Memantine Improves Recovery After Spreading Depolarization in Brain Slices and can be Considered for Future Clinical Trials

Abstract Anoxic spreading depolarization (aSD) has been hypothesized as a terminal event during oxygen–glucose deprivation (OGD) in submerged cortical slices in vitro. However, mechanical artifacts caused by aSD-triggered edema may introduce error in the assessment of neuronal viability. Here, using continuous patch-clamp recordings from submerged rat cortical slices, we first confirmed that vast majority of L4 neurons permanently lost their membrane potential during OGD-induced aSD. In some recordings, spontaneous transition from whole-cell to out-side out configuration occurred during or after aSD, and only a small fraction of neurons survived aSD with reperfusion started shortly after aSD. Secondly, to minimize artifacts caused by OGD-induced edema, cells were short-term patched following OGD episodes of various duration. Nearly half of L4 cells maintained membrane potential and showed the ability to spike-fire if reperfusion started less than 10 min after aSD. The probability of finding live neurons progressively decreased at longer reperfusion delays at a rate of about 2% per minute. We also found that neurons in L2/3 show nearly threefold higher resistance to OGD than neurons in L4. Our results suggest that in the OGD ischemia model, aSD is not a terminal event, and that the “commitment point” of irreversible damage occurs at variable delays, in the range of tens of minutes, after OGD-induced aSD in submerged cortical slices.

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Spreading depolarization and neuronal damage or survival in mouse neocortical brain slices immediately and 12 hours following middle cerebral artery occlusion

Journal of Neurophysiology ◽

10.1152/jn.00670.2018 ◽

2019 ◽

Vol 121 (5) ◽

pp. 1650-1663 ◽

Cited By ~ 2

Author(s):

Dylan Petrin ◽

Peter J. Gagolewicz ◽

Rasha H. Mehder ◽

Brian M. Bennett ◽

Albert Y. Jin ◽

...

Keyword(s):

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Neuronal Damage ◽

Brain Slices ◽

Artery Occlusion ◽

Dendritic Morphology ◽

Striatal Neurons ◽

Spreading Depolarization ◽

Cerebral Artery Occlusion

Whereas many studies have examined the properties of the compromised neocortex in the first several days following ischemia, there is less information regarding the initial 12 h poststroke. In this study we examined live mouse neocortical slices harvested immediately and 12 h after a 30-min middle cerebral artery occlusion (MCAo). We compared nonischemic and ischemic hemispheres with regard to the propensity for tissue swelling and for generating spreading depolarization (SD), as well as evoked synaptic responses and single pyramidal neuron electrophysiological properties. We observed spontaneous SD in 7% of slices on the nonstroked side and 25% in the stroked side following the 30-min MCAo. Spontaneous SD was rare in 12-h recovery slices. The region of the ischemic core and surround in slices was not susceptible to SD induced by oxygen and glucose deprivation. At the neuronal level, neocortical gray matter is surprisingly unaltered in brain slices harvested immediately poststroke. However, by 12 h, the fields of pyramidal and striatal neurons that comprise the infarcted core are electrophysiologically silent because the majority are morphologically devastated. Yet, there remains a subset of diffusely distributed “healthy” pyramidal neurons in the core at 12 h post-MCAo that persist for days poststroke. Their intact electrophysiology and dendritic morphology indicate a surprisingly selective resilience to stroke at the neuronal level. NEW & NOTEWORTHY It is generally accepted that the injured core region of the brain resulting from a focal stroke contains no functioning neurons. Our study shows that some neurons, although surrounded by devastated neighbors, can maintain their structure and electrical activity. This surprising finding raises the possibility of discovering how these neurons are protected to pinpoint new strategies for reducing stroke injury.

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Spreading Depolarization-Induced Adenosine Accumulation Reflects Metabolic Status In Vitro and In Vivo

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.146 ◽

2014 ◽

Vol 34 (11) ◽

pp. 1779-1790 ◽

Cited By ~ 15

Author(s):

Britta E Lindquist ◽

C William Shuttleworth

Keyword(s):

Brain Slices ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Artery Occlusion ◽

Metabolic Status ◽

Metabolic Demand ◽

Spreading Depolarization ◽

Clinical Conditions ◽

Cerebral Artery Occlusion

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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Effect of Nortriptyline on Spreading Depolarization

Archives of Neuroscience ◽

10.5812/ans.102102 ◽

2020 ◽

Vol 7 (3) ◽

Author(s):

Ebrahim Behzad ◽

Mojdeh Ghabaee ◽

Mohammad Reza Bigdeli ◽

Farshid Noorbakhsh ◽

Ali Gorji ◽

...

Keyword(s):

Pyramidal Neurons ◽

Neurological Diseases ◽

Brain Slices ◽

Lesion Size ◽

Extracellular Potassium ◽

Hippocampal Pyramidal Neurons ◽

Electrophysiological Properties ◽

Spreading Depolarization ◽

Significant Difference ◽

Molecular Aspects

Background: Spreading depolarization is associated with the extension of lesion size and complications in some important neurological diseases such as stroke, epilepsy, migraine, and traumatic brain injury. Objectives: This study aimed to reveal some molecular aspects of spreading depolarization and suggesting new therapeutic targets for its control by changing the function of different astrocytic and neuronal ion channels. Methods: The effects of nortriptyline on spreading depolarization in cortical and hippocampal tissues and on the electrophysiological properties of CA1 hippocampal pyramidal neurons were assessed by extra- and intracellular recording, following washing rat brain slices by the drug. Results: Nortriptyline made a significant increase in the amplitude of spreading depolarization in cortical and hippocampal tissues relative to control but did not change the duration significantly in each of the tissues. No significant difference was found in the effects of spreading depolarization on the electrophysiological properties of the CA1 pyramidal neurons between nortriptyline and control groups. Conclusions: The stimulating effect of nortriptyline on spreading depolarization is probably related to the augmentation of extracellular potassium collection in the cortex and hippocampus due to inhibition of astrocytic potassium scavenging function. This change can make more neurons prone to depolarization and increase the overall amplitude of spreading depolarization waves. Further studies should assess the effect of enhancing the clearance function of astrocyte-specific inwardly rectifying potassium channels, Kir4.1, or preventing other factors contributing to spreading depolarization on control of the process.

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Adenosine receptor activation is responsible for prolonged depression of synaptic transmission after spreading depolarization in brain slices

Neuroscience ◽

10.1016/j.neuroscience.2012.07.053 ◽

2012 ◽

Vol 223 ◽

pp. 365-376 ◽

Cited By ~ 32

Author(s):

B.E. Lindquist ◽

C.W. Shuttleworth

Keyword(s):

Synaptic Transmission ◽

Adenosine Receptor ◽

Brain Slices ◽

Receptor Activation ◽

Spreading Depolarization ◽

Adenosine Receptor Activation

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Localization of Gallium-67 in Peritoneal Cells by Electron Microscopic Autoradiography

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100072460 ◽

1973 ◽

Vol 31 ◽

pp. 404-405

Author(s):

D. C. Swartzendruber ◽

Norma L. Idoyaga-Vargas

Keyword(s):

Clinical Trials ◽

Soft Tissue ◽

Tumor Tissue ◽

Soft Tissue Tumors ◽

Clinical Usefulness ◽

Electron Microscopic ◽

Normal Cells ◽

Electron Microscopic Autoradiography ◽

Peritoneal Cells ◽

Gallium 67

The radionuclide gallium-67 (67Ga) localizes preferentially but not specifically in many human and experimental soft-tissue tumors. Because of this localization, 67Ga is used in clinical trials to detect humar. cancers by external scintiscanning methods. However, the fact that 67Ga does not localize specifically in tumors requires for its eventual clinical usefulness a fuller understanding of the mechanisms that control its deposition in both malignant and normal cells. We have previously reported that 67Ga localizes in lysosomal-like bodies, notably, although not exclusively, in macrophages of the spocytaneous AKR thymoma. Further studies on the uptake of 67Ga by macrophages are needed to determine whether there are factors related to malignancy that might alter the localization of 67Ga in these cells and thus provide clues to discovering the mechanism of 67Ga localization in tumor tissue.

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