, how KCl-induced spreading depolarizations in mouse and rat brains can be highly variable, and that they are not limited, as once thought, to a concentric, isotropic, or homogenous depolarization wave in space or in time. The reported results serve as a link between the different species, and this paper contributes to changing the way in which SD expansion is viewed in the lissencephalic brain. Here, we discuss their results with our previous observations made in the gyrencephalic swine brain, in computer simulations, and in the human brain.
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Robertson, R. Meldrum, Ken D. Dawson-Scully, and R. David Andrew. "Neural shutdown under stress: an evolutionary perspective on spreading depolarization." Journal of Neurophysiology 123, no. 3 (March 1, 2020): 885–95. http://dx.doi.org/10.1152/jn.00724.2019.
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Neural function depends on maintaining cellular membrane potentials as the basis for electrical signaling. Yet, in mammals and insects, neuronal and glial membrane potentials can reversibly depolarize to zero, shutting down neural function by the process of spreading depolarization (SD) that collapses the ion gradients across membranes. SD is not evident in all metazoan taxa with centralized nervous systems. We consider the occurrence and similarities of SD in different animals and suggest that it is an emergent property of nervous systems that have evolved to control complex behaviors requiring energetically expensive, rapid information processing in a tightly regulated extracellular environment. Whether SD is beneficial or not in mammals remains an open question. However, in insects, it is associated with the response to harsh environments and may provide an energetic advantage that improves the chances of survival. The remarkable similarity of SD in diverse taxa supports a model systems approach to understanding the mechanistic underpinning of human neuropathology associated with migraine, stroke, and traumatic brain injury.
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Smirnova, Mariia P., Tatiana M. Medvedeva, Irina V. Pavlova, and Lyudmila V. Vinogradova. "Region-Specific Vulnerability of the Amygdala to Injury-Induced Spreading Depolarization." Biomedicines 10, no. 9 (September 3, 2022): 2183. http://dx.doi.org/10.3390/biomedicines10092183.
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Spreading depolarization (SD), a self-propagated wave of transient depolarization, regularly occurs in the cortex after acute brain insults and is now referred as an important diagnostic and therapeutic target in patients with acute brain injury. Here, we show that the amygdala, the limbic structure responsible for post-injury neuropsychological symptoms, exhibits strong regional heterogeneity in vulnerability to SD with high susceptibility of its basolateral (BLA) region and resilience of its centromedial (CMA) region to triggering SD by acute focal damage. The BLA micro-injury elicited SD twice as often compared with identical injury of the CMA region (71% vs. 33%). Spatiotemporal features of SDs triggered in the amygdala indicated diverse patterns of the SD propagation to the cortex. Our results suggest that even relatively small cerebral structures can exhibit regional gradients in their susceptibility to SD and the heterogeneity may contribute to the generation of complex SD patterns in the injured brain.
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Koide, Masayo, Inna Sukhotinsky, Cenk Ayata, and George C. Wellman. "Subarachnoid Hemorrhage, Spreading Depolarizations and Impaired Neurovascular Coupling." Stroke Research and Treatment 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/819340.
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Aneurysmal subarachnoid hemorrhage (SAH) has devastating consequences on brain function including profound effects on communication between neurons and the vasculature leading to cerebral ischemia. Physiologically, neurovascular coupling represents a focal increase in cerebral blood flow to meet increased metabolic demand of neurons within active regions of the brain. Neurovascular coupling is an ongoing process involving coordinated activity of the neurovascular unit—neurons, astrocytes, and parenchymal arterioles. Neuronal activity can also influence cerebral blood flow on a larger scale. Spreading depolarizations (SD) are self-propagating waves of neuronal depolarization and are observed during migraine, traumatic brain injury, and stroke. Typically, SD is associated with increased cerebral blood flow. Emerging evidence indicates that SAH causes inversion of neurovascular communication on both the local and global level. In contrast to other events causing SD, SAH-induced SD decreases rather than increases cerebral blood flow. Further, at the level of the neurovascular unit, SAH causes an inversion of neurovascular coupling from vasodilation to vasoconstriction. Global ischemia can also adversely affect the neurovascular response. Here, we summarize current knowledge regarding the impact of SAH and global ischemia on neurovascular communication. A mechanistic understanding of these events should provide novel strategies to treat these neurovascular disorders.
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Reiffurth, Clemens, Mesbah Alam, Mahdi Zahedi-Khorasani, Sebastian Major, and Jens P. Dreier. "Na+/K+-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes." Journal of Cerebral Blood Flow & Metabolism 40, no. 3 (February 28, 2019): 622–38. http://dx.doi.org/10.1177/0271678x19833757.
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Compromised Na+/K+-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the α2 isoform of the Na+/K+-ATPase, were identified in patients with familial hemiplegic migraine type 2 (FHM2), a Mendelian model disease for SD. This suggests a distinct role for the α2 isoform in modulating SD susceptibility and raises questions about underlying mechanisms including the roles of other Na+/K+-ATPase α isoforms. Here, we investigated the effects of genetic ablation and pharmacological inhibition of α1, α2, and α3 on SD using heterozygous knock-out mice. We found that only α2 heterozygous mice displayed higher SD susceptibility when challenged with prolonged extracellular high potassium concentration ([K+]o), a pronounced post SD oligemia and higher SD speed in-vivo. By contrast, under physiological [K+]o, α2 heterozygous mice showed similar SD susceptibility compared to wild-type littermates. Deficiency of α3 resulted in increased resistance against electrically induced SD in-vivo, whereas α1 deficiency did not affect SD. The results support important roles of the α2 isoform in SD. Moreover, they suggest that specific experimental conditions can be necessary to reveal an inherent SD phenotype by driving a (meta-) stable system into decompensation, reminiscent of the episodic nature of SDs in various diseases.
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Czéh, Gabor, Peter G. Aitken, and George G. Somjen. "Membrane currents in CA1 pyramidal cells during spreading depression (SD) and SD-like hypoxic depolarization." Brain Research 632, no. 1-2 (December 1993): 195–208. http://dx.doi.org/10.1016/0006-8993(93)91154-k.
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Sukhotinsky, Inna, Mohammad A. Yaseen, Sava Sakadžić, Svetlana Ruvinskaya, John R. Sims, David A. Boas, Michael A. Moskowitz, and Cenk Ayata. "Perfusion Pressure-Dependent Recovery of Cortical Spreading Depression is Independent of Tissue Oxygenation over a Wide Physiologic Range." Journal of Cerebral Blood Flow & Metabolism 30, no. 6 (January 20, 2010): 1168–77. http://dx.doi.org/10.1038/jcbfm.2009.285.
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Spreading depression (SD) is a slowly propagating wave of transient neuronal and glial depolarization that develops after stroke, trauma and subarachnoid hemorrhage. In compromised tissue, repetitive SD-like injury depolarizations reduce tissue viability by worsening the mismatch between blood flow and metabolism. Although the mechanism remains unknown, SDs show delayed electrophysiological recovery within the ischemic penumbra. Here, we tested the hypothesis that the recovery rate of SD can be varied by modulating tissue perfusion pressure and oxygenation. Systemic blood pressure and arterial pO2 were simultaneously manipulated in anesthetized rats under full physiologic monitoring. We found that arterial hypotension doubled the SD duration, whereas hypertension reduced it by a third compared with normoxic normotensive rats. Hyperoxia failed to shorten the prolonged SD durations in hypotensive rats, despite restoring tissue pO2. Indeed, varying arterial pO2 (40 to 400 mm Hg) alone did not significantly influence SD duration, whereas blood pressure (40 to 160 mm Hg) was inversely related to SD duration in compromised tissue. These data suggest that cerebral perfusion pressure is a critical determinant of SD duration independent of tissue oxygenation over a wide range of arterial pO2 levels, and that hypotension may be detrimental in stroke and subarachnoid hemorrhage, where SD-like injury depolarizations have been observed.
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Aboghazleh, Refat, Ellen Parker, Lynn T. Yang, Daniela Kaufer, Jens P. Dreier, Alon Friedman, and Gerben van Hameren. "Brainstem and Cortical Spreading Depolarization in a Closed Head Injury Rat Model." International Journal of Molecular Sciences 22, no. 21 (October 28, 2021): 11642. http://dx.doi.org/10.3390/ijms222111642.
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Traumatic brain injury (TBI) is the leading cause of death in young individuals, and is a major health concern that often leads to long-lasting complications. However, the electrophysiological events that occur immediately after traumatic brain injury, and may underlie impact outcomes, have not been fully elucidated. To investigate the electrophysiological events that immediately follow traumatic brain injury, a weight-drop model of traumatic brain injury was used in rats pre-implanted with epidural and intracerebral electrodes. Electrophysiological (near-direct current) recordings and simultaneous alternating current recordings of brain activity were started within seconds following impact. Cortical spreading depolarization (SD) and SD-induced spreading depression occurred in approximately 50% of mild and severe impacts. SD was recorded within three minutes after injury in either one or both brain hemispheres. Electrographic seizures were rare. While both TBI- and electrically induced SDs resulted in elevated oxidative stress, TBI-exposed brains showed a reduced antioxidant defense. In severe TBI, brainstem SD could be recorded in addition to cortical SD, but this did not lead to the death of the animals. Severe impact, however, led to immediate death in 24% of animals, and was electrocorticographically characterized by non-spreading depression (NSD) of activity followed by terminal SD in both cortex and brainstem.
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Makarova, Julia, Valeri A. Makarov, and Oscar Herreras. "Generation of Sustained Field Potentials by Gradients of Polarization Within Single Neurons: A Macroscopic Model of Spreading Depression." Journal of Neurophysiology 103, no. 5 (May 2010): 2446–57. http://dx.doi.org/10.1152/jn.01045.2009.
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Spreading depression (SD) is a pathological wave of depolarization of the neural tissue producing a negative macroscopic field potential ( Vo), used as a marker for diagnostic purposes. The cellular basis of SD and neuronal mechanisms of generation of Vo at the microscopic level are poorly understood. Using a CA1 mathematical model and experimental verification, we examined how transmembrane currents in single cells scale up in the extracellular space shaping Vo. The model includes an array of 17,000 realistically modeled neurons (responsible for generating transmembrane currents) dynamically coupled to a virtual aggregate/extracellular space (responsible for Vo). The SD wave in different tissue bands is simulated by imposing membrane shunts in the corresponding dendritic elements as suggested by experimentally assessed drop in membrane resistance. We show that strong isopotential depolarization of wide domains (as in the main SD phase) produce broad central cancellation of axial and transmembrane currents in single cells. When depolarization is restricted to narrow dendritic domains (as in the late SD phase), the internal cancellation shrinks and the transmembrane current increases. This explains why in the laminated CA1 the Vo is smaller in the main phase of SD, when both dendritic layers are seized, than in the SD tail restricted to an apical band. Moreover, scattering of the neuronal somatas (as in cortical regions) further decreases the aggregate Vo due to the volume averaging. Although mechanistically the Vo associated to SD is similar to customary transient fields, its changes maybe related to spatial factors in single cells rather than cell number or depolarization strength.
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Hoffmann, Ulrike, Jeong Hyun Lee, Tao Qin, Katharina Eikermann-Haerter, and Cenk Ayata. "Gabapentin reduces infarct volume but does not suppress peri-infarct depolarizations." Journal of Cerebral Blood Flow & Metabolism 31, no. 7 (April 20, 2011): 1578–82. http://dx.doi.org/10.1038/jcbfm.2011.50.
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Spreading depression (SD) is an intense depolarization wave implicated in brain injury. In focal ischemia, recurrent peri-infarct depolarization (PID) waves akin to SD worsen the ischemic injury by exacerbating the blood flow-metabolism mismatch. We recently showed that gabapentin suppresses SD. We, therefore, tested gabapentin on PIDs and stroke outcome. Gabapentin pretreatment (200 mg/kg, intravenously) reduced the infarct volume by 23% after transient focal ischemia in mice. However, the frequency and duration of PIDs were not suppressed when recorded for 2hours during ischemia, suggesting that gabapentin reduces infarct volume independent of PID suppression.
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Tóth, Réka, Attila E. Farkas, István A. Krizbai, Péter Makra, Ferenc Bari, Eszter Farkas, and Ákos Menyhárt. "Astrocyte Ca2+ Waves and Subsequent Non-Synchronized Ca2+ Oscillations Coincide with Arteriole Diameter Changes in Response to Spreading Depolarization." International Journal of Molecular Sciences 22, no. 7 (March 26, 2021): 3442. http://dx.doi.org/10.3390/ijms22073442.
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Spreading depolarization (SD) is a wave of mass depolarization that causes profound perfusion changes in acute cerebrovascular diseases. Although the astrocyte response is secondary to the neuronal depolarization with SD, it remains to be explored how glial activity is altered after the passage of SD. Here, we describe post-SD high frequency astrocyte Ca2+ oscillations in the mouse somatosensory cortex. The intracellular Ca2+ changes of SR101 labeled astrocytes and the SD-related arteriole diameter variations were simultaneously visualized by multiphoton microscopy in anesthetized mice. Post-SD astrocyte Ca2+ oscillations were identified as Ca2+ events non-synchronized among astrocytes in the field of view. Ca2+ oscillations occurred minutes after the Ca2+ wave of SD. Furthermore, fewer astrocytes were involved in Ca2+ oscillations at a given time, compared to Ca2+ waves, engaging all astrocytes in the field of view simultaneously. Finally, our data confirm that astrocyte Ca2+ waves coincide with arteriolar constriction, while post-SD Ca2+ oscillations occur with the peak of the SD-related vasodilation. This is the first in vivo study to present the post-SD astrocyte Ca2+ oscillations. Our results provide novel insight into the spatio-temporal correlation between glial reactivity and cerebral arteriole diameter changes behind the SD wavefront.
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Lindquist, Britta E., and C. William Shuttleworth. "Evidence that adenosine contributes to Leao’s spreading depression in vivo." Journal of Cerebral Blood Flow & Metabolism 37, no. 5 (July 21, 2016): 1656–69. http://dx.doi.org/10.1177/0271678x16650696.
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Leao’s spreading depression of cortical activity is a propagating silencing of neuronal activity resulting from spreading depolarization (SD). We evaluated the contributions of action potential (AP) failure and adenosine A1 receptor (A1R) activation to the depression of evoked and spontaneous electrocorticographic (ECoG) activity after SD in vivo, in anesthetized mice. We compared depression with SD-induced effects on AP-dependent transmission, and synaptic potentials in the transcallosal and thalamocortical pathways. After SD, APs recovered rapidly, within 1–2 min, as demonstrated by evoked activity in distant projection targets. Evoked corticocortical postsynaptic potentials recovered next, within ∼5 min. Spontaneous ECoG and evoked thalamocortical postsynaptic potentials recovered together, after ∼10–15 min. The duration of ECoG depression was shortened 20% by systemic (10 mg/kg) or focal (30 µM) administration of A1R competitive antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). ECoG depression was also shortened by focal application of exogenous adenosine deaminase (ADA; 100 U/mL), and conversely, was prolonged 50% by the non-competitive ADA inhibitor deoxycoformycin (DCF; 100 µM). We concluded that while initial depolarization block is brief, adenosine A1R activation, in part, contributes to the persistent secondary phase of Leao’s cortical spreading depression.
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Terai, Haruhi, Mayeso Naomi Victoria Gwedela, Koichi Kawakami, and Hidenori Aizawa. "Electrophysiological and pharmacological characterization of spreading depolarization in the adult zebrafish tectum." Journal of Neurophysiology 126, no. 6 (December 1, 2021): 1934–42. http://dx.doi.org/10.1152/jn.00343.2021.
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Previous studies have implicated spreading depolarization (SD) in stroke and migraine. Here, we demonstrate SD, for the first time, in the adult zebrafish tectum showing waveform kinetics, c-fos expression, and attenuation by N-methyl-d-aspartate glutamate receptor blocker as observed in the rodent cortex. Since the zebrafish is an animal model amenable to genetic manipulation and chemical screening, this result could pave the way to novel diagnostic and therapeutic methods applicable to SD-associated neurological disorders.
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Jing, J., P. G. Aitken, and G. G. Somjen. "Interstitial volume changes during spreading depression (SD) and SD-like hypoxic depolarization in hippocampal tissue slices." Journal of Neurophysiology 71, no. 6 (June 1, 1994): 2548–51. http://dx.doi.org/10.1152/jn.1994.71.6.2548.
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1. Relative interstitial volume (ISV) was estimated from the concentration changes of iontophoretically administered tetramethyl- and tetraethylammonium (TMA+ and TEA+). Spreading depression (SD) was provoked by high K+, and hypoxic SD-like depolarization (HSD) was induced by withdrawing oxygen. 2. Probe ion concentrations increased dramatically and about equally during SD and HSD, except that in a few hypoxic trials signals became transiently smaller than control. Interstitial volume appeared to decrease on the average by approximately 70%. 3. The ISV that remains patent in CA1 region at the height of SD is < 4% of total tissue volume. Probe ions may occasionally have passed through cell membranes for a short time during hypoxic SD.
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Chau, Lily, Herbert T. Davis, Thomas Jones, Diana Greene-Chandos, Michel Torbey, C. William Shuttleworth, and Andrew P. Carlson. "Spreading Depolarization as a Therapeutic Target in Severe Ischemic Stroke: Physiological and Pharmacological Strategies." Journal of Personalized Medicine 12, no. 9 (September 1, 2022): 1447. http://dx.doi.org/10.3390/jpm12091447.
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Background: Spreading depolarization (SD) occurs nearly ubiquitously in malignant hemispheric stroke (MHS) and is strongly implicated in edema progression and lesion expansion. Due to this high burden of SD after infarct, it is of great interest whether SD in MHS patients can be mitigated by physiologic or pharmacologic means and whether this intervention improves clinical outcomes. Here we describe the association between physiological variables and risk of SD in MHS patients who had undergone decompressive craniectomy and present an initial case of using ketamine to target SD in MHS. Methods: We recorded SD using subdural electrodes and time-linked with continuous physiological recordings in five subjects. We assessed physiologic variables in time bins preceding SD compared to those with no SD. Results: Using multivariable logistic regression, we found that decreased ETCO2 (OR 0.772, 95% CI 0.655–0.910) and DBP (OR 0.958, 95% CI 0.941–0.991) were protective against SD, while elevated temperature (OR 2.048, 95% CI 1.442–2.909) and WBC (OR 1.113, 95% CI 1.081–1.922) were associated with increased risk of SD. In a subject with recurrent SD, ketamine at a dose of 2mg/kg/h was found to completely inhibit SD. Conclusion: Fluctuations in physiological variables can be associated with risk of SD after MHS. Ketamine was also found to completely inhibit SD in one subject. These data suggest that use of physiological optimization strategies and/or pharmacologic therapy could inhibit SD in MHS patients, and thereby limit edema and infarct progression. Clinical trials using individualized approaches to target this novel mechanism are warranted.
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Lindquist, Britta E., and C. William Shuttleworth. "Spreading Depolarization-Induced Adenosine Accumulation Reflects Metabolic Status In Vitro and In Vivo." Journal of Cerebral Blood Flow & Metabolism 34, no. 11 (August 27, 2014): 1779–90. http://dx.doi.org/10.1038/jcbfm.2014.146.
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Spreading depolarization (SD), a pathologic feature of migraine, stroke and traumatic brain injury, is a propagating depolarization of neurons and glia causing profound metabolic demand. Adenosine, the low-energy metabolite of ATP, has been shown to be elevated after SD in brain slices and under conditions likely to trigger SD in vivo. The relationship between metabolic status and adenosine accumulation after SD was tested here, in brain slices and in vivo. In brain slices, metabolic impairment (assessed by nicotinamide adenine dinucleotide (phosphate) autofluorescence and O2 availability) was associated with prolonged extracellular direct current (DC) shifts indicating delayed repolarization, and increased adenosine accumulation. In vivo, adenosine accumulation was observed after SD even in otherwise healthy mice. As in brain slices, in vivo adenosine accumulation correlated with DC shift duration and increased when DC shifts were prolonged by metabolic impairment (i.e., hypoglycemia or middle cerebral artery occlusion). A striking pattern of adenosine dynamics was observed during focal ischemic stroke, with nearly all the observed adenosine signals in the periinfarct region occurring in association with SDs. These findings suggest that adenosine accumulation could serve as a biomarker of SD incidence and severity, in a range of clinical conditions.
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Varga, Dániel P., Ákos Menyhárt, Balázs Pósfai, Eszter Császár, Nikolett Lénárt, Csaba Cserép, Barbara Orsolits, et al. "Microglia alter the threshold of spreading depolarization and related potassium uptake in the mouse brain." Journal of Cerebral Blood Flow & Metabolism 40, no. 1_suppl (January 27, 2020): S67—S80. http://dx.doi.org/10.1177/0271678x19900097.
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Selective elimination of microglia from the brain was shown to dysregulate neuronal Ca2+ signaling and to reduce the incidence of spreading depolarization (SD) during cerebral ischemia. However, the mechanisms through which microglia interfere with SD remained unexplored. Here, we identify microglia as essential modulators of the induction and evolution of SD in the physiologically intact brain in vivo. Confocal- and super-resolution microscopy revealed that a series of SDs induced rapid morphological changes in microglia, facilitated microglial process recruitment to neurons and increased the density of P2Y12 receptors (P2Y12R) on recruited microglial processes. In line with this, depolarization and hyperpolarization during SD were microglia- and P2Y12R-dependent. An absence of microglia was associated with altered potassium uptake after SD and increased the number of c-fos-positive neurons, independently of P2Y12R. Thus, the presence of microglia is likely to be essential to maintain the electrical elicitation threshold and to support the full evolution of SD, conceivably by interfering with the extracellular potassium homeostasis of the brain through sustaining [K+]e re-uptake mechanisms.
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Canals, S., I. Makarova, L. López-Aguado, C. Largo, J. M. Ibarz, and O. Herreras. "Longitudinal Depolarization Gradients Along the Somatodendritic Axis of CA1 Pyramidal Cells: A Novel Feature of Spreading Depression." Journal of Neurophysiology 94, no. 2 (August 2005): 943–51. http://dx.doi.org/10.1152/jn.01145.2004.
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We studied the subcellular correlates of spreading depression (SD) in the CA1 rat hippocampus by combining intrasomatic and intradendritic recordings of pyramidal cells with extracellular DC and evoked field and unitary activity. The results demonstrate that during SD only specific parts of the dendritic membranes are deeply depolarized and electrically shunted. Somatic impalements yielded near-zero membrane potential ( Vm) and maximum decrease of input resistance ( Rin) whether the accompanying extracellular negative potential ( Vo) moved along the basal, the apical or both dendritic arbors. However, apical intradendritic recordings showed a different course of local Vm that is hardly detected from the soma. A decreasing depolarization gradient was observed from the edge of SD-affected fully depolarized subcellular regions toward distal dendrites. Within apical dendrites, the depolarizing front moved toward and stopped at proximal dendrites during the time course of SD so that distal dendrites had repolarized in part or in full by the end of the wave. The drop of local Rin was initially maximal at any somatodendritic loci and also recovered partially before the end of SD. This recovery was stronger and faster in far dendrites and is best explained by a wave-like somatopetal closure of membrane conductances. Cell subregions far from SD-affected membranes remain electrically excitable and show evoked unitary and field activity. We propose that neuronal depolarization during SD is caused by current flow through extended but discrete patches of shunted membranes driven by uneven longitudinal depolarization.
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Wauquier, Albert, David Ashton, and Roger Marrannes. "The Effects of Flunarizine in Experimental Models Related to the Pathogenesis of Migraine." Cephalalgia 5, no. 2_suppl (May 1985): 119–23. http://dx.doi.org/10.1177/03331024850050s222.
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Two new hypotheses suggest that the key pathology in migraine has a neuronal origin. A pivotal role is assigned to brain hypoxia (1) and spreading depression (SD) (neuronal depolarization spreading gradually over the cortex) (2). Flunarizine has been tested both against brain hypoxia and SD. Its potent antihypoxic properties in animal models led to its use as a prophylactic drug in migraine therapy. Earlier experiments suggested that flunarizine shortened recovery after neuronal depolarization. Recent experiments suggest that flunarizine may enhance the threshold for the elicitation of SD. Finally, it is often unclear whether the effects observed with flunarizine are due to a vascular or a direct neuronal effect. Therefore, a study was made to show whether flunarizine affected hypoxia-induced alterations in synaptic function in slices of hippocampus held in vitro. At physiological drug concentrations in brain, flunarizine improved post-hypoxic recovery of synaptic function. A direct neuronal protective effect was thus demonstrated.
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Gidö, Gunilla, Kenichiro Katsura, Tibor Kristian, and Bo K. Siesjö. "Influence of Plasma Glucose Concentration on Rat Brain Extracellular Calcium Transients during Spreading Depression." Journal of Cerebral Blood Flow & Metabolism 13, no. 1 (January 1993): 179–82. http://dx.doi.org/10.1038/jcbfm.1993.21.
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The objective of this study was to establish whether tissues that are energy compromised, but not energy depleted, demonstrate exaggerated calcium transients when subjected to membrane depolarizations of the spreading depression (SD) type. Anesthetized and artificially ventilated rats were given insulin in order to induce progressively lower plasma glucose concentrations. Spreading depression was elicited by local application of KCl; extracellular calcium concentration (Ca2+e) as well as direct current (DC) potential were recorded. When plasma glucose concentration fell below ∼3 m M, the duration of the Ca2+e transient gradually increased to values exceeding 500% of control. The increase was associated with a corresponding increase in the duration of the DC potential shift, but the amplitude of the Ca2+e transient did not change. It is concluded that a restriction of glucose (or oxygen) supply, as occurs in hypoglycemia (or hypoxia), prolongs the calcium transient associated with depolarization of the SD type, even though tissue phosphocreatine and ATP concentrations are normal. The results support the contention that repeated depolarizations, occurring in the penumbral zone of a focal ischemic lesion, could lead to calcium-related damage.
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Müller, Michael, and George G. Somjen. "Intrinsic Optical Signals in Rat Hippocampal Slices During Hypoxia-Induced Spreading Depression-Like Depolarization." Journal of Neurophysiology 82, no. 4 (October 1, 1999): 1818–31. http://dx.doi.org/10.1152/jn.1999.82.4.1818.
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In interfaced rat hippocampal slices spreading depression (SD) and hypoxia-induced SD-like depolarization are associated with increased light reflectance and decreased light transmittance, indicating increased light scattering. By contrast, mild hypotonicity or electrical stimulation decrease light scattering, which is usually taken to be caused by cell swelling. This difference has been attributed to experimental conditions, but in our laboratory moderate osmotic challenge and SD produced opposite intrinsic optical signals (IOSs) in the same slice under identical conditions. To decide whether the SD-induced IOS is related to cell swelling, we investigated the effects of Cl− transport inhibitors and Cl−withdrawal on both light reflectance and transmittance, as well as on changes in interstitial volume and tissue electrical resistance. In normal [Cl−]o, early during hypoxia, there was a slight decrease in light reflectance paired with increase in transmittance. At the onset of hypoxic SD, coincident with the onset of cell swelling (restriction of TMA+ space), the IOS signals suddenly inverted, indicating sharply increased scattering. The SD-related IOSs started in a single spot and spread out over the entire CA1 region without invading CA3. Application of 2 mM furosemide decreased IOS intensity. When [Cl−]o was substituted by methylsulfate or gluconate, the SD-related reflectance increase and transmittance decrease were suppressed and replaced by opposite signals, indicating scattering decrease. Yet Cl−withdrawal did not prevent cell swelling measured as shrinkage of TMA+ space. The SD-related increase of tissue electrical resistance was reduced when bath Cl− was replaced by methylsulfate and almost eliminated when replaced by gluconate. The TMA+ signal is judged to be a more reliable indicator of interstitial space than tissue resistance. Neither application of cyclosporin A nor raising [Mg2+]o depressed the SD-related reflectance increase, suggesting that Cl−flux through mitochondrial “megachannels” may not be a major factor in its generation. Fluoroacetate poisoning of glial cells (5 mM) accelerated SD onset and enhanced the SD-induced reflectance increase threefold. This suggests, first, that glial cells normally moderate the SD process and, second, that neurons are the predominant generators of the light-scattering increase. We conclude that light scattering by cerebral tissue can be changed by at least two different physical processes. Cell swelling decreases light scattering, whereas a second process increases scattering. During hypoxic SD the scattering increase masks the swelling-induced scattering decrease, but the latter is revealed when Cl− is removed. The scattering increase is Cl− dependent, nevertheless it is apparently not related to cell volume changes. Its underlying mechanism is as yet not clear; possible factors are discussed.
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Sánchez-Porras, Renán, Edgar Santos, Michael Schöll, Kevin Kunzmann, Christian Stock, Humberto Silos, Andreas W. Unterberg, and Oliver W. Sakowitz. "Ketamine modulation of the haemodynamic response to spreading depolarization in the gyrencephalic swine brain." Journal of Cerebral Blood Flow & Metabolism 37, no. 5 (July 20, 2016): 1720–34. http://dx.doi.org/10.1177/0271678x16646586.
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Spreading depolarization (SD) generates significant alterations in cerebral haemodynamics, which can have detrimental consequences on brain function and integrity. Ketamine has shown an important capacity to modulate SD; however, its impact on SD haemodynamic response is incompletely understood. We investigated the effect of two therapeutic ketamine dosages, a low-dose of 2 mg/kg/h and a high-dose of 4 mg/kg/h, on the haemodynamic response to SD in the gyrencephalic swine brain. Cerebral blood volume, pial arterial diameter and cerebral blood flow were assessed through intrinsic optical signal imaging and laser-Doppler flowmetry. Our findings indicate that frequent SDs caused a persistent increase in the baseline pial arterial diameter, which can lead to a diminished capacity to further dilate. Ketamine infused at a low-dose reduced the hyperemic/vasodilative response to SD; however, it did not alter the subsequent oligemic/vasoconstrictive response. This low-dose did not prevent the baseline diameter increase and the diminished dilative capacity. Only infusion of ketamine at a high-dose suppressed SD and the coupled haemodynamic response. Therefore, the haemodynamic response to SD can be modulated by continuous infusion of ketamine. However, its use in pathological models needs to be explored to corroborate its possible clinical benefit.
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Anzabi, Maryam, Baoqiang Li, Hui Wang, Sreekanth Kura, Sava Sakadžić, David Boas, Leif Østergaard, and Cenk Ayata. "Optical coherence tomography of arteriolar diameter and capillary perfusion during spreading depolarizations." Journal of Cerebral Blood Flow & Metabolism 41, no. 9 (February 16, 2021): 2256–63. http://dx.doi.org/10.1177/0271678x21994013.
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Spreading depolarization (SD) is associated with profound oligemia and reduced oxygen availability in the mouse cortex during the depolarization phase. Coincident pial arteriolar constriction has been implicated as the primary mechanism for the oligemia. However, where in the vascular bed the hemodynamic response starts has been unclear. To resolve the origin of the hemodynamic response, we used optical coherence tomography (OCT) to simultaneously monitor changes in the vascular tree from capillary bed to pial arteries in mice during two consecutive SDs 15 minutes apart. We found that capillary flow dropped several seconds before pial arteriolar constriction. Moreover, penetrating arterioles constricted before pial arteries suggesting upstream propagation of constriction. Smaller caliber distal pial arteries constricted stronger than larger caliber proximal arterioles, suggesting that the farther the constriction propagates, the weaker it gets. Altogether, our data indicate that the hemodynamic response to cortical SD originates in the capillary bed.
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Aiba, Isamu, Xander H. T. Wehrens, and Jeffrey L. Noebels. "Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death." Proceedings of the National Academy of Sciences 113, no. 33 (August 1, 2016): E4895—E4903. http://dx.doi.org/10.1073/pnas.1605216113.
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Cardiorespiratory failure is the most common cause of sudden unexplained death in epilepsy (SUDEP). Genetic autopsies have detected “leaky” gain-of-function mutations in the ryanodine receptor-2 (RyR2) gene in both SUDEP and sudden cardiac death cases linked to catecholaminergic polymorphic ventricular tachycardia that feature lethal cardiac arrhythmias without structural abnormality. Here we find that a human leaky RyR2 mutation, R176Q (RQ), alters neurotransmitter release probability in mice and significantly lowers the threshold for spreading depolarization (SD) in dorsal medulla, leading to cardiorespiratory collapse. Rare episodes of sinus bradycardia, spontaneous seizure, and sudden death were detected in RQ/+ mutant mice in vivo; however, when provoked, cortical seizures frequently led to apneas, brainstem SD, cardiorespiratory failure, and death. In vitro studies revealed that the RQ mutation selectively strengthened excitatory, but not inhibitory, synapses and facilitated SD in both the neocortex as well as brainstem dorsal medulla autonomic microcircuits. These data link defects in neuronal intracellular calcium homeostasis to the vulnerability of central autonomic brainstem pathways to hypoxic stress and implicate brainstem SD as a previously unrecognized site and mechanism contributing to premature death in individuals with leaky RYR2 mutations.
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Smith, MI, SJ Read, WN Chan, M. Thompson, AJ Hunter, N. Upton, and AA Parsons. "Repetitive Cortical Spreading Depression in a Gyrencephalic Feline Brain: Inhibition by the Novel Benzoylamino-Benzopyran SB-220453." Cephalalgia 20, no. 6 (July 2000): 546–53. http://dx.doi.org/10.1046/j.1468-2982.2000.00092.x.
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Transient cortical depolarization is implicated in the pathology of migraine. SB-220453 is a potent anti-convulsant which inhibits neurogenic inflammation and cortical spreading depression (SD)-evoked nitric oxide release via a novel but unknown mechanism. This study further investigates the effects of SB-220453 on generation and propagation of repetitive SD in the anaesthetized cat. Vehicle or SB-220453 1, 3 or 10 mg/kg was administered intraperitoneally 90 min prior to induction of SD in the suprasylvian gyrus (SG). Changes in d.c. potential were recorded in the SG and the adjacent marginal gyrus (MG). In vehicle-treated animals ( n = 7), a brief exposure (6 min) to KCl induced a median (25–75% range) number of five (four to six) and three (two to four) depolarizations over a duration of 55 min (32–59 min) and 51 min (34–58 min) in the SG and MG, respectively. SB-220453 produced dose-related inhibition of the number of events and period of repetitive SD activity. SB-220453 also reduced SD-induced repetitive pial vasodilatation but had no effect on resting haemodynamics. However, when SD events were observed in the presence of SB-220453, it had no effect on metabolic coupling. These results show that SB-220453 produces marked inhibition of repetitive SD in the anaesthetized cat. SB-220453 may therefore have therapeutic potential in treatment of SD-like activity in migraine.
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Kirov, Sergei A., Ioulia V. Fomitcheva, and Jeremy Sword. "Rapid Neuronal Ultrastructure Disruption and Recovery during Spreading Depolarization-Induced Cytotoxic Edema." Cerebral Cortex 30, no. 10 (June 2, 2020): 5517–31. http://dx.doi.org/10.1093/cercor/bhaa134.
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Abstract Two major pathogenic events that cause acute brain damage during neurologic emergencies of stroke, head trauma, and cardiac arrest are spreading depolarizing waves and the associated brain edema that course across the cortex injuring brain cells. Virtually nothing is known about how spreading depolarization (SD)-induced cytotoxic edema evolves at the ultrastructural level immediately after insult and during recovery. In vivo 2-photon imaging followed by quantitative serial section electron microscopy was used to assess synaptic circuit integrity in the neocortex of urethane-anesthetized male and female mice during and after SD evoked by transient bilateral common carotid artery occlusion. SD triggered a rapid fragmentation of dendritic mitochondria. A large increase in the density of synapses on swollen dendritic shafts implies that some dendritic spines were overwhelmed by swelling or merely retracted. The overall synaptic density was unchanged. The postsynaptic dendritic membranes remained attached to axonal boutons, providing a structural basis for the recovery of synaptic circuits. Upon immediate reperfusion, cytotoxic edema mainly subsides as affirmed by a recovery of dendritic ultrastructure. Dendritic recuperation from swelling and reversibility of mitochondrial fragmentation suggests that neurointensive care to improve tissue perfusion should be paralleled by treatments targeting mitochondrial recovery and minimizing the occurrence of SDs.
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Klass, Anna, Renan Sánchez-Porras, and Edgar Santos. "Systematic review of the pharmacological agents that have been tested against spreading depolarizations." Journal of Cerebral Blood Flow & Metabolism 38, no. 7 (April 20, 2018): 1149–79. http://dx.doi.org/10.1177/0271678x18771440.
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Spreading depolarization (SD) occurs alongside brain injuries and it can lead to neuronal damage. Therefore, pharmacological modulation of SD can constitute a therapeutic approach to reduce its detrimental effects and to improve the clinical outcome of patients. The major objective of this article was to produce a systematic review of all the drugs that have been tested against SD. Of the substances that have been examined, most have been shown to modulate certain SD characteristics. Only a few have succeeded in significantly inhibiting SD. We present a variety of strategies that have been proposed to overcome the notorious harmfulness and pharmacoresistance of SD. Information on clinically used anesthetic, sedative, hypnotic agents, anti-migraine drugs, anticonvulsants and various other substances have been compiled and reviewed with respect to the efficacy against SD, in order to answer the question of whether a drug at safe doses could be of therapeutic use against SD in humans.
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Huang, Rong, Peter G. Aitken, and George G. Somjen. "Hypertonic Environment Prevents Depolarization and Improves Functional Recovery from Hypoxia in Hippocampal Slices." Journal of Cerebral Blood Flow & Metabolism 16, no. 3 (May 1996): 462–67. http://dx.doi.org/10.1097/00004647-199605000-00012.
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Treatments that postpone hypoxic spreading depression (SD)-like depolarization (also called anoxic depolarization) facilitate recovery of function after transient cerebral hypoxia. Hypertonia reduces cerebral excitability, and we tested whether it also offers protection against SD-like depolarization and hypoxia. Oxygen was withdrawn from hippocampal slices bathed in normal artificial cerebrospinal fluid (ACSF) and, simultaneously, from slices cut from the same hippocampus but bathed in strongly hypertonic ACSF. Extracellular osmolarity (πo) was increased by adding 100 m M mannitol or fructose to ACSF. Slices in normal πo underwent SD-like negative extracellular voltage shift (ΔVo). The hypertonic slices usually showed no SD-like ΔVo but only a small, gradual negative voltage shift. Hypertonia also prevented the precipitate drop of interstitial calcium level ([Ca2+]o). When oxygenation and normal osmolarity were restored, synaptic transmission in the previously hypertonic slices recovered completely, but 3 h after reoxygenation orthodromically transmitted population spikes of the control slices recovered only 25.1% of the initial control amplitude. We conclude that hypertonic treatment during hypoxia improves subsequent recovery of synaptic function. The protection is probably due to the prevention of calcium uptake by blocking the SD-like depolarization, with the prevention of hypoxic cell swelling playing a lesser role.
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Herreras, Oscar, and Julia Makarova. "Mechanisms of the negative potential associated with Leão’s spreading depolarization: A history of brain electrogenesis." Journal of Cerebral Blood Flow & Metabolism 40, no. 10 (June 24, 2020): 1934–52. http://dx.doi.org/10.1177/0271678x20935998.
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Spreading depolarization (SD) is a self-propagated wave that provokes transient disorder of numerous cell and tissue functions, and that may kill neurons in metabolically compromised tissue. We examined the mechanisms underlying the main hallmark of SD, a giant extracellular potential (ΔVo) for which multiple electromotive forces have been proposed. The end-point is that neurons and not glia, dendritic channels and not spatial currents, and increased sodium conductance rather than potassium gradients, appear to be the main actors in the generation of the negative ΔVo. Neuronal currents are established by two mechanisms, a voltage independent dendritic current, and the differential polarization along the neuron membranes. Notably, despite of a marked drop of ion gradients, these evolve significantly during SD, and yet the membrane potential remains clamped at zero no matter how much inward current is present. There may be substantial inward current or none in function of the evolving portion of the neuron dendrites with SD-activated channels. We propose that the ΔVo promotes swelling-induced dendritic damage. Understanding SD electrogenesis requires all elements relevant for membrane potential, action currents, field potentials and volume conduction to be jointly considered, and it has already encouraged the search for new targets to limit SD-related pathology.
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Van Dusen, Rachel A., Hannah Shuster-Hyman, and R. Meldrum Robertson. "Inhibition of ATP-sensitive potassium channels exacerbates anoxic coma in Locusta migratoria." Journal of Neurophysiology 124, no. 6 (December 1, 2020): 1754–65. http://dx.doi.org/10.1152/jn.00379.2020.
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We demonstrate the involvement of ATP-sensitive K+ (KATP) channels during recovery from spreading depolarization (SD) induced via anoxic coma in locusts. KATP inhibition using glybenclamide impaired ion homeostasis across the blood-brain barrier, resulting in a longer time to recovery of transperineurial potential following SD. Comparison with ouabain indicates that the effects of glybenclamide are not mediated by the Na+/K+-ATPase but are a result of KATP channel inhibition.
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Oliveira-Ferreira, Ana I., Sebastian Major, Ingo Przesdzing, Eun-Jeung Kang, and Jens P. Dreier. "Spreading depolarizations in the rat endothelin-1 model of focal cerebellar ischemia." Journal of Cerebral Blood Flow & Metabolism 40, no. 6 (July 7, 2019): 1274–89. http://dx.doi.org/10.1177/0271678x19861604.
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Focal brain ischemia is best studied in neocortex and striatum. Both show highly vulnerable neurons and high susceptibility to spreading depolarization (SD). Therefore, it has been hypothesized that these two variables generally correlate. However, this hypothesis is contradicted by findings in cerebellar cortex, which contains highly vulnerable neurons to ischemia, the Purkinje cells, but is said to be less susceptible to SD. Here, we found in the rat cerebellar cortex that elevated K+ induced a long-lasting depolarizing event superimposed with SDs. Cerebellar SDs resembled those in neocortex, but negative direct current (DC) shifts and regional blood flow responses were usually smaller. The K+ threshold for SD was higher in cerebellum than in previous studies in neocortex. We then topically applied endothelin-1 (ET-1) to the cerebellum, which is assumed to cause SD via vasoconstriction-induced focal ischemia. Although the blood flow decrease was similar to that in previous studies in neocortex, the ET-1 threshold for SD was higher. Quantitative cell counting found that the proportion of necrotic Purkinje cells was significantly higher in ET-1-treated rats than sham controls even if ET-1 had not caused SDs. Our results suggest that ischemic death of Purkinje cells does not require the occurrence of SD.
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Carlson, Andrew P., Mohammad Abbas, Robert L. Alunday, Fares Qeadan, and C. William Shuttleworth. "Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial." Journal of Neurosurgery 130, no. 5 (May 2019): 1513–19. http://dx.doi.org/10.3171/2017.12.jns171665.
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OBJECTIVERetrospective clinical data and case studies support a therapeutic effect of ketamine in suppression of spreading depolarization (SD) following brain injury. Preclinical data strongly support efficacy in terms of frequency of SD as well as recovery from electrocorticography (ECoG) depression. The authors present the results of the first prospective controlled clinical trial testing the role of ketamine used for clinical sedation on occurrence of SD.METHODSTen patients with severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) were recruited for this pilot trial. A standard ECoG strip was placed at the time of craniotomy, and the patients were then placed on an alternating every-6-hour schedule of ketamine or other sedation agent. The order of treatment was randomized. The ketamine dose was adjusted to clinical effect or maintained at a subanesthetic basal dose (0.1 mg/kg/hr) if no sedation was required. SD was scored using standard criteria, blinded to ketamine dosing. Occurrence of SD was compared with the hourly dose of ketamine to determine the effect of ketamine on SD occurrence.RESULTSSuccessful ECoG recordings were obtained in all 10 patients: 8 with SAH and 2 with TBI. There were a total of 1642 hours of observations with adequate ECoG: 833 hours off ketamine and 809 hours on ketamine. Analysis revealed a strong dose-dependent effect such that hours off ketamine or on doses of less than 1.15 mg/kg/hr were associated with an increased risk of SD compared with hours on doses of 1.15 mg/kg/hr or more (OR 13.838, 95% CI 1.99–1000). This odds ratio decreased with lower doses of 1.0 mg/kg/hr (OR 4.924, 95% CI 1.337–43.516), 0.85 mg/kg/hr (OR 3.323, 95% CI 1.139–16.074), and 0.70 mg/kg/hr (OR 2.725, 95% CI 1.068–9.898) to a threshold of no effect at 0.55 mg/kg/hr (OR 1.043, 95% CI 0.565–2.135). When all ketamine data were pooled (i.e., on ketamine at any dose vs off ketamine), a nonsignificant overall trend toward less SD during hours on ketamine (χ2 = 3.86, p = 0.42) was observed.CONCLUSIONSKetamine effectively inhibits SD over a wide range of doses commonly used for sedation, even in nonintubated patients. These data also provide the first prospective evidence that the occurrence of SD can be influenced by clinical intervention and does not simply represent an unavoidable epiphenomenon after injury. These data provide the basis for future studies assessing clinical improvement with SD-directed therapy.Clinical trial registration no.: NCT02501941 (clinicaltrials.gov)
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Aiba, Isamu, Andrew P. Carlson, Christian T. Sheline, and C. William Shuttleworth. "Synaptic release and extracellular actions of Zn2+ limit propagation of spreading depression and related events in vitro and in vivo." Journal of Neurophysiology 107, no. 3 (February 2012): 1032–41. http://dx.doi.org/10.1152/jn.00453.2011.
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Cortical spreading depression (CSD) is a consequence of a slowly propagating wave of neuronal and glial depolarization (spreading depolarization; SD). Massive release of glutamate contributes to SD propagation, and it was recently shown that Zn2+ is also released from synaptic vesicles during SD. The present study examined consequences of extracellular Zn2+ accumulation on the propagation of SD. SD mechanisms were studied first in murine brain slices, using focal KCl applications as stimuli and making electrical and optical recordings in hippocampal area CA1. Elevating extracellular Zn2+ concentrations with exogenous ZnCl2 reduced SD propagation rates. Selective chelation of endogenous Zn2+ (using TPEN or CaEDTA) increased SD propagation rates, and these effects appeared due to chelation of Zn2+ derived from synaptic vesicles. Thus, in tissues where synaptic Zn2+ release was absent [knockout (KO) of vesicular Zn2+ transporter ZnT-3], SD propagation rates were increased, and no additional increase was observed following chelation of endogenous Zn2+ in these tissues. The role of synaptic Zn2+ was then examined on CSD in vivo. ZnT-3 KO animals had higher susceptibility to CSD than wild-type controls as evidenced by significantly higher propagation rates and frequencies. Studies of candidate mechanisms excluded changes in neuronal excitability, presynaptic release, and GABA receptors but left open a possible contribution of N-methyl-d-aspartate (NMDA) receptor inhibition. These results suggest the extracellular accumulation of synaptically released Zn2+ can serve as an intrinsic inhibitor to limit SD events. The inhibitory action of extracellular Zn2+ on SD may counteract to some extent the neurotoxic effects of intracellular Zn2+ accumulation in acute brain injury models.
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Richter, Frank, Reinhard Bauer, Andrea Ebersberger, Alfred Lehmenkühler, and Hans-Georg Schaible. "Enhanced Neuronal Excitability in Adult Rat Brainstem Causes Widespread Repetitive Brainstem Depolarizations with Cardiovascular Consequences." Journal of Cerebral Blood Flow & Metabolism 32, no. 8 (March 28, 2012): 1535–45. http://dx.doi.org/10.1038/jcbfm.2012.40.
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The brainstem of the adult rat is relatively resistant to spreading depolarization (SD) but after enhancement of excitability SD can be evoked by local application of KCl. In the present experiments, we observed that the enhanced excitability even triggers prolonged periods of repetitive depolarizations (RDs), which elicit significant cardiovascular changes. In contrast to KCl-evoked SDs with amplitudes of ∼24 mV and spreading velocity of 4 mm/min, spontaneous RDs had amplitudes of 7 to 12 mV, propagated up to 30 times faster than KCl-evoked SDs, and depolarized larger brainstem areas including the contralateral side. Similarly as SD, RDs depended on glutamatergic neurotransmission and were blocked by MK-801 or by the calcium channel blocker agatoxin. They depended on sodium channels and were blocked by tetrodotoxin. Functionally, the invasion of RDs into the spinal trigeminal and other nuclei evoked bursts of action potentials, indicating that specific neuronal systems are affected. In fact, during episodes of RDs the blood pressure and the local blood flow at the surface of the brainstem and the cortex increased substantially. Brainstem RDs did not propagate into the cerebral cortex. We propose to consider brainstem RPs as a pathophysiological mechanism whose significance for brainstem disease states should be further explored.
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Taş, Yağmur Çetin, İhsan Solaroğlu, and Yasemin Gürsoy-Özdemir. "Spreading Depolarization Waves in Neurological Diseases: A Short Review about its Pathophysiology and Clinical Relevance." Current Neuropharmacology 17, no. 2 (January 7, 2019): 151–64. http://dx.doi.org/10.2174/1570159x15666170915160707.
Full textAbstract:
Lesion growth following acutely injured brain tissue after stroke, subarachnoid hemorrhage and traumatic brain injury is an important issue and a new target area for promising therapeutic interventions. Spreading depolarization or peri-lesion depolarization waves were demonstrated as one of the significant contributors of continued lesion growth. In this short review, we discuss the pathophysiology for SD forming events and try to list findings detected in neurological disorders like migraine, stroke, subarachnoid hemorrhage and traumatic brain injury in both human as well as experimental studies. Pharmacological and non-pharmacological treatment strategies are highlighted and future directions and research limitations are discussed.
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Els, Thomas, Joachim Röther, Christian Beaulieu, Alexander de Crespigny, and Michael Moseley. "Hyperglycemia Delays Terminal Depolarization and Enhances Repolarization after Peri-Infarct Spreading Depression as Measured by Serial Diffusion MR Mapping." Journal of Cerebral Blood Flow & Metabolism 17, no. 5 (May 1997): 591–95. http://dx.doi.org/10.1097/00004647-199705000-00015.
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We investigated the effect of hyperglycemia on the initiation and propagation of spreading depression-like peri-infarct ischemic depolarization (SD) induced by focal cerebral ischemia in rats. Peri-infarct SD were monitored during the initial 15 minutes after remotely induced middle cerebral artery occlusion (MCAO) using serial diffusion weighted magnetic resonance imaging. Maps of the apparent diffusion coefficient (ADC) were calculated and ADC decreases were monitored over time. Hyperglycemic rats (n = 6) had a significant prolongation of the time from induction of MCAO to the start of the ADC decrease as compared with normoglycemic control rats. The time to the maximal ADC decrease was significantly delayed and recovery of transient ADC declines in the area adjacent to the ischemic core was significantly faster in hyperglycemic rats. We conclude that hyperglycemia delays the terminal depolarization in the ischemic core and supports a faster repolarization in severely mal-perfused penumbral tissue after SD, which reflects the increased availability of energy substrates in the state of hyperglycemia.
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Aitken, P. G., G. C. Tombaugh, D. A. Turner, and G. G. Somjen. "Similar Propagation of SD and Hypoxic SD-Like Depolarization in Rat Hippocampus Recorded Optically and Electrically." Journal of Neurophysiology 80, no. 3 (September 1, 1998): 1514–21. http://dx.doi.org/10.1152/jn.1998.80.3.1514.
Full textAbstract:
Aitken, P. G., G. C. Tombaugh, D. A. Turner, and G. G. Somjen. Similar propagation of SD and hypoxic SD-like depolarization in rat hippocampus recorded optically and electrically. J. Neurophysiol. 80: 1514–1521, 1998. Neuron membrane changes and ion redistribution during normoxic spreading depression (SD) induced, for example, by potassium injection, closely resemble those that occur during hypoxic SD-like depolarization (HSD) induced by oxygen withdrawal, but the degree to which the two phenomena are related is controversial. We used extracellular electrical recording and imaging of intrinsic optical signals in hippocampal tissue slices to compare 1) initiation and spread of these two phenomena and 2) the effects of putative gap junction blocking agents, heptanol and octanol. Both events arose focally, after which a clear advancing wave front of increased reflectance and DC shift spread along the CA1 stratum radiatum and s. oriens. The rate of spread was similar: conduction velocity of normoxic SD was 8.73 ± 0.92 mm/min (mean ± SE) measured electrically and 5.84 ± 0.63 mm/min measured optically, whereas HSD showed values of 7.22 ± 1.60 mm/min (electrical) and 6.79 ± 0.42 mm/min (optical). When initiated in CA1, normoxic SD consistently failed to enter the CA3 region (7/7 slices) and could not be initiated by direct KCl injection in the CA3 region ( n = 3). Likewise, the hypoxic SD-like optical signal showed onset in the CA1 region and halted at the CA1/CA3 boundary (9/9 slices), but in some (4/9) slices the dentate gyrus region showed a separate onset of signal changes. Microinjection into CA1 stratum radiatum of octanol (1 mM), which when bath applied arrests the spread of normoxic SD, created a small focus that appeared to be protected from hypoxic depolarization. However, bath application of heptanol (3 mM) or octanol (2 mM) did not prevent the spread of HSD, although the onset was delayed. This suggests that, although gap junctions may be essential for the spread of normoxic SD, they may play a less important role in the spread of HSD.
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Zhou, Ning, Ravi L. Rungta, Aqsa Malik, Huili Han, Dong Chuan Wu, and Brian A. MacVicar. "Regenerative Glutamate Release by Presynaptic NMDA Receptors Contributes to Spreading Depression." Journal of Cerebral Blood Flow & Metabolism 33, no. 10 (July 3, 2013): 1582–94. http://dx.doi.org/10.1038/jcbfm.2013.113.
Full textAbstract:
Spreading depression (SD) is a slowly propagating neuronal depolarization that underlies certain neurologic conditions. The wave-like pattern of its propagation suggests that SD arises from an unusual form of neuronal communication. We used enzyme-based glutamate electrodes to show that during SD induced by transiently raising extracellular K+ concentrations ([K+]o) in rat brain slices, there was a rapid increase in the extracellular glutamate concentration that required vesicular exocytosis but unlike fast synaptic transmission, still occurred when voltage-gated sodium and calcium channels (VGSC and VGCC) were blocked. Instead, presynaptic N-methyl-D-aspartate (NMDA) receptors (NMDARs) were activated during SD and could generate substantial glutamate release to support regenerative glutamate release and propagating waves when VGSCs and VGCCs were blocked. In calcium-free solutions, high [K+]o still triggered SD-like waves and glutamate efflux. Under such a condition, glutamate release was blocked by mitochondrial Na+/Ca2+ exchanger inhibitors that likely blocked calcium release from mitochondria secondary to NMDA-induced Na+ influx. Therefore presynaptic NMDA receptor activation is sufficient for triggering vesicular glutamate release during SD via both calcium entry and release from mitochondria by mitochondrial Na+/Ca2+ exchanger. Our observations suggest that presynaptic NMDARs contribute to a cycle of glutamate-induced glutamate release that mediate high [K+]o-triggered SD.
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Somjen, G. G., P. G. Aitken, G. L. Czéh, O. Herrearas, J. Jing, and J. N. Young. "Mechanisms of spreading depression: a review of recent findings and a hypothesis." Canadian Journal of Physiology and Pharmacology 70, S1 (May 15, 1992): S248—S254. http://dx.doi.org/10.1139/y92-268.
Full textAbstract:
Spreading depression of Leão (SD) can be provoked by numerous nonspecific mechanical, electrical, and chemical stimuli. A similar, if not identical, phenomenon can be provoked by hypoxia. SD is characterized by drastic depolarization of neurons, severe reduction of membrane resistance, and redistribution of ions across cell membranes. Glial cells also depolarize but retain membrane resistance. Tetraethylammonium hastens the onset of hypoxic SD but reduces the sustained potential shift and K+ outflow from cells; 4-aminopyridine also accelerates SD but has no effect on the voltage shift. N-Methyl-D-aspartate receptor antagonists delay the onset of SD, while nickel and cobalt reduce the amplitude of SD-related redistribution of Ca2+. Yet, no specific blocker of SD has been found. Microdialysis of high-K+ solution in hippocampal CA1 region induces recurrent waves of SD propagating semi-independently in adjacent tissue layers, and a prolonged unstable depressed state that has not previously been described. Neither the release of K+ ions nor of glutamate is the unique agent of SD propagation. On the basis of recent findings we propose a hypothetical sequence of events that reconcile many of the previously seemingly paradoxical observations.Key words: spreading depression, membrane resistance, membrane ion currents, extracellular potassium, extracellular calcium.
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Sugimoto, Kazutaka, David Y. Chung, Maximilian Böhm, Paul Fischer, Tsubasa Takizawa, Sanem Aslihan Aykan, Tao Qin, et al. "Peri-Infarct Hot-Zones Have Higher Susceptibility to Optogenetic Functional Activation-Induced Spreading Depolarizations." Stroke 51, no. 8 (August 2020): 2526–35. http://dx.doi.org/10.1161/strokeaha.120.029618.
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Background and Purpose: Spreading depolarizations (SDs) are recurrent and ostensibly spontaneous depolarization waves that may contribute to infarct progression after stroke. Somatosensory activation of the metastable peri-infarct tissue triggers peri-infarct SDs at a high rate. Methods: We directly measured the functional activation threshold to trigger SDs in peri-infarct hot zones using optogenetic stimulation after distal middle cerebral artery occlusion in Thy1-ChR2-YFP mice. Results: Optogenetic activation of peri-infarct tissue triggered SDs at a strikingly high rate (64%) compared with contralateral homotopic cortex (8%; P =0.004). Laser speckle perfusion imaging identified a residual blood flow of 31±2% of baseline marking the metastable tissue with a propensity to develop SDs. Conclusions: Our data reveal a spatially distinct increase in SD susceptibility in peri-infarct tissue where physiological levels of functional activation are capable of triggering SDs. Given the potentially deleterious effects of peri-infarct SDs, the effect of sensory overstimulation in hyperacute stroke should be examined more carefully.
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Tamura, Yasuhisa, Asami Eguchi, Guanghua Jin, Mustafa M. Sami, and Yosky Kataoka. "Cortical Spreading Depression Shifts Cell Fate Determination of Progenitor Cells in the Adult Cortex." Journal of Cerebral Blood Flow & Metabolism 32, no. 10 (July 11, 2012): 1879–87. http://dx.doi.org/10.1038/jcbfm.2012.98.
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Cortical spreading depression (SD) is propagating neuronal and glial depolarization and is thought to underly the pathophysiology of migraine. We have reported that cortical SD facilitates the proliferative activity of NG2-containing progenitor cells (NG2 cells) that give rise to oligodendrocytes and immature neurons under the physiological conditions in the adult mammalian cortex. Astrocytes have an important role in the maintenance of neuronal functions and alleviate neuronal damage after intense neuronal excitation, including SD and seizures. We here investigated whether SD promotes astrocyte generation from NG2 cells following SD stimuli. Spreading depression was induced by epidural application of 1 mol/L KCl solution in adult rats. We investigated the cell fate of NG2 cells following SD-induced proliferation using 5′-bromodeoxyuridine labeling and immunohistochemical analysis. Newly generated astrocytes were observed only in the SD-stimulated cortex, but not in the contralateral cortex or in normal cortex. The astrocytes were generated from proliferating NG2 cells. Astrogenesis depended on the number of SD stimuli, and was accompanied by suppression of oligodendrogenesis. These observations indicate that the cell fate of NG2 cells was shifted from oligodendrocytes to astrocytes depending on SD stimuli, suggesting activity-dependent tissue remodeling for maintenance of brain functions.
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Funke, Frank, Miriam Kron, Mathias Dutschmann, and Michael Müller. "Infant Brain Stem Is Prone to the Generation of Spreading Depression During Severe Hypoxia." Journal of Neurophysiology 101, no. 5 (May 2009): 2395–410. http://dx.doi.org/10.1152/jn.91260.2008.
Full textAbstract:
Spreading depression (SD) resembles a concerted, massive neuronal/glial depolarization propagating within the gray matter. Being associated with cerebropathology, such as cerebral ischemia or hemorrhage, epileptic seizures, and migraine, it is well studied in cortex and hippocampus. We have now analyzed the susceptibility of rat brain stem to hypoxia-induced spreading depression-like depolarization (HSD), which could critically interfere with cardiorespiratory control. In rat brain stem slices, severe hypoxia (oxygen withdrawal) triggered HSD within minutes. The sudden extracellular DC potential shift of approximately −20 mV showed the typical profile known from other brain regions and was accompanied by an intrinsic optical signal (IOS). Spatiotemporal IOS analysis revealed that in infant brain stem, HSD was preferably ignited within the spinal trigeminal nucleus and then mostly spread out medially, invading the hypoglossal nucleus, the nucleus of the solitary tract (NTS), and the ventral respiratory group (VRG). The neuronal hypoxic depolarizations underlying the generation of HSD were massive, but incomplete. The propagation velocity of HSD and the associated extracellular K+ rise were also less marked than in other brain regions. In adult brain stem, HSD was mostly confined to the NTS and its occurrence was facilitated by hypotonic solutions, but not by glial poisoning or block of GABAergic and glycinergic synapses. In conclusion, brain stem tissue reliably generates propagating HSD episodes, which may be of interest for basilar-type migraine and brain stem infarcts. The preferred occurrence of HSD in the infant brain stem and its propagation into the VRG may be of importance for neonatal brain stem pathology such as sudden infant death syndrome.
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Müller, Michael, and George G. Somjen. "Na+ Dependence and the Role of Glutamate Receptors and Na+ Channels in Ion Fluxes During Hypoxia of Rat Hippocampal Slices." Journal of Neurophysiology 84, no. 4 (October 1, 2000): 1869–80. http://dx.doi.org/10.1152/jn.2000.84.4.1869.
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Spreading depression (SD) as well as hypoxia-induced SD-like depolarization in forebrain gray matter are characterized by near complete depolarization of neurons. The biophysical mechanism of the depolarization is not known. Earlier we reported that simultaneous pharmacological blockade of all known major Na+ and Ca2+ channels prevents hypoxic SD. We now recorded extracellular voltage, Na+, and K+concentrations and the intracellular potential of individual CA1 pyramidal neurons during hypoxia of rat hippocampal tissue slices after substituting Na+ in the bath by an impermeant cation, or in the presence of channel blocking drugs applied individually and in combination. Reducing extracellular Na+ concentration [Na+]o to 90 mM postponed the hypoxia-induced extracellular DC-potential deflection (Δ V o) and reduced its amplitude, and it also postponed the SD-like depolarization of neurons. After lowering [Na+]o to 25 mM, SD-like Δ V o became very small, indicating that an influx of Na+ is required for SD; influx of Ca2+ ions alone is not sufficient. We then asked whether the SD-related Na+ current flows through glutamate-controlled and/or through voltage-gated Na+channels. Administration of either the non- N-methyl-d-aspartate (NMDA) receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX), or the NMDA receptor antagonist (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) postponed the hypoxic Δ V o and depressed its amplitude but the effect of the combined administration of these two drugs was not greater than that of either alone. During the early phase of hypoxia, before SD onset, [K+]oincreased faster and reached a much higher level in the presence of glutamate antagonists than in their absence. The [K+]o level reached at the height of hypoxic SD was, however, not affected. When TTX was added to DNQX and CPP, SD was prevented in half the trials. When SD did occur, it was greatly delayed, yet eventually neurons depolarized to the same extent as in normal solution. The SD-related sudden drop in [Na+]o was depressed by only 19% in the presence of the three drugs, indicating that Na+ can flow into cells through pathways other than ionotropic glutamate receptors and TTX-sensitive Na+ channels. We conclude that, when they are functional, glutamate-receptor-mediated and voltage-gated Na+ currents are the major generators of the self-regenerative rapid depolarization, but in their absence other pathways can sometimes take their place. The final level of SD-like depolarization is determined by positive feedback and not by the number of channels available. A schematic flow chart of the events generating hypoxic SD is discussed.
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Müller, Michael, and George G. Somjen. "Na+ and K+ Concentrations, Extra- and Intracellular Voltages, and the Effect of TTX in Hypoxic Rat Hippocampal Slices." Journal of Neurophysiology 83, no. 2 (February 1, 2000): 735–45. http://dx.doi.org/10.1152/jn.2000.83.2.735.
Full textAbstract:
Severe hypoxia causes rapid depolarization of CA1 neurons and glial cells that resembles spreading depression (SD). In brain slices in vitro, the SD-like depolarization and the associated irreversible loss of function can be postponed, but not prevented, by blockade of Na+ currents by tetrodotoxin (TTX). To investigate the role of Na+ flux, we made recordings from the CA1 region in hippocampal slices in the presence and absence of TTX. We measured membrane changes in single CA1 pyramidal neurons simultaneously with extracellular DC potential ( V o) and either extracellular [K+] or [Na+]; alternatively, we simultaneously recorded [Na+]o, [K+]o, and V o. Confirming previous reports, early during hypoxia, before SD onset, [K+]o began to rise, whereas [Na+]o still remained normal and V o showed a slight, gradual, negative shift; neurons first hyperpolarized and then began to gradually depolarize. The SD-like abrupt negative Δ V ocorresponded to a near complete depolarization of pyramidal neurons and an 89% decrease in input resistance. [K+]oincreased by 47 mM and [Na+]o dropped by 91 mM. Changes in intracellular Na+ and K+concentrations, estimated on the basis of the measured extracellular ion levels and the relative volume fractions of the neuronal, glial, and extracellular compartment, were much more moderate. Because [Na+]o dropped more than [K+]o increased, simple exchange of Na+ for K+ cannot account for these ionic changes. The apparent imbalance of charge could be made up by Cl− influx into neurons paralleling Na+ flux and release of Mg2+ from cells. The hypoxia-induced changes in interneurons resembled those observed in pyramidal neurons. Astrocytes responded with an initial slow depolarization as [K+]o rose. It was followed by a rapid but incomplete depolarization as soon as SD occurred, which could be accounted for by the reduced ratio, [K+]i/[K+]o. TTX (1 μM) markedly postponed SD, but the SD-related changes in [K+]o and [Na+]owere only reduced by 23 and 12%, respectively. In TTX-treated pyramidal neurons, the delayed SD-like depolarization took off from a more positive level, but the final depolarized intracellular potential and input resistance were not different from control. We conclude that TTX-sensitive channels mediate only a fraction of the Na+influx, and that some of the K+ is released in exchange for Na+. Even though TTX-sensitive Na+ currents are not essential for the self-regenerative membrane changes during hypoxic SD, in control solutions their activation may trigger the transition from gradual to rapid depolarization of neurons, thereby synchronizing the SD-like event.