Experimental studies demonstrate an alkaline shift in brain intracellular pH (pH(i)) after hypoxia-ischemia (HI). In infants with neonatal encephalopathy after HI, our aims were to assess (1) brain pH(i) during the first 2 weeks after birth in infants categorized according to magnetic resonance imaging (MRI) during the first 2 weeks after birth and at more than 3 months of age, and neurodevelopmental outcome at 1 year; (2) the relationship between brain pH(i) and lactate/creatine; and (3) duration of alkaline brain pH(i). Seventy-eight term infants with neonatal encephalopathy were studied using MR techniques. One hundred and fifty-one studies were performed throughout the first year including 56 studies of 50 infants during the first 2 weeks after birth. pH(i) was calculated using phosphorus-31 MR spectroscopy and lactate/creatine was measured using proton MRS. The mean (standard deviation [SD]) brain pH(i) during the first 2 weeks after birth in infants with severely abnormal versus normal MRI was 7.24 (SD, 0.17) versus 7.04 (SD, 0.05; p < 0.001); in infants who subsequently developed cerebral atrophy versus those who did not: 7.23 (SD, 0.17) versus 7.06 (SD, 0.06; p < 0.05); in infants who died or had a severe neurodevelopmental impairment versus normal outcome: 7.28 (SD, 0.15) versus 7.11 (SD, 0.09; p < 0.05). Brain alkalosis was associated with increased brain lactate/creatine (p < 0.001). pH(i) remained more alkaline in the severe outcome group up to 20 weeks after birth (p < 0.05).

Brain alkaline intracellular pH after neonatal encephalopathy.

Nuclear magnetic resonance spectroscopy studies of the brain

In the last decade, significant progress has been made in the characterization of pH regulation in nervous tissue in vitro. However, little work has been directed at understanding how pH regulatory mechanisms function in vivo. We are interested in how ischemic acidosis can effect pH regulation and modulate the extent of post-ischemic brain damage. We used 31P-MRS to determine normal in vivo pH(i) and pH(e) simultaneously in both the isolated canine brain and the intact rat brain. We observed that the 31P(i) peak in the 31P-MRS spectrum is heterogeneous and can be deconvoluted into a number of discrete constituent peaks. In a series of experiments, we identified these peaks as arising from either extracellular or intracellular sources. In particular, we identified the peak representing the neurons and astrocytes and showed that they maintain different basal pH (6.95 and 7.05, respectively) and behave differently during hypoxic/ischemic episodes.

31P-MRS-based determination of brain intracellular and interstitial pH: its application to in vivo H+ compartmentation and cellular regulation during hypoxic/ischemic conditions.

Metabolic tolerance of low intracellular pH (pHi) was studied in well-oxygenated, perfused, neonatal, rat cerebrocortical brain slices (350 mum thick) by inducing severe hypercapnia. In each of 17 separate experiments 80 brain slices (sim 3.2 g wet weight) were suspended in an NMR tube, perfused with artificial CSF (ACSF), and studied at 4.7 T with 31P and 1H NMR spectroscopy. Spectra obtained every 5 min monitored relative concentrations of lactate or high-energy phosphate metabolites, from which pHi and extracellular pH were determined. Unperturbed slice preparations were metabolically stable for > 10 h, with no significant changes occurring in pHi, ATP, phosphocreatine (PCr), inorganic phosphate, or lactate. Different levels of hypercapnia were produced by sequentially perfusing slices with the following different ACSF batches, each having previously been equilibrated with a specific mixture of CO2 in oxygen: (a) 10% CO2, 15 min of perfusion; (b) 30% CO2, 15 min of perfusion; (c) 50% CO2, 15 min of perfusion; (d) 70% CO2, 30 min of perfusion; (e) 50% CO2, 15 min of perfusion; (f) 30% CO2, 15 min of perfusion; and (g) 10% CO2, 15 min of perfusion. At the completion of this protocol slices were again perfused with fresh ACSF that was equilibrated with a 95% O2/5% CO2 gas mixture. In each of five separate 1H and 31P experiments, brain slices were recovered within 2 h after termination of exposure to high CO2. The pHi was determined from measurements of the chemical shift difference between phosphoethanolamine and PCr, using a calibration curve obtained for our preparation. During hypercapnia, pHi decreased from 7.18 pmn 0.22 to 6.79 pmn 0.13, 6.60 pmn 0.11, 6.33 pmn 0.40, and 6.37 pmn 0.14 when CO2 concentrations were increased to 10, 30, 50, and 70%, respectively. Lactate/N-acetylaspartate ratios were unchanged until the administration of 70% CO2, which caused a relative increase from 0.83 pmn 0.15 to 1.35 pmn 0.32 (n = 5, p = 0.0024). The administration of 70% CO2 also caused complete depletion of PCr and a 46 pmn 22% (n = 5, p = 0.0024) decrease in ATP content. Metabolite and pH values returned to control values after restoration of normocapnia. The lowest tissue pHi attainable in our protocol using 30% O2/70% CO2 in our brain slice preparation was sim 6.3.

Tolerance of low intracellular pH during hypercapnia by rat cortical brain slices: A 31P/1H NMR study.

13C Nuclear Magnetic Resonance spectroscopy is the method of choice for studying brain metabolism. Indeed, the most convincing data obtained to decipher metabolic exchanges between neurons and astrocytes have been obtained using this technique, thus illustrating its power. It may be difficult for non-specialists, however, to grasp the full implication of data presented in articles written by spectroscopists. The aim of the review is, therefore, to provide a fundamental understanding of this topic to facilitate the non-specialists in their reading of this literature. In the first part of this review, we present the metabolic fate of 13 C-labelled substrates in the brain in a detailed way, including an overview of some general neurochemical principles. We also address and compare the various spectroscopic strategies that can be used to study brain metabolism. Then, we provide an overview of the 13 C Nuclear Magnetic Resonance experiments performed to analyse both intracellular and intercellular metabolic fluxes. More particularly, the role of lactate as a potential energy substrate for neurons is discussed in the light of 13 C Nuclear Magnetic Resonance data. Finally, new perspectives and applications offered by 13 C hyperpolarization are described.

/pdf/13c-nmr-spectroscopy-applications-to-brain-energy-metabolism-581n9qy1qc.pdf

13C NMR spectroscopy applications to brain energy metabolism

Cerebral metabolism and neuronal function of prefrontal brain cortex were studied in 6 dog litters from birth to 3 months of age. Noninvasive phosphorus magnetic resonance spectroscopy (31P-MRS) was used to observe longitudinal biochemical changes in the phosphorus compounds associated with cerebral metabolism. Neurological tests, examining reflex, motor and sensory nerve function, were performed in conjunction with the 31P-MRS study. During the neonatal period, exponential increases in PCr, Pi, and phophodiesters preceded neurological changes. Phosphomonoesters showed an exponential, nearly linear, decrease and PCr/Pi was maintained during the 3-month period. Developmental increases in high energy phosphates and the maintenance of PCr/Pi indicate that the increased energy demands of the developing animal are met by increased mitochondrial function (ATP turnover).

31P magnetic resonance spectroscopy study of cerebral metabolism in developing dog brain and its relationship to neuronal function

Two metabolically distinct cell populations were detected when two peaks of inorganic phosphate (Pi), corresponding to two pHi values, were recorded by Phosphorus Magnetic Resonance Spectroscopy (31P MRS). One cell population, having intracellular pH (pHi) values less than 6.3, was thought to contain neither PCr (phosphocreatine) nor ATP and was thus considered metabolically unstable or inactive. The second cell population, having normal or near normal pHi, was considered metabolically active with adequate values of ATP and PCr. We can therefore further analyze the bioenergetics in this cell population. The results were based upon studies of 14 ischemic dogs that were anesthetized with 2% isoflurane and ventilated. The amount of Pi associated with the acidic cell population (low pHi) was used to calculate the fraction of metabolically inactive brain tissues. This value correlated well with the ATP depletion of the total cell population. This suggests that in the acidic cell population, PCr and ATP supplies were depleted by dephosphorylation during ischemia, leading to an accumulation of acidic Pi. In addition, ATP synthesis in this population may be inhibited by the low intracellular pH. On the other hand, the bioenergetic state of the metabolically stable cell population having a nearly neutral pHi changed markedly during ischemia. The PCr/Pi dropped to 0.8 and the phosphorylation potential (PP) dropped to 10 mM-1 from 40 mM-1. With reperfusion, two distinct patterns of responses were observed. One group showed the restoration of ATP (recovery group) whereas the second group did not (non-recovery group). After 3 h of reperfusion, the ATP restored group showed complete recovery of PCr.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic heterogeneity in brain tissue during incomplete ischemia and reperfusion.

The phosphate metabolites, PCr, ATP, ADP and inorganic phosphate (Pi), were quantitated in the brain of the newborn, neonatal, juvenile and adult dog to investigate the potential control mechanisms responsible for increased ATP demands during development. The concentrations of PCr and Pi were measured in vivo by MRS using the enzymatic-measured ATP as the internal standard. Phosphocreatine values increased during development from 2.08 mmol/kg wet weight in the 0-2 day newborn to 5.11 mmol/kg wet weight in the adult brain and paralleled the increases in the total creatine pool (PCr + Cr) from 4.12 to 10.05 mmol/kg wet weight. Brain ATP concentrations increased approximately 40% during postnatal development; however, when expressed as intracellular concentration, no increase in ATP was apparent due to the age-dependent decrease in extracellular space. The Pi concentration, estimated by MRS, increased significantly during postnatal development with a range of 1.78 to 2.52 mmol/kg wet wt, then decreased to 1.97 mmol/kg wet weight at adulthood. In those developmental stages where total Pi was measured enzymatically on freeze-clamped tissue, the NMR visible Pi comprised about 48 to 93% of the total, with the highest percentage being visible in the newborn brain. The intracellular pH decreased from 7.21 in the newborn to 7.10 in the adult. With development, the free ADP concentration, calculated from the components of the creatine kinase equilibrium, ranged from 27 to 34 microM. These values are close to the apparent in vitro Km of ADP for oxidative phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitation of high energy phosphate compounds and metabolic significance in the developing dog brain.

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31P magnetic resonance spectroscopy study of cerebral metabolism in developing dog brain and its relationship to neuronal function

Metabolic heterogeneity in brain tissue during incomplete ischemia and reperfusion.

Quantitation of high energy phosphate compounds and metabolic significance in the developing dog brain.