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  • 11
    Electronic Resource
    Electronic Resource
    The temporal evolution of hypoglycemic brain damage (1985)
    Springer
    Acta neuropathologica 67 (1985), S. 13-24 
    Details
    ISSN: 1432-0533
    Keywords: Hypoglycemia ; Cerebral cortex ; Nerve cell injury ; Dark neurons ; Acidophilic neurons ; Mitochondria ; Golgi apparatus ; Cell necrosis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the course of a study on the pathogenesis of neuronal necrosis in severe hypoglycemia, the morphological characteristics reflecting reversible and irreversible neuronal lesions were examined as a function of time following normalization of blood glucose. To that end, closely spaced time intervals were studied in the rat cerebral cortex before, during, and up to 1 year after standardized pure hypoglycemic insults of 30 and 60 min of cerebral isoelectricity. Both the superficial and deep layers of the cerebral cortex showed dark and light neurons during and several hours after the insult. By electron microscopy (EM) the dark neurons were characterized by marked condensation of both karyoplasma and cytoplasm, with discernible, tightly packed cytoplasmic organelles. The light neurons displayed clustering of normal organelles around the nucleus with clearing of the peripheral cytoplasm. Some cells, both dark neurons and neurons of normal electron density, contained swollen mitochondrial with fractured cristae. Light neurons disappeared from the cerebral cortex by 4 h of recovery. Some dark neurons in the superficial cortex and almost all in the deep cortex evolved through transitional forms into normal neurons by 6 h recovery. Another portion of the dark neurons in the superficial cortex became acidophilic between 4 and 12 h, and by EM they demonstrated karyorrhexis with stippled electron-dense chromatin. The plasma membrane was disrupted, the cytoplasm was composed of amorphous granular debris, and the mitochondria contained flocculent densities. These definitive indices of irreversible neuronal damage were seen as early as 4–8 h recovery. Subsequently, the acidophilic neurons were removed from the tissue, and gliosis ensued. Thus, even markedly hyperchromatic “dark” neurons are compatible with survival of the cell, as are neurons with conspicuous mitochondrial swelling. Definite nerve cell death is verified as the appearance of acidophilic neurons at which stage extensive damage to mitochondria is already seen in the form of flocculent densities, and cell membranes are ruptured. Our previous results have shown that hypoglycemic neocortical damage affects the superficial laminae, chiefly layer 2. The present results demonstrate that, following the primary insult, this damage evolves relatively rapidly within the first 4–12 h. We have obtained no evidence that additional necrotic neurons are recruited after longer recovery periods.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00688120
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  • 12
    Electronic Resource
    Electronic Resource
    The temporal evolution of hypoglycemic brain damage (1985)
    Springer
    Acta neuropathologica 67 (1985), S. 37-50 
    Details
    ISSN: 1432-0533
    Keywords: Hypoglycemia ; Cerebral damage ; Dark neurons ; Neuronal necrosis ; Caudate ; Putamen ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The caudate nucleus and putamen belong to the selectively vulnerable brain regions which incur neuronal damage in clinical and experimental settings of both hypoglycemia and ischemia. We have previously documented the density and distribution of the hypoglycemic damage in rat caudoputamen, but the evolution of the injury, i.e., the sequence of structural changes, has not been assessed. Therefore, in the present study we analyze the light and electron microscopic alterations in the caudoputamen of rats exposed to standardized, pure insults of severe hypoglycemia with isoelectric EEG for 10–60 min, or in rats which, following insults of 30 or 60 min, were allowed to recover for periods from 5 min to 6 months. The hypoglycemic insult produced severe nerve cell injury in the dorsolateral caudoputamen. Immediately after the insult abnormal light neurons with clearing of the peripheral cytoplasm were present. These cells disappeared early in the receovery period, as they do in the cerebral cortex. Dark neurons were also present, but unlike those in the cerebral cortex they did not appear until recovery was instituted. Their number increased for a couple of hours and they became acidophilic within 4–6 h. At this stage, electron microscopy revealed severe clumping of the nuclear chromatin and cytoplasm as well as incipient fragmentation of cell membranes, all these changes indicating an irreversible injury. Within 24 h flocculent densities appeared in the mitochondria and by day 2–3 of recovery the great majority of the medium-sized neurons had undergone karyorrhexis and cytorrhexis, their remnants being subsequently removed by macrophages. After some weeks only large and a few medium-sized neurons remained amidst reactive astrocytes and numerous macrophages. The delay in the appearance of dark, lethally injured medium-sized neurons until the recovery was instituted suggests an effect that does not become apparent until the substrate supply and energy production are restored. Furthermore, it pointt out again the selectivity of the hypoglycemic nerve cell injury with respect to the type (metabolic characteristics?) and topographic location of the neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00688122
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  • 13
    Electronic Resource
    Electronic Resource
    Early axonal lesion and preserved microvasculature in epilepsy-induced hypermetabolic necrosis of the substantia nigra (1986)
    Springer
    Acta neuropathologica 71 (1986), S. 207-215 
    Details
    ISSN: 1432-0533
    Keywords: Epilepsy ; Substantia nigra ; Necrosis ; Encephalomalacia ; Mesencephalon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The time course of structural change in epilepsy-induced necrosis of the substantia nigra was studied by light and electron microscopy, and was correlated with previous metabolic studies. By light microscopy, tinctorial pallor appeared early, followed by pan-necrosis and macrophage infiltration. Mild lesions showed neuropil vacuolation but sparing of neurons, rather than a selective neuronal vulnerability. Electron microscopy of the evolving necrosis revealed an orderly sequence of structural damage involving first axons, then dendrites, neurons, and glia. No necrotic endothelial cells could be found, even in areas of apparent pan-necrosis by light microscopy. Pericytes near the vascular lumen were spared, whereas those in outer locations were necrotic. Edema, measured densitometrically, was absent. Previous metabolic studies of this lesion have demonstrated a pronounced focal lactic acidosis due to anaerobic hypermetabolism. Although the lesions resemble infarcts, hypermia rather than ischemia has been shown to accompany their development. Structural preservation of endothelial cells and inner pericytes likely stems from proximity to the moving blood stream, away from the site of lactic acid production in the neuropil. The findings indicate that the perfusion of necrotic tissue occurs via a persisting, intact microcirculation. The relative neuronal sparing and the early axonal rather than dendritic lesion show a clear distinction from excitotoxic pathology.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00688041
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  • 14
    Electronic Resource
    Electronic Resource
    Hypoglycemic brain injury (1980)
    Springer
    Acta neuropathologica 50 (1980), S. 31-41 
    Details
    ISSN: 1432-0533
    Keywords: Hypoglycemia ; Nerve cell injury ; Biochemistry ; Light microscopy ; Rat cerebral cortex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Profound hypoglycemia causing the disappearance of spontaneous EEG activity was induced by insulin in rats. For analysis of cerebral cortical concentrations of labile phosphates, glycolytic metabolites and amino acids, the brain was frozen in situ. For microscopic analysis of the corresponding cerebral cortical areas the brain was fixed by perfusion. Hypoglycemia with an isoelectric EEG for 30 and 60 min caused severe perturbation of the cerebral energy metabolites. After both 30 and 60 min of isoelectric EEG, two microscopically different types of nerve cell injury were seen. Type I injury was characterized by angulated, darkly stained neurons with perineuronal vacuolation, mainly affecting small neurons in cortical layer 3. Type II injured neurons, mainly larger ones in layers 5–6, were slightly swollen with vacuolation or clearing (depending on the histotechnique used) of the peripheral cytoplasm, but had no nuclear changes. Recovery was induced by glucose injection. Improvement in the cerebral energy state occurred during the 30 min recovery period even after 60 min of hypoglycemia. However, the persisting reduction in the size of adenine nucleotide and amino acid pools after 30 or 180 min recovery suggested that some cells remained damaged. In confirmation many type I injured neurons persisted during the recovery suggesting an irreversible injury. The disappearance of virtually all type II injuries indicated reversibility of these histopathological changes. The microscopic changes in hypoglycemia were different from those in anoxia-ischemia suggesting a dissimilar pathogenesis in these states despite the common final pathway of energy failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00688532
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  • 15
    Electronic Resource
    Electronic Resource
    Hypoglycemic brain injury (1980)
    Springer
    Acta neuropathologica 50 (1980), S. 43-52 
    Details
    ISSN: 1432-0533
    Keywords: Hypoglycemia ; Nerve cell injury ; Electron microscopy ; Rat cerebral cortex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Severe hypoglycemia was induced in rats by insulin. The brain was fixed in situ by perfusion after the spontaneous EEG had disappeared for 30 or 60 min or after recovery had been induced for 30 or 180 min by glucose injection. Samples from the cerebral cortex from the area corresponding to the previous metabolic studies were processed for electron microscopy. The light-microscopic finding of two different types of nerve cell injury, reported in a preceding communication (Agardh et al. 1980), was also verified at the ultrastructural level. The type I injury was characterized by cellular shrinkage, condensation of the cell sap and nuclei, and perineuronal astrocytic swelling. No swelling of mitochondria occurred. The slightly swollen type II injured neurons showed contraction of mitochondria, disintegration of ribosomes, loss of RER, and appearance of membrane whorls, while their nuclear chromatin remained evenly distributed. No transition from one type to the other was observed. Neither type of nerve cell injury in hypoglycemia was like that commonly seen in anoxic-ischemic insults indicating a different pathogenesis in these states despite the common final pathway of energy failure. The loss of endoplasmic membranes and disintegration of ribosomes suggests that these structures might be sacrificed for energy production in the absence of normal substrates. During recovery, though, the number of type I injured neurons decreased while some of the remaining ones appeared even more severely affected, suggesting irreversible damage. Type II injured neurons were no longer seen indicating reversibility of these changes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00688533
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  • 16
    Electronic Resource
    Electronic Resource
    Substantia nigra damage induced by ischemia in hyperglycemic rats (1987)
    Springer
    Acta neuropathologica 75 (1987), S. 131-139 
    Details
    ISSN: 1432-0533
    Keywords: Cerebral ischemia ; Hyperglycemia ; Substantia nigra ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Preischemic hyperglycemia induced by feeding or glucose infusion worsens the brain damage and the clinical outcome following ischemia of a given duration and density, and characteristically causes postischemic seizure activity. Light microscopy has previously showed that, in the rat, transient hyperglycemic ischemia induced by bilateral carotid occlusion in combination with arterial hypotension causes a uni- or bilateral lesion in the pars reticulata of the substantia nigra. Since this region has a central role in preventing seizure discharges the present study was carried out to determine the ultrastructural characteristics of this lesion. In rats with 10 min of transient hyperglycemic ischemia followed by recirculation for 1 to 18 h, the pars reticulata of the substantia nigra showed signs of status spongiosus, as well as extensive nerve cell alterations. These changes were observed after all recovery periods studied. The spongiotic appearance was mainly caused by swelling of dendrites and, to a lesser degree, by astrocytic swelling. The dendrites were expanded at all recovery times but the severity increased during the later periods of recirculation. These swollen dendrites contained severely expanded mitochondrias and endoplasmic reticulum. The cytoskeletal elements showed disordered lining of microtubules. Two major types of nerve cell alterations were present: a “pale” and a “dark” variety. The pale type was the most frequent cell alteration. It occurred in all experimental groups and at all time points. Redistribution of the nuclear chromatin and of cytoplasmic organelles as well as swelling of the same type as in the dendrites were the essential changes. The dark neurons were much fewer in number and occupied a peripheral position in the pars reticulata. Astrocytic foot processes appeared to be dilated around the dark neurons. Swelling of astrocyte processes was most pronounced in the 1 h recovery animals. Both types of neurons showed severe mitochondrial alterations of the type observed in dendrites. Occasionally, mitochondrial alterations were found in astrocytic processes as well. Blood vessel alterations were lacking. Previous studies have shown that in this model of ischemia the substantia nigra has a relatively well-preserved blood perfusion. In view of this the extensive histopathological lesions are surprising. We speculate that the lesions primarily involve excitotoxic damage to dendrites, with pronounced lactic acidosis playing a contributory role in causing axonal and glial pathology as well.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00687073
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  • 17
    Electronic Resource
    Electronic Resource
    Influence of acid-base changes on the intracellular calcium concentration of neurons in primary culture (1994)
    Springer
    Experimental brain research 101 (1994), S. 265-271 
    Details
    ISSN: 1432-1106
    Keywords: Calcium ions ; Neurons ; Acid-base changes ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The influence of changes in intra- and extracellular pH (pHi and pHe, respectively) on the cytosolic, free calcium concentration ([Ca2+]i) of neocortical neurons was studied by microspectrofluorometric techniques and the fluorophore fura-2. When, at constant pHe, pHi was lowered with the NH4Cl prepulse technique, or by a transient increase in CO2 tension, [Ca2+]i invariably increased, the magnitude of the rise being proportional to ΔpHi. Since similar results were obtained in Ca2+-free solutions, the results suggest that the rise in [Ca2+]i was due to calcium release from intracellular stores. The initial alkaline transient during NH4Cl exposure was associated with a rise in [Ca2+]i. However, this rise seemed to reflect influx of Ca2+ from the external solution. Thus, in Ca2+-free solution NH4Cl exposure led to a decrease in [Ca2+]i. This result and others suggest that, at constant pHe, intracellular alkalosis reduces [Ca2+]i, probably by enhancing sequestration of calcium. When cells were exposed to a CO2 transient at reduced pHe, Ca2+ rose initially but then fell, often below basal values. Similar results were obtained when extracellular HCO 3 - concentration was reduced at constant CO2 tension. Unexpectedly, such results were obtained only in Ca2+-containing solutions. In Ca2+-free solutions, acidosis always raised [Ca2+]i. It is suggested that a lowering of pHe stimulates extrusion of Ca2+ by ATP-driven Ca2+/2H+ antiport.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00228746
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  • 18
    Electronic Resource
    Electronic Resource
    Changes in the bioenergetic state of rat hippocampus during 2.5 min of ischemia, and prevention of cell damage by cyclosporin A in hyperglycemic subjects (1997)
    Springer
    Experimental brain research 114 (1997), S. 44-50 
    Details
    ISSN: 1432-1106
    Keywords: Key words Forebrain ischemia ; Hyperglycemia ; Hippocampus ; Bioenergetic state ; Cyclosporin A ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A recent study from this laboratory has shown that brief transient ischemia (2 min 30 s) in normo- and hyperglycemic rats leads to moderate neuronal necrosis in CA1 cells of the hippocampus, of equal density in the two groups. However, hyperglycemic animals failed to depolarize during the ischemia, nor did they show a decrease in extracellular calcium concentration. The present study was undertaken to study the metabolic correlates to these unexpected findings. Normoglycemic (plasma glucose ∼6 mM) and hyperglycemic (∼20 mM) rats were subjected to ischemic periods of 1 min and 2 min 15 s (2 min 30 s with freezing delay considered), and their brains were frozen in situ. Samples of dorsal hippocampus were dissected at –22°C and extracted for the measurement of phosphocreatine (PCr), creatine, ATP, ADP, AMP, glucose, glycogen, and lactate. Normoglycemic animals showed rapid depletion of PCr, ATP, glucose, and glycogen, and a rise in lactate content to 10–12 mM·kg–1 during the ischemia. Hyperglycemic animals displayed a more moderate rate of fall of PCr and ATP, with ATP values exceeding 50% of control after 2 min 30 s. Glycogen stores were largely maintained, but degradation of glucose somewhat enhanced the lactic acidosis. The results demonstrate that hyperglycemic rats maintained ATP at levels sufficient to prevent cell depolarization and calcium influx during the ischemic period. However, the metabolic perturbation observed must have been responsible for the delayed neuronal damage. We speculate that lowered ATP, increased inorganic P, and oxidative stress triggered a delayed mitochondrial permeability transition (MPT), which led to delayed neuronal necrosis. This assumption was supported by a second series of experiments in which CA1 damage in hyperglycemic rats was prevented by cyclosporin A, a virtually specific inhibitor of the MPT.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00005622
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  • 19
    Electronic Resource
    Electronic Resource
    Calcium metabolism of focal and penumbral tissues in rats subjected to transient middle cerebral artery occlusion (1998)
    Springer
    Experimental brain research 120 (1998), S. 503-509 
    Details
    ISSN: 1432-1106
    Keywords: Key words Extracellular calcium concentration ; Total tissue calcium content ; Middle cerebral artery occlusion ; Reperfusion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present experiments were undertaken to define changes in tissue calcium metabolism in focal and perifocal (“penumbral”) tissues following 2 h of transient middle cerebral artery occlusion (MCAO) in rats, induced with an intraluminal filament occlusion technique. The extracellular calcium concentration ([Ca2+]e) was measured with ion-selective microelectrodes in neocortical focus and penumbra. For measurement of total tissue calcium content, tissue samples from these areas were collected and analyzed with atomic absorption spectrometry. During MCAO, [Ca2+]e in a neocortical focal area fell from a normal value of about 1.2 mM to values around 0.1 mM, suggesting translocation of virtually all extracellular calcium to intracellular fluids. Recirculation was accompanied by re-extrusion of calcium within 5–7 min; however, [Ca2+]e never returned to normal but stabilized at about 50% of the control value for the first 6 h, and decreased further after 24 h. In penumbral areas, [Ca2+]e showed the expected transient decreases associated with spreading depression-like (or ischemic) depolarization waves. Recirculation was followed by return of [Ca2+]e towards normal values. In the focus, water content increased from about 79% to about 80.4% at the end of the 2-h period of ischemia. After 2 h and 4 h of recirculation, the edema was aggravated (mean values 81.9% and 81.2%, respectively). After 6 h and 24 h, the edema was more pronounced (83.6% and 83.8%, respectively). In the penumbra, no significant edema was observed until 6 h and 24 h of recirculation. The total tissue calcium content in the focus (expressed by unit dry weight) increased at the end of the ischemia period demonstrating calcium translocation from blood to tissue. After 6 h and 24 h, the content increased two- to threefold, compared with control. Changes in the penumbra were qualitatively similar but less pronounced, and a significant increase was not observed until after 6 h of recirculation. The results suggest that 2 h of MCAO leads to a profound perturbation of cell calcium metabolism. In focal areas, cells fail to extrude the calcium that is gradually accumulated during reperfusion and show massive calcium overload after the first 4–6 h of recirculation. Penumbral tissues show a similar increase in calcium concentration after 6 h of recirculation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002210050424
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  • 20
    Electronic Resource
    Electronic Resource
    Selective lesions of mesostriatal dopamine neurons ameliorate hypoglycemic damage in the caudate-putamen (1986)
    Springer
    Experimental brain research 63 (1986), S. 382-386 
    Details
    ISSN: 1432-1106
    Keywords: Hypoglycemia ; Brain damage ; Striatum ; Dopamine ; Mesostriatal system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system was found to ameliorate neuronal necrosis in the caudate-putamen following 30 min of insulin-induced hypoglycemic coma. We propose that increased release of dopamine in the striatum during hypoglycemia or in the recovery period potentiates a deleterious neuronal hyperexcitation, probably induced by excessive release of glutamate or related compounds, thereby aggravating neuronal necrosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00236856
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