This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

Gangliosides are unique acidic glycolipids that are selectively concentrated in the plasma membrane of cells. Surface labeling studies have demonstrated that at least a portion of the oligosaccharde chain of gangliosides extends beyond the hydrophe) is imbedded in the membrane bilayer. It is becoming increasingly apparent that gangliosides participate in the internalization of environmental signals elicited by cholera toxin and glycoprotein hormones such as thyrotropic hormone and chorionic gonadotropin as well as other substances such as interferon and possibly serotonin. The mechanism by which cholera toxin binds to a specific ganglioside receptor on the celraction of trophic agents with gangliosides. We would predict that analyogous phenomena involving gangliosides will be discovered in brain. The biosynthesis of gangliosides proceeds by the ordered sequential addition of sugars to the lipid moiety. These reactions are catalyzed by a cluster of membrane-bound glycosyltransferases. Any alteration in the activity or specificity of one of these enzymes will result in a dramatic change in the ganglioside pattern of an afflicted cell or organ. The drastic consequences that accompany abnormalities of ganglioside synthesis have been documented in a heritable metabolic disorder in vivo and in tumorigenic transformation of cells in vitro. In this article, we have attempted to unify these observations and to provide a reasonable interpretation of the role of gangliosides in mediating cell surface phenomena.

https://science.sciencemag.org/content/sci/194/4268/906.full.pdf

Biosynthesis and function of gangliosides.

Every cell in nature carries a rich surface coat of glycans, its glycocalyx, which constitutes the cell's interface with its environment. In eukaryotes, the glycocalyx is composed of glycolipids, glycoproteins, and proteoglycans, the compositions of which vary among different tissues and cell types. Many of the linear and branched glycans on cell surface glycoproteins and glycolipids of vertebrates are terminated with sialic acids, nine-carbon sugars with a carboxylic acid, a glycerol side-chain, and an N-acyl group that, along with their display at the outmost end of cell surface glycans, provide for varied molecular interactions. Among their functions, sialic acids regulate cell-cell interactions, modulate the activities of their glycoprotein and glycolipid scaffolds as well as other cell surface molecules, and are receptors for pathogens and toxins. In the brain, two families of sialoglycans are of particular interest: gangliosides and polysialic acid. Gangliosides, sialylated glycosphingolipids, are the most abundant sialoglycans of nerve cells. Mouse genetic studies and human disorders of ganglioside metabolism implicate gangliosides in axon-myelin interactions, axon stability, axon regeneration, and the modulation of nerve cell excitability. Polysialic acid is a unique homopolymer that reaches >90 sialic acid residues attached to select glycoproteins, especially the neural cell adhesion molecule in the brain. Molecular, cellular, and genetic studies implicate polysialic acid in the control of cell-cell and cell-matrix interactions, intermolecular interactions at cell surfaces, and interactions with other molecules in the cellular environment. Polysialic acid is essential for appropriate brain development, and polymorphisms in the human genes responsible for polysialic acid biosynthesis are associated with psychiatric disorders including schizophrenia, autism, and bipolar disorder. Polysialic acid also appears to play a role in adult brain plasticity, including regeneration. Together, vertebrate brain sialoglycans are key regulatory components that contribute to proper development, maintenance, and health of the nervous system.

https://www.physiology.org/doi/pdf/10.1152/physrev.00033.2013

Sialic Acids in the Brain: Gangliosides and Polysialic Acid in Nervous System Development, Stability, Disease, and Regeneration

Publisher Summary This chapter discusses the distinct morphological patterns of ischemic brain injury and discusses the possible pathogenesis of ischemic damage to selectively vulnerable brain neurons. The neuropathologists have defined at least three morphologically distinct varieties of ischemic brain damage, including autolysis, infarction, and selective neuronal necrosis (SNN). A fourth pattern may be added as generalized neuronal necrosis (GNN). Autolytic brain damage is characterized by chromatin clumping, mitochondrial swelling, and dispersion of ribosomes uniformly throughout all the brain cells. Such changes are the consequence of terminal ischemia of the brain without reperfusion and are seen in post-mortem brain tissue. Infarction has been defined by the neuropathologists as an area of pannecrosis—that is, irreversible damage to all cell types, including astroglia and endothelial cells within a specific vascular territory of the brain. The transition zone between an area of cerebral infarction and the entirely normal brain tissue frequently contains necrotic neurons but normal astroglia. Such border zone necrosis of neurons develops irrespective of the brain region, and therefore, differs from selective neuronal necrosis that occurs only in those populations of vulnerable neurons.

Selective Neuronal Vulnerability: Morphological and Molecular Characteristics*

This edition has been revised to include new data on genetics, molecular biology, and the role of cellular structures on one side and the growing experience with MR patterns of less common myelin disorders on the other. In addition, chapters have been added on disorders of which the white matter involvement was previously unclear.

Magnetic Resonance of Myelin, Myelination, and Myelin Disorders

Permanent, complete global cerebral ischemia was induced in cats by filling the cardiovascular system with a plasma substitute (37° C). At variable intervals and up to 120 min thereafter, these feline brains were perfused with aldehydes and processed for electron microscopy. The resulting cellular alterations were homogeneous and uniform throughout the entire brain; they included early chromatin clumping, gradually increasing electron lucency of the cell sap, distention of endoplasmic reticulum and Golgi cisternae, transient mitochondrial condensation followed by swelling and appearance of flocculent densities, and dispersion of ribosomal rosettes. The marked contrast between the structural alterations in permanent, complete ischemia and incomplete cerebral ischemia, suggest differences in their pathogenesis. A basic determinant factor of the structural changes appears to be the volume of flow (serum, plasma, other) which is available at the time of the injury. This analysis of global cerebral ischemia provides some insight on the nature of cellular changes occurring shortly after somatic death.

The ultrastructure of "brain death". II. Electron microscopy of feline cortex after complete ischemia

Hepatic cellular injury following lethal Escherichia coli bacteremia in rats.

Cellular and subcellular alterations of human CNS: studies utilizing in situ perfusion fixation at immediate autopsy.

Mechanisms of subcellular dysfunction of the liver in sepsis are still obscure. The present study investigates changes in oxidative phosphorylative activity and calcium-induced respiration of rat liver mitochondria following live Escherichia coli injection (E coli, Serotype: 0--18. A 1.25--1.5 X 10(9)/100 gm body wt inoculum of E coli bacteria was injected via the tail vein, causing a 100% mortality rate within 24 hours after injection. In order to determine alteration of liver mitochondrial membrane permeability, serum ornithine carbamoyltransferase activity was measured following E coli injection. This activity increased ten to 100-fold over that of controls with time following injection. However, the yield of liver mitochondria from treated rats, estimated by the amount of collected mitochondrial protein and the recovery rate of succinate dehydrogenase activity in the final mitochondrial suspensions, was not significantly different from that of controls. Mitochondrial oxidative phosphorylative activity measured using glutamate as a substrate was enhanced throughout all period to death (P less than 0.01 at three and six hours, P less than 0.05 in the fatal stage) and was associated with concomitant increases in respiratory control ratios. Similar results were obtained using beta-hydroxybutyrate as a substrate. This enhancement was accompanied by an increase in 2-4-dinitrophenol-stimulated ATPase activity (160% at three hours and 130% in the fatal stage). Calcium-induced stimulation of mitochondrial respiration as well as initial calcium uptake rate linked to respiration, using glutamate as a substrate, were higher in liver mitochondria from rats with E coli treatment than in those of controls throughout all periods (P less than 0.01 or less). These results suggest the coexistence of hyperfunctioning as well as deteriorated mitochondria following lethal treatment with E coli.

A study of oxidative phosphorylative activity and calcium-induced respiration of rat liver mitochondria following living Escherichia coli injection.

The effects of hypothermia on survival time and ECGs were investigated in hemorrhagic-shocked rats. Acute blood loss corresponding to LD84 was achieved within 1 min through cannulation of the carotid artery. Immediately following the hemorrhagic episode, extracorporeal cooling was performed by placing the animals, with ice packs attached to their lateral sides, in a cold water bath. Rewarming was achieved by removing the ice packs and resetting the temperature of the water bath to 37 degrees C. With this system, the survival time of the hemorrhagic rats was lengthened from 40 to 60 min without rewarming and to 123 min with rewarming. ECGs showed sinus bradycardia, prolonged PR and QRS intervals, AV block, and finally ventricular fibrillation in both the control and hemorrhagic groups during extracorporeal cooling. During rewarming, the above ECG changes returned to normal in the control group as did body temperature. In contrast, animals in the hemorrhagic group did not survive. Body temperature in this group began to rise toward normal, and above ECG changes showed slight but not complete improvement. It is concluded that extracorporeal cooling can lengthen the survival time of hemorrhagic-shocked rats and that recovery of the disturbed conduction system is a prerequisite for survival from severe hypothermia.

Effect of hypothermia on survival time and ECG in rats with acute blood loss.

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