The inorganic phosphate and phosphocreatine of brain especially during metabolism <i>in vitro</i>

McIlwain, H.; Buchel, L; Cheshire, Jenny

doi:10.1042/bj0480012

Cited by 123 publications

(34 citation statements)

References 15 publications

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“…Ribose-5-phosphate can be formed directly from d-ribose by ribokinase (10), or via isomerisation of inosine (INO)-derived ribose-1-phosphate (14), thereby increasing PRPP levels. Adenine and d-ribose feed into the salvage pathway and increase tissue ATP levels via adenylate kinasemediated phosphorylation of AMP and thence to ATP (3). AMP can also be formed from adenosine via adenosine kinase (5).…”

Section: Atp: More Than Just Currencymentioning

confidence: 99%

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Frenguelli

2017

Neurochem Res

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Brain slices have been the workhorse for many neuroscience labs since the pioneering work of Henry McIlwain in the 1950s. Their utility is undisputed and their acceptance as appropriate models for the central nervous system is widespread, if not universal. However, the skeleton in the closet is that ATP levels in brain slices are lower than those found in vivo, which may have important implications for cellular physiology and plasticity. Far from this being a disadvantage, the ATP-impoverished slice can serve as a useful and experimentally-tractable surrogate for the injured brain, which experiences similar depletion of cellular ATP. We have shown that the restoration of cellular ATP in brain slices to in vivo values is possible with a simple combination of d-ribose and adenine (RibAde), two substrates for ATP synthesis. Restoration of ATP in slices to physiological levels has implications for synaptic transmission and plasticity, whilst in the injured brain in vivo RibAde shows encouraging positive results. Given that ribose, adenine, and a third compound, allopurinol, are all separately in use in man, their combined application after acute brain injury, in accelerating ATP synthesis and increasing the reservoir of the neuroprotective metabolite, adenosine, may help reduce the morbidity associated with stroke and traumatic brain injury.

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Section: Atp: More Than Just Currencymentioning

confidence: 99%

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Frenguelli

2017

Neurochem Res

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“…Ironically, this preparation was originally developed for use in biochemical studies characterizing energy metabolism in neuronal tissue. These early studies demonstrated that, under appropriate experimental conditions, acutely prepared shces of brain tissue could maintain normal levels of ATP and phosphocreatine for several hours (Mcllwain et al, 1951). Soon after, Mcllwain and his colleagues discovered that, in addition to demonstrating biochemical markers of viability, neurons in brain slices could actually maintain viable membrane potentials (Li and Mcllwain, 1957).…”

Section: The In Vitro Tissue Slice Preparationmentioning

confidence: 99%

Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

Valenzuela¹,

Savage²,

Weiner³

2002

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SUPPLEMENTARY NOTES 12a. DISTRIBUTION /AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited 12b. DISTRIBUTION CODE Abstract (Maximum 200 Words) labstract should contain no proprietary or confidential information)We have been testing the hypothesis that chronic alcohol exposure alters expression and/or function of kainate receptors (KA-Rs) in the hippocampus. KA-Rs control hippocampal excitability and an ethanol-induced upregulation of KA-Rs could contribute to the hyperexcitability associated with alcohol withdrawal. Unexpectedly, Western immunoblotting and immunohistochemical studies have demonstrated that chronic ethanol exposure does not upregulate KA-R subunit expression. However, studies with cultured neurons suggest that alcohol withdrawal itself, but not chronic ethanol exposure, upregulates KA-R function. Therefore, we are now focusing our efforts at testing if this is also true for animals exposed to ethanol. We have switched to a different method of alcohol exposure; we are using the inhalation route, which reproducibly produces high ethanol levels. We are currently processing brain sections from control rats and rats withdrawn from a 14-day inhalational ethanol exposure paradigm. These sections will be immunostained with anti-GluR6/7 antibodies and will be used for radioligand binding experiments. We have also characterized the acute effects of ethanol on the function of interneuronal KA-Rs. Moreover, a preliminary experiment with hippocampal slices from rats withdrawn from a 6-day inhalational exposure paradigm suggests that the function of these receptors is upregulated. During the last year of support, we will concentrate on characterizing the function of KA-Rs in the CA1 and CAS regions in alcohol withdrawn rats. Alcohol-related medical disorders affect many organs and systems of the body, including the central nervous system (CNS). As with other drugs of abuse, long-term alcohol ingestion results in the development of tolerance, addiction, and dependence. Alcohol produces these effects by altering the actions of neurotransmitters and their receptors in the brain. Chronic ethanol exposure has complex and long-lasting effects on the function and/or expression of a myriad of neurotransmitter receptors and their modulators. A group of proteins affected by chronic ethanol exposure are hgand-gated ion channels such as the glutamatergic ionotropic receptors. Glutamate activates three major classes of ionotropic receptors. These three major types of channels are the NMD A, AMPA and kainate receptors (KA-Rs). The purpose of this proposal is to test whether or not chronic ethanol exposure results in alterations in subunit expression and/or function of KA-Rs in the hippocampus. Maladaptive changes in hippocampal KA-R expression could contribute to the pathophysiology of alcohol withdrawal syndrome. The alcohol withdrawal syndrome is associated with neuronal hyperexcitabiUty and seizures. Since kainate receptors are important regulators of excitability in the hippocampus, upregulation o...

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“…We speculate that primary energy failure occurs during decapitation and slicing of the brain slices. This phenomenon, "primary energy failure," associated with brain slice preparation was demonstrated more than 50 y ago; after depletion of PCr and ATP during slicing, sliced brain tissue was able to resynthesize high-energy phosphates to around two-thirds of in vivo levels when placed in saline with glucose and oxygen as substrates (26). These experiments demonstrated that stable levels of PCr and ATP could be maintained for at least 2 h after preparation and that, during this time, the tissue was responsive to the metabolic demands of electrical pulses (37).…”

Section: Neuroprotection In Rat Brain Slicesmentioning

confidence: 99%

“…Compared with intact brain, slices have a lower ATP and PCr (26) with an increased production of lactate (27). The precise mechanisms leading to these metabolic differences between the brain slice and intact brain are unclear, but we considered that reduced high-energy phosphates and intracellular alkalosis suggests that brain slices may be undergoing a process similar to the secondary energy failure seen after transient HI in newborn infants (4 -7).…”

mentioning

confidence: 99%

Hypothermia and Amiloride Preserve Energetics in a Neonatal Brain Slice Model

et al. 2005

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A period of secondary energy failure consisting of a decline in phosphocreatine/inorganic phosphate (PCr/Pi), a rise in brain lactate, and alkaline intracellular pH (pH i ) has been described in infants with neonatal encephalopathy. Strategies that ameliorate this energy failure may be neuroprotective. We hypothesized that a neonatal rat brain slice model undergoes a progressive decline in energetics, which can be ameliorated with hypothermia or amiloride. Interleaved phosphorus ( 31 P) and proton ( 1 H) magnetic resonance (MR) spectra were obtained from 350 m neonatal rat brain slices over 8 h in a bicarbonate buffer at 37°C and at 32°C in 7-and 14-d models.31 P MR spectra were obtained with amiloride in a bicarbonate-free buffer at 37°C in the 14-d model. Findings were similar in 7-and 14-d models. In the 14-d model, there was a Pi doublet structure corresponding to alkaline pH i values of 7.50 Ϯ 0.02 and 7.21 Ϯ 0.04. Compared with the stabilized baseline of 100, at 5 h PCr/Pi was 65 Ϯ 6.3 and lactate/NAA was 187 Ϯ 3 at 37°C, but PCr/Pi and lactate/NAA were not significantly different from baseline at 32°C. Nucleotide triphosphate (NTP)/phosphomonoester (PME) was 0.93 Ϯ 0.23 at 37°C and 1.81 Ϯ 0.21 at 32°C at 5 h. With amiloride exposure in the 14-d model, baseline pH i values were 7.25 Ϯ 0.09 and 6.98 Ϯ 0.02 and NTP/PME was 1.81 Ϯ 0.05; these parameters were not significantly different at 5 h. Our interpretation of these findings is that the brain slice model underwent secondary energy failure, which was delayed with hypothermia or amiloride. Studies in term infants with neonatal encephalopathy (NE) suggest that, although antenatal or genetic factors might predispose some infants to perinatal brain injury (1,2), events in the immediate perinatal period are important in neonatal brain injury (3). A consistent pattern of energy derangement has been observed by several groups in infants with NE due to intrapartum asphyxia using phosphorus ( 31 P) and proton ( 1 H) magnetic resonance (MRS), spectroscopy (4 -7). 31 P and 1 H MR spectra were often normal within the first few hours after resuscitation, but after 8 -24 h there was a progressive decline in PCr/Pi and rise in brain lactate despite adequate oxygenation and circulation in the infant. The nadir of the energetic disturbance was seen after 12-24 h and the magnitude of the fall in PCr/Pi and rise in brain lactate correlated with the subsequent neurodevelopmental abnormality (8,9). This sequence of events was termed "secondary energy failure" to distinguish it from the "primary" decline in PCr and ATP and rise in lactate seen during the insult in experimental animal models of hypoxia-ischemia (HI) (10,11). The biphasic pattern of energy failure during and after HI has been the cornerstone behind the realization that neuroprotective strategies might interrupt the cascade of irreversible injury if administered within hours of a perinatal insult (12), and the concept has been an important catalyst in the development of neuroprotection trials with moderate hypoth...

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The inorganic phosphate and phosphocreatine of brain especially during metabolism in vitro

Cited by 123 publications

References 15 publications

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

Hypothermia and Amiloride Preserve Energetics in a Neonatal Brain Slice Model

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