Effect of dichloroacetate on recovery of brain lactate, phosphorus energy metabolites, and glutamate during reperfusion after complete cerebral ischemia in rats.

The effects of dichloroacetate (DCA) on brain lactate, intracellular pH (pHi), phosphocreatine (PCr), and ATP during 60 min of complete cerebral ischemia and 2 h of reperfusion were investigated in rats by in vivo 1H and 31P magnetic resonance spectroscopy; brain lactate, water content, cations, and amino acids were measured in vitro after reperfusion. DCA, 100 mg/kg, or saline was infused before or immediately after the ischemic period. Preischemic treatment with DCA did not affect brain lactate or pHi during ischemia, but reduced lactate and increased pHi after 30 min of reperfusion (p < 0.05 vs. controls) and facilitated the recovery of PCr and ATP during reperfusion. Postischemic DCA treatment also reduced brain lactate and increased pHi during reperfusion compared with controls (p < 0.05), but had little effect on PCr, ATP, or Pi during reperfusion. After 30 min of reperfusion, serum lactate was 67% lower in the postischemic DCA group than in controls (p < 0.05). The brain lactate level in vitro was 46% lower in the postischemic DCA group than in controls (p < 0.05). DCA did not affect water content or cation concentrations in either group, but it increased brain glutamate by 40% in the preischemic treatment group (p < 0.05). The potential therapeutic effects of DCA on brain injury after complete ischemia may be mediated by reduced excitotoxin release related to decreased lactic acidosis during reperfusion.     

In vivo 31phosphorus spectroscopy during transient cerebral ischaemia in the gerbil

The depletion of the high energy phosphates; phosphocreatine and ATP, during cerebral ischaemia disrupts normal cellular function and can lead to cerebral infarction. Using in vivo nuclear magnetic resonance spectroscopy, the metabolic effects of the gerbil model of transient bilateral carotid artery occlusion were quantified. By examining the changes in the inorganic phosphate (Pi), phosphocreatine (PCr) and beta-ATP peaks, the PCr/Pi ratio, the PCr/beta-ATP ratio and intracellular pH (pHi) before, during and after an ischaemic insult were calculated. Preischaemic values for these parameters were: PCr/Pi = 2.466 +/- 0.130, PCr/beta-ATP = 1.691 +/- 0.053, pHi = 7.112 +/- 0.021. By the end of 20 min of global ischaemia, the PCr and beta-ATP peaks fell to levels similar to background in most animals. Calculated values were: PCr/Pi = 0.488 +/- 0.126, PCr/beta-ATP = 1.833 +/- 0.179, pHi = 6.551 +/- 0.258. With reperfusion, PCr/Pi increased rapidly back towards preischaemic levels but pHi improvement was delayed 10 min after that of PCr/Pi. By 1 h of reperfusion, both PCr/Pi and pHi were statistically equivalent to preischaemic values. During ischaemia, ATP was lost more rapidly than the storage form, PCr, but recovery of both was parallel. This suggested an intact ability to store such energy. These data indicate that the gerbil brain recovers normal high energy phosphate levels within an hour following a 20 min ischaemic insult, but that initial reperfusion does not immediately correct intracellular acidosis. Such a delay may prove a useful marker of those animals with more severe ischaemic injury.     

In vivo 31phosphorus spectroscopy during transient cerebral ischaemia in the gerbil

The depletion of the high energy phosphates; phosphocreatine and ATP, during cerebral ischaemia disrupts normal cellular function and can lead to cerebral infarction. Using in vivo nuclear magnetic resonance spectroscopy; the metabolic effects of the gerbil model of transient bilateral carotid artery occlusion were quantified. By examining the changes in the inorganic phosphate (Pi), phosphocreatine (PCr) and μ-ATP peaks, the PCr/Pi ratio, the PCr/μ-ATP ratio and intracellular pH (pHi) before, during and after an ischaemic insult were calculated. Preischaemic values for these parameters were: PCr/Pi = 2.466 ± 0.130, PCr/μ-ATP = 1.691 ± 0.053, pHi = 7.112 ± 0.021. By the end of 20 min of global ischaemia, the PCr and μ-ATP peaks fell to levels similar to background in most animals. Calculated values were: PCr/Pi = 0.488 ± 0.126, PCr/μ-ATP = 1.833 ± 0.179, pHi = 6.551 ± 0.258. With reperfusion, PCr/Pi increased rapidly back towards preischaemic levels but pHi improvement was delayed 10 min after that of PCr/Pi. By 1 h of reperfusion, both PCr/Pi and pHi were statistically equivalent to preischaemic values. During ischaemia, ATP was lost more rapidly than the storage form, PCr, but recovery of both was parallel. This suggested an intact ability to store such energy. These data indicate that the gerbil brain recovers normal high energy phosphate levels within an hour following a 20 min ischaemic insult, but that initial reperfusion does not immediately correct intracellular acidosis. Such a delay may prove a useful marker of those animals with more severe ischaemic injury.     

Effects of hypoxia on rat brain metabolism: unilateral in vivo carotid infusion

An in vivo brain perfusion technique was used to examine effects of hypoxia on cerebral cortical metabolism in barbiturate-anesthetized rats. Dulbecco's phosphate-buffered solution (PBS), or Dulbecco's PBS + 6 mM glucose, was infused into the right carotid circulation for 0 to 3 min, at a rate that reduced regional cerebral blood flow to the ipsilateral parietal lobe by more than 40% and O2 delivery by about 50%. The duration of infusion of either solution was correlated negatively with the ipsilateral parietal lobe concentrations of glucose, ATP, and phosphocreatine (PCr), and positively with parietal concentrations of lactate and cAMP. cGMP increased in relation to infusion duration of Dulbecco's PBS. Statistically significant elevations of brain lactate occurred after 1 min of infusion of Dulbecco's PBS; lactate was elevated and glucose was reduced after 2 min of infusion of either solution. Brain ATP, PCr, and glycogen concentrations decreased in relation to the elevation in brain lactate, and the [PCr]:[ATP] ratio declined. The results demonstrated that limited hypoxia stimulated cerebral glycolysis and produced a concurrent decrease in brain ATP and PCr. However, ATP was spared to a degree, at the expense of PCr.     

Cerebral energy metabolism during recovery from carbon monoxide hypoxia-oligemia

The effects of 1 h exposure to 1% CO and right common carotid artery clamping upon the cerebral energy metabolism, perfusion and histology were studied in anesthetized (70%N(2)O) and unanesthetized rats following reoxygenation for 0-6 h. At 0 h recovery the clamped hemispheres showed decreases of ATP, PCr and glycogen, and increases of ADP, AMP, inorganic phosphate and lactate which indicated an advanced derangement of the tissues' energy homeostasis. Exposure in unanesthetized animals was associated with lower levels of ATP and glycogen, and with larger increases of lactate in the clamped hemisphere which suggested the presence of a more intense hypoxic-oligemic insult. The metabolic differences in the clamped hemisphere of unanesthetized and anesthetized animals became more marked after 1 h reoxygenation, with anesthetized animals showing large restitutions of ATP, PCr, glycogen and lactate, whereas in unanesthetized animals these metabolites showed severe persistent defects over the 6 h reoxygenation period. Since the arterial oxygen content and tension, and perfusion patterns were equivalent in the 2 series at 0 and 1 h recovery, it is concluded that even minor anesthetic agents such as 70%N(2)O or other non-hypoxic variables during exposure or recovery may cause significant alterations in the metabolic restitution of the hypoxic-oligemic brain.     

Reversibility of energy metabolism and intracellular pH after cerebral ischaemia evaluated by 31P-MRS.

We have previously developed a reproducible model of transient forebrain ischaemia in rats by bilateral carotid artery occlusion combined with temporary increase of ICP. With this model, reversibility of the energy metabolism and intracellular pH (pHi) was investigated by 31P-MRS during 120 min of recirculation in three groups of, respectively, 30, 60, and 120 min of ischaemia. With the induction of ischaemia, ATP and phosphocreatine (PCr) disappeared, and measurement of pHi showed severe acidosis in all rats. In the 30 min ischaemia group, both energy metabolism and pHi recovered almost completely. In the 60 min ischaemia group, ATP recovered to 74% of control values, but pHi showed full recovery. In the 120 min ischaemia group, ATP recovered to about 50% of control values, and recovery of pHi was variable. Showing logarithmical changes during recirculation in ATP and PCr, the rate of metabolic recovery was fast during 60 min of recirculation, but it decreased and reached plateau thereafter in all groups. Recovery of pHi was affected by ATP levels, and was precipitously accelerated as ATP levels exceeded 50% of pre-ischaemic values. These results suggest that prolongation of the duration of ischaemia limits the restoration of the energy state, and the quality of pHi recovery after cerebral ischaemia is affected by the degree of ATP recovery during 60 min of recirculation.     

Effect of glucose on recovery of energy metabolism following hypoxia-oligemia in mouse brain: dose-dependence and carbohydrate specificity

Unilateral cerebral hypoxia-oligemia was produced in anesthetized mice using carotid artery occlusion combined with systemic hypoxia (10% O2). In the cerebral cortex ipsilateral to the carotid occlusion, ATP levels were depleted during a 30-min insult, but were restored to 64% of control during 60 min of recovery. Pretreatment of animals with glucose diminished the restoration of ATP in a dose-dependent manner. Thus, when blood glucose levels exceeded 12-13 mM (225 mg/dl), ATP recovery was greatly impaired. Neither galactose nor 3-O-methylglucose mimicked the detrimental effect of glucose. However, pretreatment with mannose, which is readily metabolized by brain, impaired restoration of ATP. The impairment, therefore, appears to be specific for substrates of cerebral metabolism. The ischemic accumulation of lactate in the ipsilateral cortex was augmented by only 30% at blood glucose levels well above the threshold for ATP recovery. Thus, unless recovery of energy metabolism is sensitive to small increments in brain lactate, it is difficult to explain the glucose-induced energy failure on the basis of enhanced lactic acidosis. Ipsilateral cerebral blood flow (CBF), measured with [14C]iodoantipyrine during hypoxia and recovery, was lower in glucose-pretreated than in saline-pretreated animals. However, the poor correlation between CBF and ATP, measured in the same tissue samples at 15 min recovery, failed to substantiate that regeneration of ATP was flow-limited early in recovery.     

Reversibility of energy metabolism and intracellular pH after cerebral ischaemia evaluated by 31P-MRS

Abstract

We have previously developed a reproducible model of transient forebrain ischaemia in rats by bilateral carotid artery occlusion combined with temporary increase of ICP. With this model, reversibility of the energy metabolism and intracellular pH (pHi) was investigated by 31P-MRS during 120 min of recirculation in three groups of, respectively, 30, 60, and 120 min of ischaemia. With the induction of ischaemia, ATP and phosphocreatine (PCr) disappeared, and measurement of pHi showed severe acidosis in all rats. In the 30 min ischaemia group, both energy metabolism and pHi recovered almost completely. In the 60 min ischaemia group, ATP recovered to 74% of control values, but pHi showed full recovery. In the 120 min ischaemia group, ATP recovered to about 50% of control values, and recovery of pHi was variable. Showing logarithmical changes during recirculation in ATP and PCr, the rate of metabolic recovery was fast during 60 min of recirculation, but it decreased and reached plateau thereafter in all groups. Recovery of pHi was affected by ATP levels, and was precipitously accelerated as ATP levels exceeded 50% of pre-ischaemic values. These results suggest that prolongation of the duration of ischaemia limits the restoration of the energy state, and the quality of pHi recovery after cerebral ischaemia is affected by the degree of ATP recovery during 60 min of recirculation.     

Cerebral metabolic profile, selective neuron loss, and survival of acute and chronic hyperglycemic rats following cardiac arrest and resuscitation

Cortical metabolites and regional cerebral intracellular pH (pHi) were measured in normoglycemic (NM), acute hyperglycemic (AH), and chronic hyperglycemic (CH, 2 week duration, streptozotocin-induced) Wistar rat brains during cardiac arrest and resuscitation. During total ischemia in AH and CH rats (plasma glucose approximately 30 mM), cortical ATP, PCr, glucose, and glycogen all fell significantly as expected. Lactate levels increased dramatically in association with a concomitant intracellular acidosis. Although lactate reached higher concentrations in AH and CH than NM, pHi was significantly lower only in the AH group. With 5 min of reperfusion, all groups recovered to near baseline in all variables, though lactate remained elevated. In a separate aspect of the study, animals from each experimental group were allowed to recover for 4 days following resuscitation, with outcome being gauged by mortality rate and hippocampal CA1 neuron counts. NM survival rate was significantly better than AH and CH. In particular, no CH rats survived for 4 days despite rapid initial recovery. After 4 days, the AH group had suffered significantly greater CA1 neuron loss than the NM rats. In summary, our research identified differences in intra-ischemic acid-base status in the two hyperglycemic groups, suggesting that chronic hyperglycemia may alter the brain's buffering capacity. These observations may account for differences between acutely and chronically hyperglycemic subjects regarding outcome, and they suggest that factors other than hydrogen ion production during ischemia are responsible for modulating outcome.     

Simultaneous 31P- and 1H-nuclear magnetic resonance studies of hypoxia and ischemia in the cat brain

The objective of this study was to evaluate simultaneous 31P/1H nuclear magnetic resonance (NMR) spectroscopy as a technique for monitoring and correlating changes in brain energy metabolism during hypoxia and ischemia. Five cats were studied with a protocol that involved 20 min of hypoxia (PaO2 20 mm), 60 min of recovery, 10 min of hypoxia with relative ischemia (bilateral carotid occlusion, PaO2 20 mm), and 60 min of recovery. Bifrontal and biparietal electrocorticograms (ECoG) were monitored continuously during the entire protocol. The results demonstrate that the degree of metabolic response is different in individual cats, but a number of quantitative relationships between metabolic parameters are consistently observed for all cats. First, there is agreement between increases in lactate and changes in intracellular pH; the observed relationship corresponds to an in vivo cerebral buffer capacity of 29 mumol/g/pH unit. Second, the delayed recovery of PCr is due to the effect of metabolic acidosis on the creatine kinase equilibrium and not to a delayed recovery of the ATP/ADP ratio. Third, the observed rate of lactate clearance from the cell is zero-order (k = 0.36 mumol/g/min) for lactate levels greater than 5 microns/g and may be composed of both lactate efflux from the cell and lactate oxidation.     

NMR spectroscopic investigation of the recovery of energy and acid-base homeostasis in the cat brain after prolonged ischemia

The effects of 1 h of complete global ischemia on the recovery of high-energy phosphates, intracellular pH (pHi), and lactate in the cat brain in vivo was investigated by 31P and 1H NMR spectroscopy. Ischemia led to a decrease in creatine phosphate (CrP), nucleoside triphosphates (NTP), and pHi, while inorganic phosphate and lactate increased. Intracellular pH decreased from a control value of 7.07 +/- 0.04 to 6.17 +/- 0.12 after 1 h of ischemia (N = 7). The degree of metabolic recovery after recirculation was variable. In three animals CrP and NTP were detected within 4 min and NTP increased to greater than or equal to 90% of control within 1 h; these levels were maintained for the 3 h of observation. In four other animals, CrP and NTP reached only 20 to 80% of control; however, high-energy phosphates decreased and lactate increased spontaneously between 1 and 2.5 h. Immediately following recirculation, pHi decreased further by an average of 0.3 units. The rate of recovery of cerebral pHi was slower than that of PCr and NTP for the majority of animals. Recovery of pHi was not detected for an average of 32 min after recirculation--by this time, NTP had attained 80 +/- 10% of their preischemic level. Recovery of pHi (and lactate) was not observed in two animals where PCr and NTP recovered transiently to only 30-43% of the preischemic level. Recovery of cerebral pHi was markedly heterogeneous in one animal, since two Pi peaks were detected shortly after recirculation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic changes during experimental cerebral ischemia in hyperglycemic rats, observed by 31P and 1H magnetic resonance spectroscopy

Progressive cerebral ischemia was induced in seven anesthetized hyperglycemic rats by carotid artery ligation and hemorrhagic hypotension. Phosphorus metabolites, intracellular pH, and lactate in the brain were monitored by 31P and 1H magnetic resonance spectroscopy. Under conditions in which blood flow was low, phosphocreatine (PCr) concentration and intracellular pH decreased and the concentration of lactate increased. The decrease in ATP was approximately one-third that of PCr until only 25% PCr remained, after which ATP was lost more rapidly than PCr. These changes were interpreted in terms of three regions observed by the magnetic resonance coil, one of complete ischemia, one of partial ischemia, and one of perfusion sufficient to maintain normal metabolite levels. The extent of the three regions was estimated quantitatively. Broadening and splitting of the inorganic phosphorus (Pi) peak into two components provided further evidence of distinct populations of cells, one very acidic and another less so. Apparent intracellular buffering capacity was calculated as 23.6 +/- 1.3 mumol lactate/g wet wt/pH.     

Brain metabolism and extracellular space diffusion parameters during and after transient global hypoxia in the rat cortex

Hypoxia results in both reversible and irreversible changes in the brain extracellular space (ECS). This study utilized microdialysis to monitor changes in the energy-related metabolites lactate, pyruvate, glucose and glutamate in the rat cortex before, during and after 30-min transient global hypoxia, induced in anesthetized rats by reducing inspired oxygen to 6% O(2) in nitrogen. Changes in metabolite levels were compared with ECS diffusion parameters calculated from diffusion curves of tetramethylammonium applied by iontophoresis. Significant increases in lactate concentration and the lactate/pyruvate ratio, as well as decreased glucose levels, were found in the cortex immediately after the induction of hypoxia. Following recovery to ventilation with air, extracellular lactate and glucose levels and the lactate/pyruvate ratio returned to control levels within 40, 20 and 30 min, respectively. Glutamate levels started to increase 20-30 min after the onset of hypoxia and returned to prehypoxic values within 30-40 min of reoxygenation. The ECS volume fraction alpha decreased by about 5% from 0.18+/-0.01 during the first 20-25 min of hypoxia; after 25 min alpha dropped a further 22% to 0.14+/-0.01. Within 10 min of reoxygenation, alpha returned to control values, then increased to 0.20+/-0.01 and remained at this level until the end of the experiment. The observed 22% decrease in alpha markedly influences dialysate levels measured during hypoxia. In our study, the complete posthypoxic recovery of cortical metabolite levels and ECS diffusion properties suggests that metabolic enzymes and related cellular components (e.g., mitochondria) may tolerate prolonged hypoxic periods and recover to prehypoxic values.     

Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy.

Previous animal and human studies showed that photic stimulation (PS) increased cerebral blood flow and glucose uptake much more than oxygen consumption, suggesting selective activation of anaerobic glycolysis. In the present studies, image-guided 1H and 31P magnetic resonance spectroscopy (MRS) was used to monitor the changes in lactate and high-energy phosphate concentrations produced by PS of visual cortex in six normal volunteers. PS initially produced a significant rise (to 250% of control, p less than 0.01) in visual cortex lactate during the first 6.4 min of PS, followed by a significant decline (p = 0.01) as PS continued. The PCr/Pi ratios decreased significantly from control values during the first 12.8 min of PS (p less than 0.05), and the pH was slightly increased. The positive P100 deflection of the visual evoked potential recorded between 100 and 172 ms after the strobe was significantly decreased from control at 12.8 min of PS (p less than 0.05). The finding that PS caused decreased PCr/Pi is consistent with the view that increased brain activity stimulated ATPase, causing a rise in ADP that shifted the creatine kinase reaction in the direction of ATP synthesis. The rise in lactate together with an increase in pH suggest that intracellular alkalosis, caused by the shift of creatine kinase, selectively stimulated glycolysis.     

Piracetam and vinpocetine exert cytoprotective activity and prevent apoptosis of astrocytes in vitro in hypoxia and reoxygenation

The aim of the present study was to establish whether piracetam (2-pyrrolidon-N-acetamide; PIR) and vinpocetine (a vasoactive vinca alkaloid; VINP) are capable of protecting astrocytes against hypoxic injury. Using the model of astrocyte cell culture we observed the cells treated with PIR and VINP during and after in vitro simulated hypoxia. Cell viability was determined by Live/Dead Viability/Cytotoxicity Assay Kit, LDH release assay and MTT conversion test. Apoptotic cell death was distinguished by a method of Hoechst 33342 staining underfluorescence microscope and caspase-3 colorimetric assay. In addition the intracellular levels of ATP and phosphocreatine (PCr) were evaluated by bioluminescence method. Moreover, the effect of the drugs on the DNA synthesis was evaluated by measuring the incorporation of [3H]thymidine into DNA of astrocytes. PIR (0.01 and 1 mM) and VINP (0.1 and 10 microM) were added to the medium both during 24 h normoxia, 24 h hypoxia or 24 h reoxygenation. Administration of 1 mM PIR or 0.1 microM VINP to the cultures during hypoxia significantly decreases the number of dead and apoptotic cells. The antiapoptic effects of drugs in the above mentioned concentrations was also confirmed by their stimulation of mitochondrial function, the increase of intracellular ATP, and the inhibition of the caspase-3 activity. The prevention of apoptosis was accompanied by the increase in ATP and PCr levels and increase in the proliferation of astrocytes exposed to reoxygenation. The higher concentration of VINP (10 microM) was detrimental in hypoxic conditions. Our experiment proved the significant cytoprotective effect of 1 mM PIR and 0.1 microM VINP on astrocytes in vitro.     

Slower recovery of muscle phosphocreatine in malignant hyperthermia-susceptible individuals assessed by 31P-MR spectroscopy

Our aim was to develop an exercise protocol using ³¹P-magnetic resonance spectroscopy (³¹P-MRS), which can discriminate between malignant hyperthermia-susceptible (MHS) individuals and controls. MRS spectra of the forearm muscles were recorded at rest, during and after a standardized exercise protocol in 10 MHS patients and compared with spectra obtained in 10 controls. There was no difference in resting intracellular pH (pHi) or PCr/ (Pi+PCr) ratio between the groups (PCr = phosphocreatine, Pi = inorganic phosphorus). At the end of the exercise and during the initial recovery phase, the pHi and PCr/(Pi+PCr) ratio were significantly lower in the MHS group ([pHi: 6.37 (0.07) for MHS vs 6.70 (0.05) for controls, P < 0.005; PCr/(Pi+PCr): 0.784 (0.017) for MHS vs 0.954 (0.020) for controls, P < 0.0005]). For PCr/ (Pi+PCr), complete separation between the two groups was observed during the initial recovery phase. The mean recovery time of PCr/ (Pi+PCr) was 0.57 min for the control group and 1.28 min for the MHS group. The slower recovery of PCr/ (Pi+PCr) is likely to be caused by a combination of several factors, including the lower pHi in MHS subjects at the start of recovery (inhibiting ATP production) and excessive sarcoplasmic calcium overload (causing continued enzyme activation and ATP consumption). Our exercise protocol can be a valuable adjunct to discriminate between MHS and non susceptible subjects. Received: 10 July 1996 Received in revised form: 7 August 1997 Accepted: 11 August 1997     

Metabolic effects of 1-methyl-4-phenylpyridinium (MPP(+)) in primary neuron cultures

Disruption of mitochondrial function has been proposed as an action of 1-methyl-4-phenylpyridinium (MPP(+)) that is responsible for its toxicity. In order to characterize effects of MPP(+) on energy metabolism in primary culture neurons, we monitored levels of several metabolites in cultured rat cerebellar granule cells exposed to MPP(+). The toxin produced a rapid concentration-dependent reduction in intracellular phosphocreatine (PCr), amounting to a 50-80% decrease within 30-60 min at 50 microM, that was maintained through the 1 week exposure interval examined. In contrast, ATP levels remained comparable to those of untreated neurons for approximately 4 days, at that time a 50% reduction in ATP was observed in association with a decrease in cell viability. Acute decreases in PCr were accompanied by increases in creatine such that the total creatine levels were maintained. Lactate levels in the culture medium were significantly increased (from 4.5 to 6.0 mM) within 6 hr after addition of MPP(+), with a concentration dependence similar to that observed for the reduction in PCr. Increased lactate production in the presence of MPP(+) coincided with a more rapid depletion of glucose in the culture medium. MPP(+) induced a rapid and sustained decrease in intracellular pH calculated from the creatine kinase equilibrium, and this acidification is considered primarily responsible for the observed decrease in PCr. These studies provide direct evidence that toxic concentrations of MPP(+) have acute effects on energy metabolism in primary culture neurons, consistent with an increased dependence on glycolysis to meet metabolic demand, but indicate that toxicity is not associated with overt, immediate failure to maintain cellular ATP.     

Cortical spreading depression is associated with arachidonic acid accumulation and preservation of energy charge

The present study aimed to study the relation between the release of arachidonic acid (AA) and the energy state in cerebral cortices of rats during single episodes of cortical spreading depression (CSD). The changes in concentrations of AA, labile phosphate compounds [ATP, ADP, AMP, and phosphocreatine (PCr)], and glycolytic metabolites (lactate, pyruvate, glucose, and glycogen) were studied during and following the large change of the local direct current (DC) potential. Free AA increased markedly during the DC shift, continued to increase during the subsequent 3 min, and returned to control levels at 4-5 min after CSD. PCr decreased by 38% in the first minutes following the DC shift, while ADP increased by 38%. Both returned to normal within a few minutes. ATP, AMP, and energy charge remained constant throughout the experimental period. Glucose decreased by 47% and glycogen by 34% for a few minutes following CSD, while lactate increased by 105% at 2-3 min and by 77% at 4-5 min after CSD. The metabolites returned to control levels at 10 min after CSD. Considering the constant energy charge at all time points during CSD, it is suggested that the AA rise reflects augmented phospholipase activity due to either increased intracellular [Ca2+] or receptor stimulation or both. The possibility that N-methyl-D-aspartate receptors play a role in the release of AA, and that free AA in turn could be part of the mechanism of CSD, is discussed.     

Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy

We measured brain energy phosphate metabolism and intracellular pH (pHi) in a cross-sectional study of migraine patients by in vivo phosphorus 31 NMR spectroscopy. During a migraine attack the ratio ATP/total phosphate signal (mole % ATP) was preserved, but there was a decrease in mole % phosphocreatine (PCr) and an increase in mole % inorganic phosphate (Pi) resulting in a decrease of the PCr/Pi ratio, an index of brain phosphorylation potential. This was found in classic but not common migraine. Mole % Pi was also increased in combined brain regions between attacks. There was no alteration in brain pHi during or between attacks. Energy phosphate metabolism but not pHi appears disordered during a migraine attack.