Survival of energy failure in the anoxic frog brain: delayed release of glutamate.

1997 ◽  
Vol 200 (22) ◽  
pp. 2913-2917 ◽  
Author(s):  
P L Lutz ◽  
R Reiners
Keyword(s):  
Neurotransmitter Release ◽  
Energy Charge ◽  
Atp Depletion ◽  
Extracellular Adenosine ◽  
Frog Brain ◽  
Adenosine Concentration ◽  
Excitatory Neurotransmitters ◽  
The Relationship ◽  
Brain Energy ◽  
Energy Failure

This study investigated the relationship between energy failure and neurotransmitter release in the frog (Rana pipiens) brain during 1-3 h of anoxia. Unlike truly anoxia-tolerant species, the frog does not defend its brain energy charge. When exposed to anoxia at 25 degrees C, there is an immediate fall in brain ATP levels, which reach approximately 20% of normoxic levels in approximately 60 min. The frog, nevertheless, survives another 1-2 h of anoxia. At 100 min of anoxia, there is an increase in extracellular adenosine concentration, probably originating from the increased intracellular adenosine concentration caused by the breakdown of intracellular ATP. Increases in the levels of extracellular glutamate and GABA do not occur until 1-2 h after ATP depletion. This response is quite unlike that recorded for other vertebrates, anoxia-tolerant or anoxia-intolerant, where energy failure quickly results in an uncontrolled and neurotoxic release of excitatory neurotransmitters. In the frog, the delay in excitotoxic neurotransmitter release may be one of the factors that allow a period of survival after energy failure. Clearly, energy failure by itself is not a fatal event in the frog brain.

scholarly journals Triheptanoin Mitigates Brain ATP Depletion and Mitochondrial Dysfunction in a Mouse Model of Alzheimer’s Disease

2020 ◽  
Vol 78 (1) ◽  
pp. 425-437
Author(s):  
Xiaodong Yuan ◽  
Lu Wang ◽  
Neha Tandon ◽  
Huili Sun ◽  
Jing Tian ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Tricarboxylic Acid Cycle ◽  
Synaptic Function ◽  
Atp Depletion ◽  
Atp Production ◽  
Model Of Alzheimer’S Disease ◽  
Brain Energy ◽  
Energy Failure

Background: Brain energy failure is an early pathological event associated with synaptic dysfunction in Alzheimer’s disease (AD). Thus, mitigation or enhancement of brain energy metabolism may offer a therapeutic avenue. However, there is uncertainty as to what metabolic process(es) may be more appropriate to support or augment since metabolism is a multiform process such that each of the various metabolic precursors available is utilized via a specific metabolic pathway. In the brain, these pathways sustain not only a robust rate of energy production but also of carbon replenishment. Objective: Triheptanoin, an edible odd-chain fatty acid triglyceride, is uncommon in that it replenishes metabolites in the tricarboxylic acid cycle (TCA) cycle via anaplerosis in addition to fueling the cycle via oxidation, thus potentially leading to both carbon replenishment and enhanced mitochondrial ATP production. Methods: To test the hypothesis that triheptanoin is protective in AD, we supplied mice with severe brain amyloidosis (5×FAD mice) with dietary triheptanoin for four and a half months, followed by biological and biochemical experiments to examine mice metabolic as well as synaptic function. Results: Triheptanoin treatment had minimal impact on systemic metabolism and brain amyloidosis as well as tauopathy while attenuating brain ATP deficiency and mitochondrial dysfunction including respiration and redox balance in 5×FAD mice. Synaptic density, a disease hallmark, was also preserved in hippocampus and neocortex despite profound amyloid deposition. None of these effects took place in treated control mice. Conclusion: These findings support the energy failure hypothesis of AD and justify investigating the mechanisms in greater depth with ultimate therapeutic intent.

scholarly journals Modulatory effects of dynamic fMRI-based neurofeedback on emotion regulation networks in adolescent females

2018 ◽  
Author(s):  
Catharina Zich ◽  
Nicola Johnstone ◽  
Michael Lührs ◽  
Stephen Lisk ◽  
Simone P W Haller ◽  
...  
Keyword(s):  
Emotion Regulation ◽  
State Anxiety ◽  
Adolescent Females ◽  
Anterior Cingulate ◽  
Childhood And Adolescence ◽  
Functional Magnetic Resonance ◽  
Thought Control ◽  
Excitatory Neurotransmitters ◽  
The Relationship ◽  
Thought Control Ability

ABSTRACTResearch has shown that difficulties with emotion regulation abilities in childhood and adolescence increase the risk for developing symptoms of mental disorders, e.g anxiety. We investigated whether functional magnetic resonance imaging (fMRI)-based neurofeedback (NF) can modulate brain networks supporting emotion regulation abilities in adolescent females.We performed three studies (total N=63). We first compared different NF implementations regarding their effectiveness of modulating prefrontal cortex (PFC)-amygdala functional connectivity (fc). Further we assessed the effects of fc-NF on neural measures, emotional/metacognitive measures and their associations. Finally, we probed the mechanism underlying fc-NF by examining concentrations of inhibitory and excitatory neurotransmitters.Results showed that NF implementations differentially modulate PFC-amygdala fc. Using the most effective NF implementation we observed important relationships between neural and emotional/metacognitive measures, such as practice-related change in fc was related with change in thought control ability. Further, we found that the relationship between state anxiety prior to the MRI session and the effect of fc-NF was moderated by GABA concentrations in the PFC and anterior cingulate cortex.To conclude, we were able to show that fc-NF can be used in adolescent females to shape neural and emotional/metacognitive measures underlying emotion regulation. We further show that neurotransmitter concentrations moderate fc-NF-effects.

scholarly journals Relation of Apparent Diffusion Coefficient Changes and Metabolic Disturbances after 1 Hour of Focal Cerebral Ischemia and at Different Reperfusion Phases in Rats

2001 ◽  
Vol 21 (4) ◽  
pp. 430-439 ◽  
Author(s):  
Laszlo Olah ◽  
Stefan Wecker ◽  
Mathias Hoehn
Keyword(s):  
Energy Metabolism ◽  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Focal Cerebral Ischemia ◽  
Artery Occlusion ◽  
Atp Depletion ◽  
Apparent Diffusion ◽  
Tissue Acidosis ◽  
Cerebral Artery Occlusion ◽  
Energy Failure

Changes in apparent diffusion coefficients (ADC) were compared with alterations of adenosine triphosphate (ATP) concentration and pH in different phases of transient focal cerebral ischemia to study the ADC threshold for breakdown of energy metabolism and tissue acidosis during ischemia and reperfusion. Male Wistar rats underwent 1 hour of middle cerebral artery occlusion without recirculation (n = 3) or with 1 hour (n = 4) or 10 hours of reperfusion (n = 5) inside the magnet, using a remotely controlled thread occlusion model. ADC maps were calculated from diffusion-weighted images and normalized to the preischemic value to obtain relative ADC maps. Hemispheric lesion volume (HLV) was determined on the last relative ADC maps at different relative ADC thresholds and was compared to the HLV measured by ATP depletion and by tissue acidosis. The HLVs, defined by ATP depletion and tissue acidosis, were 26.0% ± 10.6% and 38.1% ± 6.5% at the end of ischemia, 3.3% ± 2.4% and 4.8% ± 3.5% after 1 hour of reperfusion, and 11.2% ± 4.7% and 10.9% ± 5.2% after 10 hours of recirculation, respectively. The relative ADC thresholds for energy failure were consistently approximately 77% of the control value in the three different groups. The threshold for tissue acidosis was higher at the end of ischemia (86% of control) but was similar to the results obtained for ATP depletion after 1 hour (78% of control) and 10 hours (76% of control) of recirculation. These results indicate that the described relative ADC threshold of approximately 77% of control provides a good estimate for the breakdown of energy metabolism not only during middle cerebral artery occlusion but also at the early phase of reperfusion, when recovery of energy metabolism is expected to occur, or some hours later, when development of secondary energy failure was described.

Slow ATP loss and the defense of ion homeostasis in the anoxic frog brain

2001 ◽  
Vol 204 (20) ◽  
pp. 3547-3551
Author(s):  
Debra L. Knickerbocker ◽  
Peter L. Lutz
Keyword(s):  
Initial Phase ◽  
Ion Homeostasis ◽  
Atp Depletion ◽  
Neuronal Membrane ◽  
Anoxia Tolerance ◽  
Frog Brain ◽  
Atp Levels ◽  
Anoxic Depolarization ◽  
Rate Of Increase ◽  
The Brain

SUMMARY For most vertebrates, cutting off the oxygen supply to the brain results in a rapid (within minutes) loss of ATP, the failure of ATP-dependent ion-transport process, subsequent anoxic depolarization of neuronal membrane potential and consequential neuronal death. The few species that survive brain anoxia for days or months, such as the freshwater turtle Trachemys scripta, avoid anoxic depolarization and maintain brain ATP levels through a coordinated downregulation of brain energy demand processes. The frog Rana pipiens represents an intermediate in anoxia-tolerance, being able to survive brain anoxia for hours. However, the anoxic frog brain does not defend its energy stores. Instead, anoxia-tolerance appears to be related to a retarded rate of ATP depletion. To investigate the relationship between this slow ATP depletion and the loss of ionic homeostasis, cerebral extracellular K+ concentrations were monitored and ATP levels measured during anoxia, during the initial phase of anoxic depolarization and during complete anoxic depolarization. Extracellular K+ levels were maintained at normoxic levels for at least 3 h of anoxia, while ATP content decreased by 35 %. When ATP levels reached 0.33±0.06 mmol l–1 (mean ± s.e.m., N=5), extracellular K+ levels slowly started to increase. This value is thought to represent a critical ATP concentration for the maintenance of ion homeostasis. When extracellular [K+] reached an inflection value of 4.77±0.84 mmol l–1 (mean ± s.e.m., N=5), approximately 1 h later, the brain quickly depolarized. Part of the reduction in ATP demand was attributable to an approximately 50 % decrease in the rate of K+ efflux from the anoxic frog brain, which would also contribute to the retarded rate of increase in extracellular [K+] during the initial phase of anoxic depolarization. However, unlike the anoxia-tolerant turtle brain, adenosine did not appear to be involved in the downregulation of K+ leakage in the frog brain. The increased anoxia-tolerance of the frog brain is thought to be a matter more of slow death than of enhanced protective mechanisms.

Oxygen partial pressure and free intracellular adenosine of isolated cardiomyocytes

1991 ◽  
Vol 260 (4) ◽  
pp. C708-C714 ◽  
Author(s):  
R. T. Smolenski ◽  
J. Schrader ◽  
H. de Groot ◽  
A. Deussen
Keyword(s):  
Oxygen Consumption ◽  
Extracellular Space ◽  
Oxygen Supply ◽  
Oxygen Demand ◽  
Nucleoside Transport ◽  
Isolated Cardiomyocytes ◽  
Homocysteine Thiolactone ◽  
Rat Cardiomyocytes ◽  
Extracellular Adenosine ◽  
Adenosine Concentration

Adenosine formation by the heart is known to critically depend on the ratio of oxygen supply to oxygen demand, but the sensitivity of cardiomyocytes to defined changes in PO2 is not known. Isolated metabolically stable rat cardiomyocytes were incubated up to 45 min at constant PO2 values ranging from 0.1 to 100 mmHg using a feedback-controlled incubation system (oxystat system). Changes of the free intracellular adenosine concentration were measured after trapping of adenosine by cytosolic S-adenosylhomocysteine (SAH) hydrolase in the presence of 200 microM L-homocysteine thiolactone. Rate of SAH formation was constant at a PO2 between 3 and 100 mmHg and gradually increased at PO2 less than 3 mmHg. Cellular ATP decreased only at PO2 less than 1 mmHg, and this was accompanied by a decline of oxygen consumption. Treatment of cells with 5.5 mM deoxyglucose and 4 micrograms/ml oligomycin increased SAH formation 60-fold and was associated with elevated intra- and to a lesser extent extracellular adenosine levels. Inhibition of nucleoside transport with 20 microM S-(p-nitrobenzyl)-6-thioinosine steepened the transmembrane adenosine gradient. Our findings suggest that the cardiomyocyte responds to metabolic poisoning and oxygen deprivation with an enhanced formation of adenosine. This adenosine is mainly formed intracellularly and reaches the extracellular space by diffusion. Threshold for adenosine formation is as low as 3 mmHg.

Coupling among changes in energy metabolism, acid-base homeostasis, and ion fluxes in ischemia

1992 ◽  
Vol 70 (S1) ◽  
pp. S170-S175 ◽  
Author(s):  
Ken-ichiro Katsura ◽  
Anders Ekholm ◽  
Bo K. Siesjö
Keyword(s):  
Energy Metabolism ◽  
Ion Homeostasis ◽  
Ion Fluxes ◽  
Acid Base ◽  
Cellular Energy ◽  
Initial Event ◽  
Extra Cellular Fluid ◽  
The Relationship ◽  
Energy Failure ◽  
Ion Conductances

This article attempts correlating changes in cellular energy metabolism, acid-base alterations, and ion homeostasis in ischemia and other conditions. It is emphasized that loss of ion homeostasis, with thermodynamically downhill fluxes of K+, Ca2+, Na+, Cl−, and H+, occurs because energy production fails and (or) ion conductances are increased. In ischemia, energy failure is the leading event but, in hypoglycemia, activation of ion conductances is what precipitates energy failure. The initial event is a rise in K+e, at least in part caused by activation of K+ conductances modulated by Ca2+ or ATP/ADP ratio. Secondarily, this leads to release of excitatory amino acids and massive activation of unspecific cation (and anion) conductances. Production of H+ occurs in states characterized by energy failure (ischemia and hypoxia) or by alkalosis (hypocapnia and ammonia accumulation). H+ equilibrates between intra- and extra-cellular fluid via nonionic diffusion of lactic acid, and transmembrane fluxes of H+ or HCO3− via ion channels. Since the relationship between lactate and either pHi or pHe is linear, there are no abrupt pH shifts explaining why hyperglycemia worsens ischemic damage. The reversible insults seem to induce a sustained stimulation of H+ extrusion from cells giving rise to intracellular alkalosis and extracellular acidosis.Key words: energy metabolism, acid-base homeostasis, ion fluxes, ischemia.

Adenosine metabolism in human skin fibroblasts

1985 ◽  
Vol 248 (1) ◽  
pp. C21-C26 ◽  
Author(s):  
M. J. Holland ◽  
E. Murphy ◽  
J. K. Kelleher
Keyword(s):  
Initial Rate ◽  
Adenine Nucleotide ◽  
Adenine Nucleotides ◽  
Product Formation ◽  
Human Skin Fibroblasts ◽  
Metabolic Fate ◽  
Normal Cells ◽  
Extracellular Adenosine ◽  
Adenosine Concentration ◽  
The Media

When normal fibroblasts were incubated in media containing various initial concentrations of [8-14C]adenosine, ranging from 0.25 to 400 microM, under conditions where product formation was linear, greater than 90% of the intracellular label was found in adenine nucleotides, largely in the form of ATP, less than 1% of the intracellular label appeared in the nucleic acids, the remaining intracellular label was found in adenosine, inosine, and hypoxanthine, and the media contained two labeled products, inosine and hypoxanthine. Production of labeled inosine and hypoxanthine from adenosine was considerably lower in adenosine deaminase (ADA)-deficient cells than in normal cells and virtually eliminated in normal cells by the presence of 1 microM deoxycoformycin (a potent ADA inhibitor), suggesting that labeled inosine and hypoxanthine production requires ADA activity. Initial rates of deamination (inosine and hypoxanthine formation) and phosphorylation (adenine nucleotide formation) were estimated by examining the metabolic fate of [8-14C]adenosine in hypoxanthine phosphoribosyltransferase-deficient cells, which cannot recycle hypoxanthine. The estimate of the initial rate of phosphorylation exceeded that of deamination only at the lowest adenosine concentration examined (0.25 microM). The ratio of deamination to phosphorylation rose from approximately 1 at 0.41 microM to approximately 15 at 400 microM extracellular adenosine.

Adenosine and the regional differences in adipose tissue metabolism in women

1988 ◽  
Vol 118 (3) ◽  
pp. 327-331 ◽  
Author(s):  
Susanna Stoneham ◽  
Tuula Kiviluoto ◽  
Leila Keso ◽  
Jorma J. Ohisalo
Keyword(s):  
Adipose Tissue ◽  
Regional Differences ◽  
Lipoprotein Lipase Activity ◽  
Extracellular Adenosine ◽  
Lactating Women ◽  
Femoral Site ◽  
Acting Insulin ◽  
Adenosine Concentration ◽  
Wet Weight ◽  
Menstruating Women

Abstract. Adenosine content in abdominal and femoral adipose tissue in menstruating women was 0.38 ± 0.10 and 0.59 ± 0.14 nmol/g of wet weight, respectively (mean ± sem; N = 17). No difference in adenosine sensitivity was found between abdominal and femoral adipocytes. In lactating women, the adenosine content was lower in femoral than in abdominal adipose tissue (0.40 ± 0.08 and 0.57 ± 0.08 nmol/g of wet weight, respectively; N = 10). Adenosine sensitivity in femoral adipocytes was not increased during lactation. As adenosine is a locally acting insulin-like effector, these results suggest that the higher adenosine content in femoral adipose tissue in menstruating women could explain its higher lipoprotein lipase activity and tendency to accumulate fat. During lactation, the lower extracellular adenosine concentration would allow lipid mobilization preferentially from the femoral site.

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