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.     

Measurements of in vivo energy metabolism in experimental cerebral ischaemia using 31P-NMR for the evaluation of protective effects of perfluorochemicals and glycerol

Effects of perfluorochemical (PFC) and glycerol on energy metabolism in cerebral ischaemia were examined by the sequential measurements of in vivo ³¹P-NMR spectrum using topical magnetic resonance (TMR). Experimental cerebral ischaemia was induced in forty-five Wistar rats by a four-vessel occlusion method. The ³¹P-NMR spectrum and the EEG were monitored during preischaemic and ischaemic periods and after circulation was restored for various periods up to 240 min. There were several peaks in the ³¹P-NMR spectrum of the preischaemic rat brain; β-ATP, α-ATP, γ-ATP, phosphocreatine (PCr), phosphodiesters, inorganic phosphate (Pi) and sugar phosphate. As soon as the ischaemia was induced, PCr and ATP decreaseq and Pi increased. The chemical shift of the increased Pi peak decreased, showing acidosis of the brain tissue. After circulation was restored following the 30 min ischaemia, recovery of the ³¹ P-NMR spectrum occurred within 30 min in all sixteen untreated rats. Recovery of the ³¹P-NMR spectrum was induced by recirculation only in half of the six rats in the untreated 60 min ischaemia group. None of the six rats in the untreated group showed recovery of the spectrum after 120 min ischaemia. When 20% Fluosol-DA was administered at a dose of 20 ml/kg before the induction of ischaemia, all eight rats showed recovery of the spectrum after 120 min ischaemia. Moreover, four of six rats treated with both PFC and glycerol showed temporary recovery even after 240 min ischaemia. The results showed that measurements of in vivo ³¹P-NMR spectrum using TMR are very valuable for examining the energy metabolism of cerebral ischaemia, as well as to evaluate the effect of therapeutic drugs on cerebral ischaemia.     

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.     

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.     

Measurement of somatosensory evoked potential in the Mongolian gerbil: the effects of cerebral ischaemia

Normal somatosensory evoked potential (SEP) as well as changes after incomplete cerebral ischaemia following bilateral carotid artery occlusion (BCO) were characterized in the Mongolian gerbil. BCO significantly decreased cerebral blood flow (CBF). Reperfusion CBF at 10 min and 2, 3 and 4 h was significantly below preischaemic control values. BCO decreased SEP amplitude but had no effect on EP-P3 central conduction time. BCO did significantly increase EP-P11 central conduction time. Reperfusion amplitudes at 10 min and 2, 3 and 4 h revealed a significant increase only at 4 h when compared to the ischaemic amplitude. EP-P11 central conduction time at 10 min reperfusion showed dramatic improvement compared to ischaemic values, although values at 2, 3 and 4 h reperfusion were not statistically different from ischaemic values. A separate group of animals prepared identically but without BCO showed no significant changes in either SEP or CBF over time. These studies establish the protocol necessary to measure SEP in the Mongolian gerbil. In the future SEP may be used as an integral tool in the study of the primary determinants of neurophysiological recovery following cerebral ischaemia.     

Measurement of somatosensory evoked potential in the Mongolian gerbil: the effects of cerebral ischaemia

Normal somatosensory evoked potential (SEP) as well as changes after incomplete cerebral ischaemia following bilateral carotid artery occlusion (BCO) were characterized in the Mongolian gerbil. BCO significantly decreased cerebral blood flow (CBF). Reperfusion CBF at 10 min and 2, 3 and 4 h was significantly below preischaemic control values. BCO decreased SEP amplitude but had no effect on EP-P₃ central conduction time. BCO did significantly increase EP-P₁₁ central conduction time. Reperfusion amplitudes at 10 min and 2, 3 and 4 h revealed a significant increase only at 4 h when compared to the ischaemic amplitude. EP-P₁₁ central conduction time at 10 min reperfusion showed dramatic improvement compared to ischaemic values, although values at 2, 3 and 4 h reperfusion were not statistically different from ischaemic values. A separate group of animals prepared identically but without BCO showed no significant changes in either SEP or CBF over time. These studies establish the protocol necessary to measure SEP in the Mongolian gerbil. In the future SEP may be used as an integral tool in the study of the primary determinants of neurophysiological recovery following cerebral ischaemia.     

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     

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.     

Brain ornithine decarboxylase activity following transient cerebral ischaemia: relationship to cerebral oedema development

Ornithine decarboxylase (ODC) activity, the first and generally rate-limiting enzyme for polyamine synthesis, is stimulated in permanent focal cerebral ischaemia in areas of incomplete ischaemia which are developing ischaemic brain oedema. As polyamines are ubiquitous ornithine-derived molecules which are obligatory in cold-induced vasogenic oedema, we studied the effect of transient dense cerebral ischaemia with reperfusion on ischaemic oedema development and ODC activity. Fifty-nine Mongolian gerbils were anaesthetized with ketamine hydrochloride (160 mg/kg i.p. plus supplementation as needed). Both common carotid arteries were isolated and a tracheotomy placed in position. EEG was monitored with needle electrodes and temperature maintained at 37-38°C. Twenty-nine gerbils underwent 40 min of bilateral carotid artery occlusion followed by reperfusion times of 10 min, 1, 2, 4, 6 or 8 h. Non-ischaemic control groups were monitored for equal intervals. At sacrifice, the brain was rapidly removed and forebrain samples analysed for ODC activity (enzymatic assay) and cerebral oedema (gravimetric determination). Marked loss of EEG amplitude was noted in all gerbils subjected to bilateral carotid artery occlusion. Ischaemia produced significant levels of cortical oedema throughout the reperfusion period (maximal decrease in specific gravity at 4 h postischaemia; control: 1.0456 ± 0.0013; ischaemia: 1.0355 ± 0.0021, mean ± SD; p > 0.0001). Significant subcortical oedema was produced at 10 min, 2 and 4 h postischaemia. A biphasic response was observed in brain ODC activity. Throughout the first 2 h of reperfusion, ODC activity was significantly depressed in ischaemic versus control animals (10 min: 1423 ± 824 versus 3049 ± 1019; 1 h: 704 ± 635 versus 2621 ± 902; 2 h: 348 ± 184 versus 3654 ± 2072 pmoles/g tissue/60 min; p > 0.05). This difference was no longer detectable by 4 h postischaemia and by 6 h, ODC levels were significantly higher in ischaemic animals (ischaemia: 9314 ± 2652; control: 3065 ± 2000 pmoles/g tissue/60 min; p > 0.01). Although not significant, ODC was also greater in ischaemic animals at 8 h postischaemia. ODC levels at 6 and 8 h postischaemia were significantly higher (p > 0.05) than ODC levels at 10 min, 1 and 2 h postischaemia among ischaemic animals. These data indicate that transient ischaemia initially suppresses then stimulates ODC activity over the initial 8 h following transient global ischaemia in the gerbil. Since stimulation of ODC activity does not occur until early cerebral oedema is established, it is unlikely that polyamines are involved in the early cytotoxic oedema. Later stages of ischaemic oedema, however, with mixed cytotoxic and vasogenic components may be affected by the delayed rise in ODC activity after transient ischaemia.     

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.     

Lipoxygenase metabolites of arachidonic acid and the development of ischaemic cerebral oedema

This study examined the changes in cerebral blood flow, water content, and lipoxygenase metabolites (leukotrienes) following bilateral carotid artery occlusion (BCO) and reperfusion in the gerbil. The effect of inhibiting lipoxygenase with nordihydroguaretic acid (NDGA) was also examined. BCO caused cerebral blood flow (measured using H₂ clearance) to decline from 23.5 ± 1.9 to 4.5 ± 1.9 ml/min/l00 gm. Reperfusion increased flow to 27.9 ± 4 ml/min/100 gm at 10 min, which declined to 13.7 ± 1.3 ml/min/100 gm at 50 min. Concomitant oedema measurement revealed brain specific gravity decreasing to 1.0402 ± 0.0014 at 10 min and to 1.0325 ± 0.0006 at 50 min reperfusion (nonoccluded controls). Leukotriene B₄ (LTB₄) increased from 26.8 ± 4.6 to 33.5 ± 2.1 pg/mg protein 10 min after reperfusion (p < 0.05), but declined to 21.8 ± pg/mg protein by 100 rnin (vs nonischaemic control = 21.3 ± 2.9 pg/mg protein). Activation of arachidonate metabolism was confirmed by significantly increased 6 keto PGF_1α. Pretreatment of the animals with NDGA did not alter CBF, but increased specific gravity above saline-treated controls at 50 min of reperfusion (NDGA = 1.0370 ± 0.002 vs control = 1.0325 ± 0.0006, p < 0.05). Similarly, NDGA blunted the increase in LTB₄ formation 10 min after reperfusion (control =26.8 ± 4.6 pg/mg protein vs NDGA =29.7 ± 2.9 pg/mg protein, p = N.S.). These findings indicate that LTB₄ production is stimulated by BCO and reperfusion in the gerbil, and that this stimulation occurs early on in the reperfusion. Further, we observe that the lipoxygenase inhibitor NDCA limits the formation of ischaemic cerebral oedema. Thus, our results indicate that the lipoxygenase pathway of arachidonicacid metabolism may be an important source of factors contributing to the development of ischaemic cerebral oedema.     

Beagle puppy model of perinatal asphyxia: alterations in cerebral blood flow and metabolism

Perinatal asphyxia remains a major cause of neurodevelopmental handicap. The neuropathologic and clinical sequelae of perinatal asphyxia are likely attributable to alterations in cerebral blood flow (CBF) to the developing brain with uncoupling of CBF and metabolism. The newborn beagle puppy model was used to study the control of CBF in physiologic and pathologic conditions in the developing brain. Pups, 2-10 days of age, were randomized to asphyxial insult (i.e., ventilator lines clamped for 5 min) or no insult. In the first series, pups underwent radioactive microsphere determinations of CBF immediately prior to insult (t = 0), at the end of insult (t = 5), and after 60 min of observation (t = 65). In the second series, utilizing a 2.0 tesla superconducting magnet, pups underwent continuous serial in vivo 31P nuclear magnetic resonance spectral analysis of cerebral hemispheric metabolic state. Animals exposed to insult had significant alterations in PO2, PCO2, pH, and mean arterial pressure at the end of insult compared to control pups (all pups: p less than 0.001). Serial CBF data demonstrated decreases in flow in cortical gray and white matter regions during insult and return to baseline 1 hour later; brainstem structures were hyperemic during insult. Analysis of phosphorylated metabolites inorganic phosphorus (Pi), phosphocreatine (PCr), and ATP demonstrated that during insult both the PCr/Pi and ATP/Pi ratios were depressed but by 20-30 min following insult, these ratios of cerebral phosphorylated metabolites had almost returned to baseline values. These data demonstrate that even after a severe asphyxial episode which results in electrocerebral silence, CBF and metabolism may return to normal.     

Reduced oxidative muscle metabolism in chronic fatigue syndrome

The purpose of this study was to determine if chronic fatigue syndrome (CSF) is characterized by abnormalities in oxidative muscle metabolism. Patients with CFS according to Centers for Disease Control (CDC) criteria (n = 22) were compared to normal sedentary subjects (n = 15). CFS patients were also tested before and 2 days after a maximal treadmill test. Muscle oxidative capacity was measured as the maximal rate of postexercise phosphocreatine (PCr) resynthesis using the ADP model (V_max) in the calf muscles using ³¹P magnetic resonance spectroscopy. V_max was significantly reduced in CFS patients (39.6 ± 2.8 mmol/L/min, mean ± SE) compared to controls (53.8 ± 2.8 mmol/L/min). Two days postexercise there was no change in resting inorganic phosphate (Pi)/PCr or V_max in the CFS patients (n = 14). In conclusion, oxidative metabolism is reduced in CFS patients compared to sedentary controls. In addition, a single bout of strenuous exercise did not cause a further reduction in oxidative metabolism, or alter resting Pi/PCr ratios. © 1996 John Wiley & Sons, Inc.     

Frontal lobe phosphorus metabolism and neuropsychological function in aging and in alzheimer's disease

³¹P Magnetic resonance spectroscopy of the frontal lobe was performed in 17 patients with Alzheimer's disease (AD), 8 elderly controls (EC), and 17 young controls (YC). The phosphocreatine/inorganic phosphate (PCr/Pi) ratio in AD (2.32 ± 0.26 SD) was significantly lower than in EC (2.65 ± 0.41). In AD patients, a correlation was observed between the PCr/Pi ratio and the dementia rating scale (r = ?0.50, p = 0.04). A significant positive correlation between PCr/Pi ratio and age was observed in both AD (r = 0.67, p 0.003) and YC (r = 0.63, p 0.006) groups, however, suggesting caution in interpretation of this ratio in AD. We did not find differences between AD, EC, or YC in any other spectroscopic measure. A significant sex difference in the phosphomonoester/phosphodiester ratio (PME/PDE) ratio was observed in AD brain. Females had a lower PME/PDE ratio than males.     

Cerebral energy metabolism and intracellular pH during severe hypoxia and recovery: a study using 1H, 31P, and 1H [13C] nuclear magnetic resonance spectroscopy in the guinea pig cerebral cortex in vitro

1H and 31P nuclear magnetic resonance spectroscopy was used to study intracellular pH (pHi), high-energy phosphates, lactate, and amino acids in cortical brain slices superfused in Krebs-Henseleit bicarbonate buffer during and after severe hypoxia at 0, 10, and 50 mM glucose. An extensive drop in phosphocreatine (PCr) and a rapid build-up of intracellular lactate and H+ were the first signs of hypoxia. Adenosine triphosphate (ATP) was significantly more resistant to hypoxia provided that glucose was present. In the preparations that had been exposed to hypoxia in the presence of glucose, PCr became detectable within 2 min of reoxygenation, and both PCr and ATP concentrations were restored to 72-80% of normoxic levels within 30 min. Lactate was washed out, and pHi returned to normal within 4-8 min. Using 1-[13C]glucose as a tracer, we demonstrated that the rate of lactate production in the immediate posthypoxic period was at the prehypoxic level, indicating that the elevated lactate during this period was due solely to that produced during hypoxia. During reoxygenation of the preparations that were denied glucose during hypoxia, only 30% of total creatine + PCr and 18% of PCr were restored, and ATP was not detectable. The lactate concentration rose twofold in this period, and pHi became significantly more alkaline than before the hypoxic insult. Thus acute metabolic damage was considerably greater if glucose was absent during the insult, suggesting that either anaerobic ATP production or low pH may exert some protective effect against acute cell damage.     

Cerebral intracellular pH regulation during hypercapnia in unanesthetized rats: a 31P nuclear magnetic resonance spectroscopy study

The energy metabolism and the brain intracellular pH regulation under arterial CO2 tensions of 25-90 mm Hg were investigated in unanesthetized spontaneously breathing rats by in vivo phosphorus nuclear magnetic resonance spectroscopy (31P NMR). The 31P brain spectra, recorded with a high resolution spectrometer (AM 400 Brucker), allowed repeated non-invasive measurements of cerebral pH (pHi), phosphocreatine (PCr), inorganic phosphate (Pi) and adenosine triphosphate (ATP) levels in 15 rats breathing a gas mixture containing 21% O2, N2, and a varied percentage of CO2. The pHi decreased significantly when the paCO2 was increased by hypercapnia. The percentage of pH regulation, estimated from the linear regression analysis of pHi versus the logarithm of the paCO2 was 78%. This result indicates that spontaneously breathing unanesthetized animals have better pHi regulation under hypercapnia investigated than that estimated for higher levels of hypercapnia in previous studies on unanesthetized animals, suggesting that there is a threshold for this highly efficient regulation. Furthermore, there were no significant correlations between the PCr, ATP and Pi levels and the paCO2 levels during hypercapnia. This indicates that physiological variations of the CO2 tension in the blood, and consequently in the brain parenchyma, have little effect on cerebral energy metabolism in unanesthetized spontaneously breathing animals.     

Neuroprotection of creatine supplementation in neonatal rats with transient cerebral hypoxia-ischemia

We hypothesized that creatine (Cr) supplementation would preserve energy metabolism and thus ameliorate the energy failure and the extent of brain edema seen after severe but transient cerebral hypoxia-ischemia (HI) in the neonatal rat model. Six-day-old (P6) rats received subcutaneous Cr monohydrate injections for 3 consecutive days (3 g/kg body weight/day), followed by 31P-magnetic resonance spectroscopy (MRS) at P9. In a second group, P4 rats received the same Cr dose as above for 3 days prior to unilateral common carotid artery ligation followed 1 h later by 100 min of hypoxia (8% O2) at P7. Rats were maintained at 37 degrees C rectal temperature until magnetic resonance imaging was performed 24 h after HI. Cr supplementation for 3 days significantly increased the energy potential, i.e. the ratio of phosphocreatine to beta-nucleotide triphosphate (PCr/betaNTP) and PCr/inorganic phosphate (PCr/Pi) as measured by 31P-MRS. Rats with hemispheric cerebral hypoxic-ischemic insult that had received Cr showed a significant reduction (25%) of the volume of edemic brain tissue compared with controls as calculated from diffusion-weighted images (DWI). Thus, prophylactic Cr supplementation demonstrated a significant neuroprotective effect 24 h after transient cerebral HI. We hypothesize that neuroprotection is probably due to the availability of a larger metabolic substrate pool leading to a reduction of the secondary energy failure because DWI has been reported to correlate with the PCr/Pi ratio in the acute phase of injury. Additional protection by Cr may be related to prevention of calcium overload, prevention of mitochondrial permeability transition pore opening and direct antioxidant effects.     

Correction of ischaemic brain acidosis with SQ29,548/1-benzylimidazole

Abstract

Thromboxane A2 (TXA2) is a proaggregatory vasoconstrictor that is synthesized and released during reperfusion of ischaemic brain. We administered a TXA2 receptor antagonist, SQ29,548, and a thromboxane A synthase inhibitor, 1-benzylimidazole (1-BI), to rats subjected to 30 min of reversible forebrain ischaemia. Cerebral thromboxane B2 (TXB2), the stable metabolite of TXA2, measured after 60 min of reperfusion was 0.37 ± 0.08 ng/mg brain protein in animals treated with SQ29.548/1-BI compared with 1.20 ±0.16 in ischaemic controls (p < 0.05). Cerebral pH determined by31P magnetic resonance spectroscopy was higher in treated animals, 7.06 + 0.04, than in ischaemic controls, 6.5 + 0.01, after 20 min of reperfusion (p < 0.01). The significant elevation of cerebral pH in treated animals persisted at 30 (7.17 + 0.05 vs. 6.5 + 0.01; p ≤ 0.01), 35 (7.17 ± 0.05 vs. 6.44 + 0.04; p ≤ 0.01), and 40 min of reperfusion (7.06 + 0.06 vs. 6.37 ± 0.01; p < 0.05). We conclude that SQ29,548/1-BI reduces thromboxane levels and promotes resolution of tissue acidosis in ischaemic brain. The combination of a TXA2 receptor antagonist with a thromboxane A synthase inhibitor deserves further study as a potential treatment for acute cerebral infarction. [Neurol Res 1992; 14: 335-339]