Elevated blood ketone and glucagon levels cannot account for 1,3-butanediol induced cerebral protection in the Levine rat.

Lundy, Edward F.; Klima, Lawrence D.; Huber, Thomas S.; Zelenock, Gerald B.; DʼAlecy, Louis G.

doi:10.1161/01.str.18.1.217

Cited by 9 publications

(8 citation statements)

References 23 publications

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“…23 However, our results indicate that ethanol, unlike butanediol, does not prevent the development of edema secondary to embolization and are consistent with those of other studies that reported no beneficial effect of ethanol in various models of brain injury. Pretreatment with 47 mmol/kg ethanol, unlike pretreatment with butanediol, did not increase survival time in the Levine rat model, 24 and high doses of ethanol (87 mmol/kg) potentiated traumatic spinal cord and cerebral hemisphere damage in cats. 25 -26 Ethanol (100 mmol/kg) had no significant effect on the concentrations of cerebral energy metabolites in intact or ischemic rats, 27 which contrasts with the metabolic effects of butanediol that we report.…”

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confidence: 79%

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Beneficial effect of 1,3-butanediol on cerebral energy metabolism and edema following brain embolization in rats.

Gueldry

Marie

Rochette

et al. 1990

Stroke

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We assessed the effect of 1,3-butanediol on cerebral energy metabolism and edema after inducing multifocal brain infarcts in 108 rats by the intracarotid injection of 50-jim carbonized microspheres. An ethanol dimer that induces systemic ketosis, 25 mmol/kg i.p. butanediol was injected every 3 hours to produce a sustained increase in the plasma level of 0-hydroxybutyrate. Treatment significantly attenuated ischemia-induced metabolic changes by increasing the concentrations of phosphocreatine, adenosine triphosphate, and glycogen and by reducing the concentrations of pyruvate and lactate. Lactate concentration 2, 6, and 12 hours after embolization decreased by 13%, 44%, and 46%, respectively. Brain water content increased from 78.63% in six unembolized rats to 80.93% in 12 saline-treated and 79.57% in seven butanedioltreated rats 12 hours after embolization. (p<0.05). The decrease in water content was associated with significant decreases in the concentrations of sodium and chloride. The antiedema effect of butanediol could not be explained by an osmotic mechanism since equimolar doses of urea or ethanol were ineffective. Our results support the hypothesis that the beneficial effect of butanediol is mediated through cerebral utilization of ketone bodies arising from butanediol metabolism, reducing the rate of glycolysis and the deleterious accumulation of lactic acid during ischemia. (Stroke 1990;21:1458-1463) P revious studies have shown that treatment with 1,3-butanediol, an ethanol dimer (CH 3 -CHOH-CH r CH 2 OH), has beneficial effects in models of hypoxia and ischemia. Butanediol prolongs the survival time in mice exposed to 4-5% (V; it extends the time to isoelectric electroencephalogram and reduces the neurologic deficit in ischemichypoxic Levine rats 2 -3 ; and it attenuates neurologic deficit, histologic damage, and cerebral metabolic alterations induced by four-vessel occlusion in rats. 4 -5 Butanediol is converted in the body to /3-hydroxyburyrate, 6 and it has been proposed 1 that damage is attenuated through a cerebral protective effect mediated by ketone metabolism.We examined the effect of butanediol in a rat model of multifocal brain infarction produced by the intracarotid injection of calibrated microspheres. 7 We studied the effect of butanediol over 12 hours by measuring cerebral energy metabolism and edema. In addition, to test whether a direct effect or an osmotic effect contributed to the beneficial action of Received February 19, 1990; accepted June 12, 1990. butanediol, we compared its effect with those of ethanol and urea administered at equimolar doses. Materials and MethodsWe performed experiments on 154 male SpragueDawley rats weighing 280-320 g that were allowed free access to water and food.Cerebral microembolism was produced in 108 rats under ether anesthesia by injecting approximately 4,000 carbonized microspheres 50 /im in diameter labeled with strontium-85 and suspended in 20% polyvinylpyrrolidone (3M, Minneapolis) into the left internal carotid artery as previously descr...

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confidence: 79%

“…36 - 37 Intracerebral production of /3-hydroxybutyrate seems to be an important factor in the protective action of butanediol. Lundy et al 24 reported that acute elevation of blood ketone levels of /3-hydroxybutyrate infusion was not sufficient to provide cerebral protection in the Levine rat model.…”

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confidence: 99%

Beneficial effect of 1,3-butanediol on cerebral energy metabolism and edema following brain embolization in rats.

Gueldry

Marie

Rochette

et al. 1990

Stroke

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“…As mentioned earlier, immediate postischemic infusion of acetyl‐ L ‐carnitine is neuroprotective, possibly by providing alternative oxidative fuel in the presence of reduced conversion of pyruvate to acetyl CoA. Other researchers have demonstrated neuroprotection by administration of ketone bodies, e.g., β‐hydroxybutyrate, in animal models of ischemia, trauma, and Parkinson's disease (Lundy et al, 1984, 1987; Marie et al, 1987; Sims and Heward, 1994; Kashiwaya et al, 2000; Ottani et al, 2003; Tieu et al, 2003; Yosunkaya et al, 2004). Although the mechanism of neuroprotection by ketone bodies is not characterized, they similarly bypass the PDHC reaction and provide fuel to the TCA cycle.…”

Section: Potential Therapeutic Interventionsmentioning

confidence: 93%

Pyruvate dehydrogenase complex: Metabolic link to ischemic brain injury and target of oxidative stress

Martin

Rosenthal

Fiskum

2004

J of Neuroscience Research

145

114

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The mammalian pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme complex (greater than 7 million Daltons) that catalyzes the oxidative decarboxylation of pyruvate to form acetyl CoA, nicotinamide adenine dinucleotide (the reduced form, NADH), and CO(2). This reaction constitutes the bridge between anaerobic and aerobic cerebral energy metabolism. PDHC enzyme activity and immunoreactivity are lost in selectively vulnerable neurons after cerebral ischemia and reperfusion. Evidence from experiments carried out in vitro suggests that reperfusion-dependent loss of activity is caused by oxidative protein modifications. Impaired enzyme activity may explain the reduced cerebral glucose and oxygen consumption that occurs after cerebral ischemia. This hypothesis is supported by the hyperoxidation of mitochondrial electron transport chain components and NAD(H) that occurs during reperfusion, indicating that NADH production, rather than utilization, is rate limiting. Additional support comes from the findings that immediate postischemic administration of acetyl-L-carnitine both reduces brain lactate/pyruvate ratios and improves neurologic outcome after cardiac arrest in animals. As acetyl-L-carnitine is converted to acetyl CoA, the product of the PDHC reaction, it follows that impaired production of NADH is due to reduced activity of either PDHC or one or more steps in glycolysis. Impaired cerebral energy metabolism and PDHC activity are associated also with neurodegenerative disorders including Alzheimer's disease and Wernicke-Korsakoff syndrome, suggesting that this enzyme is an important link in the pathophysiology of both acute brain injury and chronic neurodegeneration.

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“…22 However, motor performance was not improved by BD following severe forebrain ischemia, afford cerebral protection. 24 In addition, other known effects of BD such as changes in blood glucagon, insulin, and glucose levels were not found to correlate with the protective effect. 24 So far, the mechanisms by which BD exerts its protective effect remain unknown.…”

Section: Ischemic Brain Damage Is Not Ameliorated By 13-butanediol Imentioning

confidence: 93%

“…24 In addition, other known effects of BD such as changes in blood glucagon, insulin, and glucose levels were not found to correlate with the protective effect. 24 So far, the mechanisms by which BD exerts its protective effect remain unknown. Nevertheless, Marie et al 25 showed that BD ameliorates ischemic brain damage, accompanied by a reduced brain lactate accumulation and a reduced diminution of high-energy metabolite concentrations after transient forebrain ischemia in rats.…”

Section: Ischemic Brain Damage Is Not Ameliorated By 13-butanediol Imentioning

confidence: 93%

Ischemic brain damage is not ameliorated by 1,3-butanediol in hyperglycemic rats.

Lundgren

Smith

Mans

et al. 1992

Stroke

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Background and Purpose: Treatment with the ketone body precursor 1,3-butanediol has been suggested to ameliorate hypoxic/ischemic brain damage. Butanediol could provide an alternative energy substrate for the brain, thereby decreasing the amount of glycolytically produced lactate. Hyperglycemia aggravates brain damage after brain ischemia and causes fatal postischemic seizures, probably by increasing the production of lactate and decreasing the pH. We studied whether butanediol treatment altered the adverse consequences following ischemia complicated by hyperglycemia.Methods: Hyperglycemic adult male rats were given 25 or 50 mmol • kg' 1 body wt butanediol intravenously 30 minutes before 10 minutes of transient forebrain ischemia. Morphological evaluation was performed following perfusion-fixation after 15 hours of recovery. Blood concentrations of/3-hydroxybutyrate, acetoacetate, glucose, and lactate and brain tissue concentrations of energy metabolites were measured before and after ischemia.Results: Blood levels of ketone bodies increased in the butanediol-treated rats. Ischemia decreased the blood levels of acetoacetate but increased the levels of /3-hydroxybutyrate by a similar amount, resulting in unchanged high levels of total ketone bodies in the animals that received butanediol. Brain tissue levels of glucose, energy metabolites, and lactate showed no difference between butanediol-and saline-treated rats. Furthermore, compared with saline-treated animals butanediol-treated rats showed no decrease in brain damage and no attenuation in the development of postischemic seizures.Conclusions: The ketone body precursor 1,3-butanediol offers no protective effect in transient forebrain ischemia complicated by hyperglycemia. (Stroke 1992;23:719-724) KEY WORDS • butanediols • cerebral ischemia • ketones • neuronal damage • rats

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Elevated blood ketone and glucagon levels cannot account for 1,3-butanediol induced cerebral protection in the Levine rat.

Cited by 9 publications

References 23 publications

Beneficial effect of 1,3-butanediol on cerebral energy metabolism and edema following brain embolization in rats.

Beneficial effect of 1,3-butanediol on cerebral energy metabolism and edema following brain embolization in rats.

Pyruvate dehydrogenase complex: Metabolic link to ischemic brain injury and target of oxidative stress

Ischemic brain damage is not ameliorated by 1,3-butanediol in hyperglycemic rats.

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