The free radical pathology and the microcirculation in the major central nervous system disorders

H. B. Demopoulos, Eugene S. Flamm, D. D. Pietronigro, M. L. Seligman

Research output: Contribution to journalArticle

586 Citations (Scopus)

Abstract

Regional ischemia and acute spinal cord injury, in experimental feline models, are both associated with distinct free radical pathology which affects the predominant membrane lipids in the ischemic or traumatized tissues. In these models, the polyunsaturated fatty acids are selectively lost from the membrane phospholipids while saturated ones are not, because the unsaturated lipids are very susceptible to free radical damage. Cholesterol, a major component of plasma membranes and myelin, is also adversely affected by free radical reactions. The characteristic lipid losses were analyzed by gas chromatography and mass spectrometry. The consumption of a major CNS antioxidant, ascorbic acid, in the ischemic or traumatized tissues occurs before the loss of the lipids, and is an important factor in establishing the free radical nature of some of the pathologic changes. A practical, clinically-oriented consideration in these studies in the question of precisely what factors lead to the irreversible changes. In the regional cerebral ischemia model, wherein one middle cerebral artery is occluded in the cat, there is a period of approximately two hours during which the situation is reversible; removal of the occluding clip before 2 hours in this model results in no discernible infarction and no clinical deficits. Therefore, whatever changes have occurred up to this time do not constitute irreversibility. In a somewhat similar way, acute spinal cord impact models result in minimal, initial structural damage; by 4 hours, only 25% of axons show periaxonal swelling and some myelin fragmentation by electron microscopy. In regional cerebral ischemia models there is an immediate 70-80% decline in blood flow following occlusion, but at three hours, this is reduced further to 90-95%. In the spinal cord impact model, major decreases in blood flow occur 2-3 hours after injury at the site of the lesion. These declines in blood flow appear to coincide to some degree with irreversibility and amplification of morpholigic damage, and could be the result of lipid peroxides, which are products of lipid free radical reactions, inhibiting the synthesis of PGI2. The latter is constantly produced by endothelium and counteracts the pro-aggregating properties of thromboxane A2 in platelets. Unfortunately, lipid peroxides selectively inhibit the synthesis of PGI2 and result in platelet-induced micro-occlusions. We confirmed the hypothesis by examining the microcirculation in the ischemic or traumatized tissues using scanning electron microscopy. There is sequential development, after the first hour, of platelet and leucocyte adherance, endothelial cell damage, and finally micro-occlusions, in both model systems. Treatment of the regional cerebral ischemia model with large doses of methohexital, a short-acting lipid-doluble barbiturate, prevented: the lipid free radical changes, the pathologic consumption of ascorbic acid, the microcirculatory pathology and gross and histologic evidence of cerebral infarction. This study demonstrates that pathologic lipid free radical reactions can result in marked amplification and acceleration of irreversible tissue damage by adversely affecting PGI2 synthesis, and thereby result in the initiation of the intravascular coagulation process.

Original languageEnglish (US)
Pages (from-to)91-119
Number of pages29
JournalActa Physiologica Scandinavica
Volume110
Issue numberSuppl. 492
StatePublished - 1980
Externally publishedYes

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Central Nervous System Diseases
Microcirculation
Free Radicals
Pathology
Lipids
Epoprostenol
Brain Ischemia
Blood Platelets
Lipid Peroxides
Myelin Sheath
Ascorbic Acid
Spinal Cord
Methohexital
Thromboxane A2
Felidae
Cerebral Infarction
Middle Cerebral Artery
Membrane Lipids
Unsaturated Fatty Acids
Spinal Cord Injuries

ASJC Scopus subject areas

  • Physiology

Cite this

Demopoulos, H. B., Flamm, E. S., Pietronigro, D. D., & Seligman, M. L. (1980). The free radical pathology and the microcirculation in the major central nervous system disorders. Acta Physiologica Scandinavica, 110(Suppl. 492), 91-119.

The free radical pathology and the microcirculation in the major central nervous system disorders. / Demopoulos, H. B.; Flamm, Eugene S.; Pietronigro, D. D.; Seligman, M. L.

In: Acta Physiologica Scandinavica, Vol. 110, No. Suppl. 492, 1980, p. 91-119.

Research output: Contribution to journalArticle

Demopoulos, HB, Flamm, ES, Pietronigro, DD & Seligman, ML 1980, 'The free radical pathology and the microcirculation in the major central nervous system disorders', Acta Physiologica Scandinavica, vol. 110, no. Suppl. 492, pp. 91-119.
Demopoulos, H. B. ; Flamm, Eugene S. ; Pietronigro, D. D. ; Seligman, M. L. / The free radical pathology and the microcirculation in the major central nervous system disorders. In: Acta Physiologica Scandinavica. 1980 ; Vol. 110, No. Suppl. 492. pp. 91-119.
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