The relation of brain eicosanoids to progression of cerebral edema was studied in stroke-resistant spontaneously hypertensive rats subjected to incomplete global brain ischemia induced by bilateral occlusion of the common carotid arteries. Thromboxane B 2 and 6-keto prostaglandin F lo levels were significantly elevated 5 minutes after reperfusion but returned to control levels by 30 minutes. In contrast, leukotriene C 4 levels increased 2 hours after bilateral common carotid artery occlusion and peaked 30 minutes after reperfusion, with higher levels persisting until 60 minutes after reperfusion. Cerebral ischemia was accompanied by cerebral edema early after reperfusion. The edema correlated with increased leukotriene C 4 levels. That the increased brain water content was causally related to an increase in leukotriene C 4 was supported by results obtained following administration of the 5-lipoxygenase inhibitors ONO-LP-016 and AA-861. Both inhibitors suppressed the increased leukotriene C 4 and brain water contents after reperfusion. Our results indicate that leukotriene C 4 is closely associated with an induction of ischemic cerebral edema. (Stroke 1988;19:372-377) F atty acids are liberated from the plasma membranes of ischemic tissue through various pathways. 1 " 3 It is believed that these free fatty acids, particularly arachidonic acid, aggravate cell damage imposed on ischemic brain. Arachidonic acid has been the focus of repeated investigation as it relates to brain edema* 4 " 8 and endothelial cell damage of cerebral arteries. 9When the brain is subjected to severe ischemia, the amount of free arachidonic acid increases abruptly and then decreases gradually when circulation is restored. Since increased levels of arachidonic acid persist when the oxygen supply is restored, conditions exist for enhanced oxidation of arachidonic acid. For example, recirculation is accompanied by a prominent increase in prostaglandins, 10 " 12 which are formed from arachidonic acid by cyclooxygenase. Among these prostaglandins, thromboxane A 2 (TXA 2 ), which is derived primarily from platelets, has potent platelet aggregating and vasoconstrictor effects. By contrast, prostaglandin I 2 (PGI 2 ), which is derived predominantly from vascular endothelial cells, acts to prevent platelet aggregation and vasoconstriction. TXA 2 and PGI 2 are rapidly converted to the stable metabolites TXB 2 and 6-keto-PGF,,,. Received August 30, 1986; accepted September 3, 1987. 5-lipoxygenase dehydrase to leukotrienes. Of these substances, leukotriene C 4 (LTC 4 ) has particularly strong vasoconstrictor activity and promotes increased vascular permeability, perhaps by damage to the blood-brain barrier. 1516We examined the effect of incomplete global cerebral ischemia on the levels of TXB 2 , 6-keto-PGF, a , and LTC 4 in the brain of stroke-resistant spontaneously hypertensive rats (SHRSR) and the relation between LTC 4 and the progression of cerebral edema. (2-Amino -4 -1 -butyl -6-(ct-hydroxy-4-chlorobenzy l)phenolhydrochloride (ONO-LP-01...

This study explored (a) whether postischemic accumulation of calcium in hippocampal neurons precedes or occurs pari passu with light microscopical signs of delayed neuronal necrosis, and (b) whether calcium initially accumulates in dendritic domains, presumed to have a high density of agonist-operated calcium channels. Transient ischemia of 10-min duration was induced in rats, and the animals were studied after 1, 2, 3, and 4 days of recovery. We measured total calcium and potassium contents in the stratum oriens, pyramidale, radiatum, and moleculare of the CA1 and CA3 sectors, using particle induced x-ray emission (PIXE) in the proton microprobe mode. The results showed significant accumulation of calcium and loss of potassium after 3 and 4 days of recovery in the CA1 sector, which developed neuronal necrosis, but not in the CA3 sector, which showed only occasional damage. In a few animals, calcium accumulation (and loss of potassium) was observed with no or only mild visible damage, but in the majority of animals the accumulation of calcium correlated to signs of neuronal necrosis. Since calcium accumulation was similar in all strata examined, the results failed to reveal preferential accumulation in dendritic or somal regions. Based on our results and those of Dux et al., we emphasize the possibility that delayed neuronal death is, at least in part, caused by increased calcium cycling of plasma membranes and gradual calcium overload of mitochondria.

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 hyperglycemia 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Status epilepticus of greater than 30-min duration in rats gives rise to a conspicuous lesion in the substantia nigra pars reticulata (SNPR) and globus pallidus (GP). The objective of the present study was to explore whether the lesion, which encompasses necrosis of both neurons and glial cells, is related to intra- and extracellular acidosis. Using the flurothyl model previously described to produce seizures, we assessed regional pH values with the autoradiographic 5,5-dimethyl[2-14C]oxazolidine-2,4-dione technique. Regional pH values were assessed in animals with continuous seizures for 20 and 60 min, as well as in those allowed to recover for 30 and 120 min after seizure periods of 20 or 60 min. In additional animals, changes in extracellular fluid pH (pHe) were measured with ion-selective microelectrodes, and extracellular fluid (ECF) volume was calculated from the diffusion profile for electrophoretically administered tetramethylammonium. In structures such as the neocortex and the hippocampus, which show intense metabolic activation during seizures, status epilepticus of 20- and 60-min duration was accompanied by a reduction of the "composite" tissue pH (pHt) of 0.2-0.3 unit. Recovery of pHt was observed upon termination of seizures. In SNPR and in GP, the acidosis was marked to excessive after 20 and 60 min of seizures (delta pHt approximately 0.6 after 60 min).(ABSTRACT TRUNCATED AT 250 WORDS)

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