Information obtained over the past 25 years indicates that the amino acid glutamate functions as a fast excitatory transmitter in the mammalian brain. Studies completed during the last 15 years have also demonstrated that glutamate is a powerful neurotoxin, capable of killing neurons in the central nervous system when its extracellular concentration is sufficiently high. Recent experiments in a variety of preparations have shown that either blockade of synaptic transmission or the specific antagonism of postsynaptic glutamate receptors greatly diminishes the sensitivity of central neurons to hypoxia and ischemia. These experiments suggest that glutamate plays a key role in ischemic brain damage, and that drugs which decrease the accumulation of glutamate or block its postsynaptic effects may be a rational therapy for stroke.

Glutamate and pathophysiology of hypoxic-ischemic brain damage

Glutamate and the pathophysiology of hypoxic--ischemic brain damage.

Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease.

All cells in living organisms have a limited life span, and when the time set by their biological clocks has run out, they will die , their highly orga­ nized macromolec ular structure will disintegrate, and the low-molec ul ar degrad ation products be­ come part of the disorder of the surroundings . In thermodynamic terms, this series of events consti­ tutes what has been c alled the entropic doom. We know little about those molec ul ar mechanisms that limit the life span of cells in the absence of dise ase. For the clinician, therefore, the important task is to prevent or tre at dise ases that jeopardize the proper functioning and viability of cells whose biologic al clocks have not yet run out . Measures instituted to prevent brain cell death have a special importance . This i s partly due t o the fact that w e equate human life with the functioning of the brain. However, this importance also resides in the v ulnerability of brain cells to conditions that allow cells of most other tissue to survive , and to continue or res ume their activitie s . The clinically most important conditions leading to brain cell death are those associated with cere­ brovascul ar dise ase, particularly stroke, and with head trauma. We will begin, though, by rec alling the traditional view of the occ urrence and loc alization of neuronal damage in four conditions that lead to more disseminated alterations, e specially since they have been considered to c ause nerve cell injury of a

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1981.18

Cell Damage in the Brain: A Speculative Synthesis

Publisher Summary This chapter discusses prostaglandins and thromboxanes. The prostaglandins are C 20 acids formed from polyunsaturated fatty acids by oxygenation and cyclization. The thromboxanes, which were originally found in platelets, have now been identified in a variety of tissues. Rapid progress is being made in understanding their biological roles. Earlier studies on vascular and airway smooth muscle demonstrated that endoperoxides had unique effects that could not be attributed to conversion into the stable prostaglandins. Because aspirin, an inhibitor of endoperoxide formation, inhibits the second wave of aggregation, it was suggested that the endoperoxides play a role in the release reaction. The potency of the endoperoxides in causing contractions of the isolated rabbit aorta was of particular interest. However, the occurrence of thromboxanes is not limited to platelets. The transformation of arachidonic acid into thromboxane B 2 has also been observed in lung tissue, spleen, kidney, leukocytes, umbilical artery, and brain.

Prostaglandins and thromboxanes.

Since a review on this topic in this Journal appeared (Wolfe, 1982), the CNS has proved to be a major focus in eicosanoid research. Although our knowledge is limited at the moment, the research in this field is rapidly growing. In this short review, we summarize recent progress of research (1982-1989) in this field with special attention directed to eicosanoid metabolism, functions of eicosanoids in the neuroendocrine system and synaptic transmission, current information on eicosanoid receptors, and the link between eicosanoids and cerebral circulation. Knowledge of the eicosanoids has paved the way to a better understanding of intercellular signal transduction systems, including neuronal functions.

Arachidonic acid cascade and signal transduction.

In recent years, knowledge of the biochemistry of oxygenated metabolites of arachidonic acid has greatly increased. Their biological functions in acceleration and prevention of platelet aggregation and in inflammatory and immune reactions are becoming much clearer. The therapeutic value, particularly of PGI2 as well as selective inhibitors of synthesis, is also rapidly advancing. Despite much effort, the functional importance of prostaglandins and thromboxanes in the cNS in normal ongoing physiological processes is still quite uncertain. However, when parenchymal or vascular elements are damaged or invaded by extraneural cells, the synthesis of one or the other member of the eicosanoids is greatly increased and contributes significantly to pathophysiological reactions. Thus, prevention of synthesis is likely to have increasing importance in clinical neurology, particularly in cerebrovascular diseases.

Eicosanoids: prostaglandins, thromboxanes, leukotrienes, and other derivatives of carbon-20 unsaturated fatty acids.

The ceroid-lipofuscinoses (Batten disease) are neurodegenerative inherited lysosomal storage diseases of children and animals. A common finding is the occurrence of fluorescent storage bodies (lipopigment) in cells. These have been isolated from tissues of affected sheep. Direct protein sequencing established that the major component is identical to the dicyclohexylcarbodiimide (DCCD) reactive proteolipid, subunit c, of mitochondrial ATP synthase and that this protein accounts for at least 50% of the storage body mass. No other mitochondrial components are stored.

Direct sequencing of storage bodies isolated from tissues of children with juvenile and late infantile ceroid-lipofuscinosis established that they also contain large amounts of complete and normal subunit c. It is also stored in the disease in cattle and dogs but is not present in storage bodies from the human infantile form.

Subunit c is normally found as part of the mitochondrial ATP synthase complex and accounts for 2–4% of the inner mitochondrial membrane protein. Mitochondria from affected sheep contain normal amounts of this protein. The P1 and P2 genes that code for it are normal as are mRNA levels. Oxidative phosphorylation is also normal.

These findings suggest that ovine ceroid-lipofuscinosis is caused by a specific failure in the degradation of subunit c after its normal inclusion into mitochondria, and its consequent abnormal accumulation in lysosomes. This implies a unique pathway for subunit c degradation. It is probable that the human late infantile and juvenile diseases and the disease in cattle and dogs involve lesions in the same pathway.

Mitochondrial ATP synthase subunit c storage in the ceroid-lipofuscinoses (Batten disease).

RECENT advances in the diagnosis and classifcxation of epileptic seizures and epileptic syndromes, together with improvemenss in anticonvulsant therapy, have enabled the great majority of patients ...

Progressive myoclonus epilepsies: specific causes and diagnosis.

A review of 118 cases published as Kufs' disease revealed only 50 cases, including 2 patients described herein, that fulfilled our criteria for this diagnosis. Of the other 68 cases, 16 had inadequate data for analysis, 21 had evidence of a storage disease other than Kufs' disease, 10 did not have clear evidence of any neuronal storage, and 21 had atypical clinical features considered outside the spectrum of Kufs' disease. The 50 cases accepted as Kufs' disease comprised two clinical phenotypes; progressive myoclonus epilepsy (Type A) and dementia with motor disturbances (Type B). Marked photosensitivity was a striking feature of some Type A cases, and facial dyskinesias were common amongst Type B patients. Onset was typically at around the age of 30 years. A few cases began in adolescence; these differ from the protracted juvenile form of neuronal ceroid-lipofuscinosis by the absence of visual failure. Demonstration of fingerprint profiles or granular osmiophilic deposits by electron microscopy is mandatory for definitive diagnosis. Urinary sediment dolichol levels were markedly elevated in our 2 cases. This biochemical finding confirms the relationship of Kufs' disease to the early forms of neuronal ceroid-lipofuscinosis and is consistent with our hypothesis that these diseases are due to defects in the intracellular processing of lysosomal and related membranes.

Leonhard S. Wolfe

Papers

Arachidonic acid cascade and signal transduction.

Eicosanoids: prostaglandins, thromboxanes, leukotrienes, and other derivatives of carbon-20 unsaturated fatty acids.

Mitochondrial ATP synthase subunit c storage in the ceroid-lipofuscinoses (Batten disease).

Progressive myoclonus epilepsies: specific causes and diagnosis.

Kufs' disease: a critical reappraisal.