Metabolic Alterations in Brain During Anoxic-Anoxia and Subsequent Recovery

Drewes, Lester R.; Gilboe, David D.; Betz, A. Lorris

doi:10.1001/archneur.1973.00490300047005

Cited by 81 publications

(21 citation statements)

References 26 publications

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“…An increased rate of glycolytic metabolism is commonly observed in acute cerebral ischemia or hypoxia, but cerebral energy metabolism remains relatively unchanged despite the high oxygen requirement of the brain (19)(20)(21)(22)(23). These observations suggest that acute cerebral ischernia or hypoxia does not lead to a crucially decreased cerebral blood flow or critically profound cellular hypoxia compatible with cerebral energy failure.…”

Section: Discussionmentioning

confidence: 91%

Relationship Between Cerebral Energy Failure and Free Fatty Acid Accumulation Following Prolonged Brain Ischemia

Kuwashima

Nakamura

Fujitani

et al. 1978

Japanese Journal of Pharmacology

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Abstract--Prolonged ischemia by bilateral carotid artery ligation in rats resulted in cerebral edema with a reduced energy state. Mitochondria isolated from the ischemic brain showed an impairment of oxidative phosphorylation.The ischemic brain was also characterized by a remarkable accumulation of free fatty acids known to have properties as an uncoupling factor. The major components of increased free fatty acids were palmitic, stearic, oleic and arachidonic acids. The analysis of saponified myelin and mitochondrial lipids from the ischemic brain showed a decrease in fatty acid contents.The main components of decreased fatty acids in these subcellular fractions corresponded to those of free fatty acids accumulating in the ischemic brain. These results indicate that cerebral energy failure in the ischemic brain is related to the accumulation of free fatty acids, which are derived from endogenous brain lipids.Although considerable efforts have been devoted to the study on experimental brain edema, the biochemical alterations associated with the pathogenesis still remain to be eluci dated. Current evidence suggests that cerebral swelling is accompanied by a reduction of the cerebral energy state (1-3) and an impairment of mitochondrial function (4-6). A deficiency of available energy is assumed to cause a disturbance of active ionic transport across the cell membrane, which could lead to cerebral swelling or cell damage. In a previous report (7), we showed that unilateral brain edema produced in rats by the combination of ischemia and hypoxic exposure was characterized by a considerable increase of free fatty acids in the brain. Our experiments also demonstrated that oleic and arachidonic acids, which increased markedly in the edematous brain, inhibited oxidative phosphorylation of in vitro mitochondrial preparations (7). These observations provided information for further study on the biochemical mechanism of cerebral energy failure in brain edema.In the present study, we investigated cerebral energy metabolism in another form of brain edema produced in rats by a permanent ligation of bilateral carotid arteries. This paper deals with biochemical events associated with cerebral energy failure and the free fatty acid change in the subcellular lipids of the edematous brain. MATERIALS AND METHODS Brain ischennaMale Wistar rats weighing 80-100 g were anesthetized with sodium hexobarbital (150 mg/

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Section: Discussionmentioning

confidence: 91%

Relationship Between Cerebral Energy Failure and Free Fatty Acid Accumulation Following Prolonged Brain Ischemia

Kuwashima

Nakamura

Fujitani

et al. 1978

Japanese Journal of Pharmacology

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“…More pronounced changes are induced in hypotensive ani mals (22). On the other hand, the ordered changes among the adenine nucleotides are a consequence of the constant sum of adenosine mono-, di and triphosphates and of the slight changes in the adenosine diphosphate, which together force an inverse relationship between adenosine monophosphate and adenosine triphosphate (4,8,22). In the pre sent work, the hypoxiemic condition emphasizes that the changes of the redox potential of the lactate/pyruvate system do not reflect the actual modifications of the cerebral energy state, even though the two phenomena are obviously related and interdependent.…”

Section: Discussionmentioning

confidence: 99%

An Analysis of the Drugs Acting on Cerebral Energy Metabolism

Benzi

1975

Japanese Journal of Pharmacology

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Abstract-The behaviour of (a) the redox potential of the lactate/pyruvate system and the changes of the redox potential of the lactate/pyruvate system across the brain; (b) the energy charge potential of the adenylate pool, was studied in the brain of cura rized beagle dogs. The influence of certain drugs (amobarbital, nicergoline, theo phylline, papaverine, bamethan, dipyridamole, bemegride) on these parameters was evaluated under control conditions, during hypoxemia and during post-hypoxiemic recovery. On the whole, the action on energetic metabolism appears to be unrelated to the action believed to be exerted by drugs on cerebral vessels.Some of the basic problems at the cerebral level concern both the ability of drugs to interfere with energy metabolism, and the relationships between energy metabolism and blood flow. Until recently, energy metabolism and blood fluximetry were regarded as being so interdependent that a substance able to increase cerebral blood flow was always regarded as being also useful in the treatment of acute and chronic cerebropathies.Lately, this criterion has been regarded as highly questionable. The present work was planned in order to carry out a critical evaluation of the action of various drugs at the cerebral level by means of experimental methods which in our laboratory have been used for many years in the study of cerebral metabolism. Our investigations were focused on the energy charge of the adenylate pool and on the redox potential of the lactate pyru vate system under control conditions, during hypoxemia and during post-hypoxia recovery.At the same time, the action of various drugs (papaverine, theophylline, nicergoline, di pyridamole, bamethan, bemegride and amobarbital) was evaluated. MATERIALS AND METHODS Animals and anaesthesiaThe experiments were carried out on 84 male beagle dogs aged 240-360 days and weigh ing from 8.7 to 13.2 kg. Before the experiments, the dogs were maintained under the same environmental conditions (22±1°, relative humidity =60±5%) and were fed only a standard diet with water ad libitum.The surgical procedure was performed on animals pre-anaesthetized with urethane (0.4 g/kg i.p.). Electrical activity of the brain was used to determine the degree of anaes thesia (9), which was induced and maintained only during the surgical procedure by chlora lose (20-40 mg/kg i.v.). The anaesthetics affect labile phosphates and the extra and intra cellular brain lactate and pyruvate concentrations (14,21). Therefore the restoration of

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“…The initial dip in lactate concentration could be explained by the simple reasoning of higher consumption than production of this monocarboxylate. As to the issue of increased levels of substrates, there are ample examples of increases in glucose levels of brain tissue after activation or after trauma due to a drop in its utilization (Drewes et al, 1973;Ljunggren et al, 1974;Steen et al, 1979;Hu and Wilson, 1997). It is reasonable to assume that any rise in lactate levels after activation indicates that the rate of lactate production exceeds its rate of utilization.…”

Section: Testing the Hypothesismentioning

confidence: 99%

Lactate: The Ultimate Cerebral Oxidative Energy Substrate?

Schurr

2006

J Cereb Blood Flow Metab

265

236

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Research over the past two decades has renewed the interest in lactate, no longer as a useless end product of anaerobic glycolysis in brain (and other tissues), but as an oxidative substrate for energy metabolism. While this topic would be considered blasphemy only three decades ago, much recent evidence indicates that lactate does play a major role in aerobic energy metabolism in the brain, the heart, skeletal muscle, and possibly in any other tissue and organ. Nevertheless, this concept has challenged the old dogma and ignited a fierce debate, especially among neuroscientists, pitting the supporters of glucose as the major oxidative energy substrate against those who support lactate as a possible alternative to glucose under certain conditions. Meanwhile, researchers working on energy metabolism in skeletal muscle have taken great strides toward bridging between these two extreme positions, while avoiding the high decibels of an emotional debate. Employing their findings along with the existing old and new data on cerebral energy metabolism, it is postulated here that lactate is the only major product of cerebral (and other tissues) glycolysis, whether aerobic or anaerobic, neuronal or astrocytic, under rest or during activation. Consequently, this postulate entails that lactate is a major, if not the only, substrate for the mitochondrial tricarboxylic acid cycle. If proven true, this hypothesis could provide better understanding of the biochemistry and physiology of (cerebral) energy metabolism, while holding important implications in the field of neuroimaging. Concomitantly, it could satisfy both 'glucoseniks' and 'lactatians' in the ongoing debate.

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Metabolic Alterations in Brain During Anoxic-Anoxia and Subsequent Recovery

Cited by 81 publications

References 26 publications

Relationship Between Cerebral Energy Failure and Free Fatty Acid Accumulation Following Prolonged Brain Ischemia

Relationship Between Cerebral Energy Failure and Free Fatty Acid Accumulation Following Prolonged Brain Ischemia

An Analysis of the Drugs Acting on Cerebral Energy Metabolism

Lactate: The Ultimate Cerebral Oxidative Energy Substrate?

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