Regional cerebral energy metabolism in bicuculline induced seizures

In order to assess the early regional changes in energy metabolism in bicuculline induced seizures, mice were injected and sacrificed before the onset of overt seizure activity, and shortly after clonic-tonic seizures began. The energy metabolites glucose, ATP, and phosphocreatine were measured in layers of the motor cortex and the cerebellar vermis. Results showed minimal metabolite changes in the cerebellum, whereas changes in energy metabolism in the motor cortex were largely localized to the layers containing pyramidal cells. These results are in agreement with previous studies showing a relative sparing of the cerebellum, and suggest early cortical changes occur in pyramidal cells.     

METABOLITE LEVELS IN BRAIN FOLLOWING EXPERIMENTAL SEIZURES: THE EFFECTS OF ISONIAZID AND SODIUM VALPROATE IN CEREBELLAR AND CEREBRAL CORTICAL LAYERS

Abstract— Levels of glucose, lactate, GABA and cyclic nucleotides were examined in discrete layers of the cerebellum and cerebral cortex of mice following treatment with the anticonvulsant, sodium valproate, and/or the convulsant, isoniazid. The concentrations of the metabolites were essentially uniform among the layers of each region, whether from control or from drug-treated mice. Metabolite concentrations in the isoniazid-treated mice were determined either 30 min after administration (preconvulsive state), or immediatley after the onset of seizures. Glucose and lactate, two markers of energy status in the brain, were only minimally affected by drug treatment. However, the levels of GABA and cyclic nucleotides were markedly different from control values in the drug-treated animals. In the preconvulsive state, GABA levels in cerebellar layers were depressed and the cyclic nucleotides were elevated in most layers of both regions. At the onset of seizures, the reduction of GABA and the elevation of cyclic AMP in both regions was more pronounced than during the preconvulsive state. While the concentration of cyclic GMP remained elevated in the cerebellar layers at the onset of seizures, the level in the cerebral cortex returned to control values. Valproate elevated GABA in all the layers of both regions and decreased the cyclic GMP in the cerebellar layers. Generally, when valproate was administered in combination with isoniazid, it dampened the isoniazid induced changes in the metabolites. The events leading up to a seizure as well as those that sustain it may be reflected by the disparate responses of the metabolites in the cerebellum and cerebral cortex.     

Regional levels of glucose,amino acids,high energy phosphates,and cyclic nucleotides in the central nervous system during hypoglycemic stupor and behavioral recovery

The effects of insulin-induced hypoglycemic stupor and subsequent treatment with glucose on mouse cerebral cortical, cerebellar and brain stem levels of glucose, glycogen, ATP, phosphocreatine, glutamate, aspartate and GABA and on cerebral cortical and cerebellar levels of cyclic AMP and cyclic GMP have been measured. Hypoglycemia decreased glucose, glycogen and glutamate levels and had no effect on ATP levels in all three regions of brain. GABA levels were decreased only in cerebellum. Aspartate levels rose in cerebral cortex and brain stem, and creatine phosphate increased in cerebral cortex and cerebellum. In the hypoglycemic stuporous animals, cyclic GMP levels were elevated in cerebral cortex and depressed in cerebellum whereas cyclic AMP levels were unchanged from control values. Intravenous administration of 2.5-3.5 mmol/kg of glucose to the hypoglycemic stuporous animals produced recovery of near normal neurological function within 45 s. Only brain glucose and aspartate levels returned to normal prior to behavioral recovery. These results suggest that of the several substances examined in this study, only glucose and perhaps aspartate have important roles in the biochemical mechanisms producing neurological abnormalities in hypoglycemic animals.     

Functional, Metabolic, and Circulatory Changes Associated with Seizure Activity in the Postischemic Brain

Abstract: The present study was undertaken to explore how transient ischemia in rats alters cerebral metabolic capacity and how postischemic metabolism and blood flow are coupled during intense activation. After 6 h of recovery following transient forebrain ischemia 15 min in duration, bicuculline seizures were induced, and brains were frozen in situ after 0.5 or 5 min of seizure discharge. At these times, levels of labile tissue metabolites were measured, whereas the cerebral metabolic rate for oxygen (CMRO₂) and cerebral blood flow (CBF) were measured after 5 min of seizure activity. After 6 h of recovery, and before seizures, animals had a 40–50% reduction in CMRO₂, and CBF. However, because CMRO₂ rose threefold and CBF fivefold during seizures, CMRO₂ and CBF during seizures were similar in control and postischemic rats. Changes in labile metabolites due to the preceding ischemia encompassed an increased phosphocreatine/ creatine ratio, as well as raised glucose and glycogen concentrations. Seizures gave rise to minimal metabolic perturbation, essentially comprising reduced glucose and glycogen contents and raised lactate concentrations. It is concluded that although transient ischemia leads to metabolic depression and a fall in CBF, the metabolic capacity of the tissue is retained, and drug-induced seizures lead to a coupled rise in metabolic rate and blood flow.     

Developmental Changes in Brain Glucose, Glycogen, Phosphocreatine, and ATP Levels in DBA/2J and C57BL/6J Mice, and Audiogenic Seizures

Abstract. Brains of rodents are primarily dependent on ketone bodies as a source of hydrogen for NADH and of acetyl-CoA during the perinatal period characterized by suckling. A mouse dam begins to wean her pups at about 14 days of age (DOA), the same age at which the brain reaches near-adult size and begins to shift to dependence on carbohydrate-derived sources of acetyl-CoA for normal function. Also at this time, the ear canals open, and mice of some strains become susceptible to audiogenic seizures (AGS). There may be a genetically determined derangement in the orderly transition from one source of brain energy to the other in AGS-prone mice, with a concomitant brief (days) reduction in the in situ energy reserve during the transition. In mice with a decreased energy reserve, a large energy expenditure within a short period of time (s), such as that induced by a substantial acoustic stimulus to newly opened acoustic pathways, might briefly lead to CNS disorganization before body energy repletion processes may occur, resulting in the onset of an AGS. Since glucose, glycogen, ATP, and phosphocreatine provide the bulk of the brain energy reserve, a developmental study was performed to measure the concentrations of these metabolites in brain tissues of DBA/2J mice (genetically/developmentally susceptible to AGS: onset at 12–14 DOA, peak at 18–21 DOA, rapid decline until 30 DOA, essentially lost by 42 DOA) and in C57BL/6J mice (not developmentally susceptible to AGS). Samples of frontal, temporal, cerebellar, and diencephalic regions were taken from mice 0–44 DOA and assayed. With the exception of higher glycogen levels in both DBA and C57 mice in cerebellar and diencephalic samples 0–16 DOA, no regional differences were found. A decrease in glycogen in all regions was observed in DBA mice 16–30 DOA, which was the inverse of susceptibility to AGS in these mice. This dip was not found in C57 mice. ATP levels were elevated in DBA mice 14–18 DOA, and glucose levels were decreased in DBA mice 24–40 DOA. These data lend support to the hypothesis that lowered brain energy reserves, or lowered access to brain reserves, underlies susceptibility to AGS.     

Partial Restoration of Cerebral Myelination of the Congenitally Hypothyroid Mouse by Parenteral or Breast Milk Administration of Thyroxine

The objective of the present study was to assess metabolic changes in the neocortex and hippocampus of well-oxygenated or moderately hypoxic rats in which fluorothyl-induced seizures were sustained for 5 or 20 min, or which were allowed recovery periods of 5, 15, or 45 min following cessation of 20-min seizure activity by withdrawal of the convulsant gas. Sustained fluorothyl-induced seizures were found to cause metabolic alterations qualitatively and quantitatively similar to those previously observed with other commonly used convulsants. Thus, although the phosphorylation state of the adenine nucleotide pool remained only moderately perturbed, if at all, there were decreases in tissue concentrations of phosphocreatine and glycogen, and increases in those of cyclic AMP, lactate, and pyruvate, with a calculated fall in intracellular pH of about 0.15 units and a rise in the cytoplasmic NADH/NAD+ ratio. The enhanced metabolic rate was reflected in a marked reduction in the tissue-to-plasma glucose concentration ratio. Induced moderate hypoxia (arterial PO2 40-50 mm Hg) had no metabolic effect after 5 min of seizures but moderately increased lactate concentrations after 20 min (from about 10 to about 15 mumol X g-1). On cessation of seizure discharge cyclic AMP and phosphocreatine concentrations normalized already within 5 min, whereas glycogen and lactate concentrations normalized more slowly. In the neocortex (but not the hippocampus) postepileptic tissue-to-plasma glucose concentration ratios rose above control, probably reflecting metabolic depression. The results suggest that intracellular pH promptly returned to control, and that postepileptic alkalosis developed. They also suggest that some elevation of the NADH/NAD+ ratio persisted even after 45 min of recovery.     

Compartmentation of Lactate Originating from Glycogen and Glucose in Cultured Astrocytes

Brain glycogen metabolism was investigated by employing isofagomine, an inhibitor of glycogen phosphorylase. Cultured cerebellar and neocortical astrocytes were incubated in medium containing [U-¹³C]glucose in the absence or presence of isofagomine and the amounts and percent labeling of intra- and extracellular metabolites were determined by mass spectrometry (MS). The percent labeling in glycogen was markedly decreased in the presence of isofagomine. Surprisingly, the percent labeling of intracellular lactate was also decreased demonstrating the importance of glycogen turnover. The decrease was limited to the percent labeling in the intracellular pool of lactate, which was considerably lower compared to that observed in the medium in which it was close to 100%. These findings indicate compartmentation of lactate derived from glycogenolysis and that derived from glycolysis. Inhibiting glycogen degradation had no effect on the percent labeling in citrate. However, the percent labeling of extracellular glutamine was slightly decreased in neocortical astrocytes exposed to isofagomine, indicating an importance of glycogen turnover in the synthesis of releasable glutamine. In conclusion, the results demonstrate that glycogen in cultured astrocytes is continuously synthesized and degraded. Moreover, it was found that lactate originating from glycogen is compartmentalized from that derived from glucose, which lends further support to a compartmentalized metabolism in astrocytes. Special issue dedicated to Dr. Bernd Hamprecht.     

Glycogen, ammonia and related metabolities in the brain during seizures evoked by methionine sulphoximine

Abstract— The levels of ATP, P-creatine, glucose, glycogen, lactate, glutamate and ammonia were measured in mouse brain after administration of the convulsive agent methionine sulphoximine (MSO). No changes were observed in ATP and P-creatine levels either before or during the seizures. Lactate levels were unchanged until the onset of seizures (4–5 hr) at which time the levels increased an average of 65 per cent. Glucose and glycogen levels increased progressively. Just before the onset of seizures the levels had increased 95 and 62 per cent, respectively. During the seizures both substances had increased a total of 130 per cent. Comparable changes were found in cerebral cortex, cerebellum and subcortical forebrain. Through the use of quantitative histochemical methods it was found that the greatest increases in glycogen occurred in layers I and III (layers II and IV were not analysed). Progressively smaller changes were found in layers V and VI and no increase at all was found in the subjacent white matter. Glucose, in contrast to glycogen, increased to about the same degree in all cerebral layers and in subjacent white matter. The increase in glycogen after MSO administration may be related to the fact that MSO also causes an increase in the ratio of brain to serum glucose levels. This would indicate that an increase in intracellular glucose had occurred. Ammonia levels were increased 300–400 per cent in both cerebrum and cerebellum. A time study in cerebellum showed that the increase begins early and reaches maximal levels long before the onset of seizures. Glutamate levels were reduced by small but statistically significant amounts in both cerebrum and cerebellum. Administration of methionine sulphoximine completely prevented seizures and the increase in lactate, but did not prevent the increases in glycogen and glucose. The rise in ammonia was reduced but not prevented. During 20 sec of complete ischaemia (decapitation) ATP, P-creatine and glucose fell somewhat more rapidly than normal in brain of animals undergoing MSO seizures. From the changes it was calculated that the metabolic rate had been increased about 20 per cent by the seizure. A new sensitive and specific enzymic method for determination of tissue ammonia is presented together with evised enzymic procedures for lactate and glutamate.     

Cerebral Metabolic State During the Ethanol Withdrawal Reaction in the Rat

Abstract: A severe ethanol withdrawal reaction was induced in rats by means of repeated intragastric intubation during a 4-day period. At the peak of the withdrawal reaction cerebral cortical tissue was frozen in situ for analysis of glycogen, glucose, phosphocreatine, creatine, ATP, ADP, AMP, lactate, pyruvate, GAB A, β-hydroxybutyrate, acetoacetate, cAMP and cGMP. Blood glucose concentration was also measured. The level of brain glycogen was decreased during ethanol withdrawal. Brain glucose concentration was increased, probably secondary to the increase in blood glucose concentration. The calculated NADH/NAD⁺ ratio was slightly increased during the withdrawal and brain ATP concentration and adenine nucleotide pool size were decreased. The adenylate energy charge remained unchanged. The overall changes in the metabolites were in agreement with the previously shown metabolic activation during ethanol withdrawal. The brain concentrations of ketone bodies (β-hydroxybutyrate and acetoacetate) during withdrawal did not deviate from controls, indicating that no abnormal ketone metabolism had developed as a consequence of the long-lasting ethanol intoxication. No changes were observed in the concentrations of GABA, cAMP, or cGMP in the rat cerebral cortex during ethanol withdrawal.     

IN VIVO EFFECTS OF AMPHETAMINE ON METABOLITES AND METABOLIC RATE IN BRAIN

—The concentrations of several metabolites, including glucose, glycogen, glucose-6-phosphate, lactate, ATP and phosphocreatine have been measured in the brains of mice rapidly frozen at various intervals after the intraperitoneal injection of d -amphetamine sulphate (5 mg/kg). During the initial 30 min following injection, amphetamine induced a fall in cerebral glycogen and phosphocreatine and an elevation of lactate. Changes in glucose and brain/blood glucose ratios were less marked over this period. The metabolite levels returned to control values at 60 min. The cerebral metabolic rate calculated by the ‘closed system’ technique also showed a biphasic change. An initial depression of energy flux over the first 15 min following amphetamine injection was followed by an increase that appeared to be closely associated with the increase in locomotor activity over this period. The results have been discussed in relation to the known catecholamine-releasing action of amphetamine, and differential effects on glial cells and neurons have been proposed.     

Azolylchromans as a novel scaffold for anticonvulsant activity

A series of azolylchroman derivatives were prepared as conformationally constrained analogs of (arylalkyl)azole anticonvulsants. The anticonvulsant activities of the compounds were evaluated by determining seizure latency and protective effect against pentylenetetrazole (PTZ)-induced lethal convulsions in mice at a dose of 5mg/kg. Among these compounds, 7-chloro-3-(1H-imidazol-1-yl)chroman-4-one and 3-(1H-1,2,4-triazol-1-yl)chroman-4-one exhibited significant action in delaying seizures as well as effective protection against PTZ-induced seizures and deaths.     

Ethosuximide affects both pentylenetetrazole- and kainate-induced clonic seizures but differentiates between tonic-clonic seizures

Young (25-day-old) and adult (90-day-old) rats pretreated with ethosuximide (62.5 or 125 mg/kg i.p.) were injected with either s.c. pentylenetetrazole (100 mg/kg) or i.p. kainate (10 or 14 mg/kg). The incidences and latencies of minor (clonic) and major (tonic-clonic) seizures were registered. Ethosuximide (125 mg/kg) completely blocked clonic seizures induced by the lower dose of kainate, and slightly suppressed or delayed those induced by the higher dose of kainate or pentylenetetrazole in both age groups. The effect of ethosuximide on major kainate-induced seizures (elicited in young rats only) was insignificant (ethosuximide only partially decreased the incidence of major seizures), whereas ethosuximide abolished major pentylenetetrazole-induced seizures in both age groups. Ethosuximide also failed to affect the latencies of kainate-induced automatisms (e.g., scratching, wet dog shakes). Similarities between kainate- and pentylenetetrazole-induced clonic seizures, as well as a similar action of ethosuximide on both, suggest a common generator for the pattern of clonic seizures.     

Effect of chronic hypernatremic dehydration and rapid rehydration on brain carbohydrate, energy, and amino acid metabolism in weanling mice

Abstract: This is a study of the effects of chronic hypernatremic dehydration and rehydration on carbohydrate, energy, and amino acid metabolism in the brains of weanling mice. Chronic hypernatremic dehydration induced by 4 days of water deprivation and salt loading was associated with severe weight loss (no other observed clinical effects), increased brain Na⁺ levels, and a decreased brain water content. Changes in the concentrations of brain glucose, glycolytic and citric acid cycle metabolic intermediates, and phosphocreatine were compatible with reduced cerebral metabolic rate. In adaptation to chronic hypernatremia, there was a significant increase in the content of the measured brain amino acids. Rapid rehydration over a 4-h period with 2.5% dextrose in water returned plasma Na⁺ levels and brain Na⁺ and water contents to normal. After rehydration, metabolites were altered in a manner consistent with increased fluxes through the glycolytic pathway and citric acid cycle; the brain glycogen content almost tripled. Brain taurine and glutamine levels were not lowered by rehydration, and the total content of the measured amino acids in brain was still significantly higher than in controls. We speculate that these metabolic perturbations may relate to the development of cerebral edema and seizures or coma following rapid rehydration of humans with chronic hypernatremic dehydration.     

Effect of inferior olive lesion on seizure threshold in the rat

Cerebellar stimulation has been associated with anticonvulsant activity in several experimental seizure models. We examined the effect of destruction of cerebellar climbing fibers, by systemic administration of 3-acetylpyridine (3AP) or electrothermic lesion of the inferior olive, on seizures produced by various chemical convulsants in rats. We found that inferior olive lesioned rats had lower threshold to seizures induced by strychnine and brucine, both glycine antagonists. The dose response curve for strychnine seizure was shifted 2.5 times to the left in 3AP lesioned rats. No difference in seizure threshold was seen when picrotoxin, bicuculline or pentylenetetrazole PTZ) were used to produce seizures. Abnormal motor behavior (AMB) including myoclonus, backward movement and hyperextension, produced by all of the convulsants tested, was significantly aggravated in 3AP pretreated rats. The inferior olive-climbing fiber projection to the cerebellum appears to modulate seizures induced by inhibition of glycinergic neurotransmission.     

Long-term L-NAME treatment potentiates the blood-brain barrier disruption during pentylenetetrazole-induced seizures in rats

We investigated whether the severity of blood-brain barrier disruption caused by pentylenetetrazole-induced seizures is modified by long-term nitric oxide synthase inhibition in rats. Rats were given N-omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in drinking water for 4 weeks, and then treated with pentylenetetrazole to induce seizures. Damage to the blood-brain barrier was investigated using Evans blue dye extravasation. Serum nitric oxide concentration was decreased in L-NAME-treated rats (P<0.01). L-NAME and/or pentylenetetrazole treatments elevated systolic blood pressure of animals (P<0.01). L-NAME caused an increase in the mortality rate after pentylenetetrazole injection leading to the death of animals at about 15 min after the onset of the seizure. Pentylenetetrazole-induced seizures in rats treated with L-NAME caused a significant increase in Evans blue dye extravasation into cerebral cortex, diencephalon and cerebellum, as compared with seizures evoked by pentylenetetrazole injection to L-NAME-untreated rats (P<0.01). Data presented here suggest that the degree of blood-brain barrier disruption induced by seizures is more pronounced in long-term nitric oxide deficiency.     

Elevated γ-Aminobutyric Acid Levels Attenuate the Metabolic Response to Biateral Ischemia

Bilateral ischemia has been shown to alter the net brain levels of energy metabolites such as ATP, phosphocreatine, glucose, and glycogen. The amino acid neurotransmitter gamma-aminobutyric acid (GABA) exerts a tonic inhibitory influence on neural activity. The present studies were designed to evaluate the influence of elevated GABA levels on the metabolic sequelae of ischemia. The GABA transaminase inhibitor gamma-vinyl-GABA (GVG; vigabatrin) was administered to Mongolian gerbils before the production of a bilateral ischemic incident. GABA levels were elevated in all regions assayed. Levels of energy metabolites were also increased, an indication of reduced energy utilization. In control animals, in the absence of GVG, 1 min of bilateral ischemia produced decreases in the levels of all metabolites. In animals pretreated with GVG, the effects of 1 min of bilateral ischemia were attenuated. These data suggest that the level of ongoing activity may affect the response to an ischemic insult. Furthermore, GVG may have a clinical indication in reducing the effect of minor ischemic incidents.     

Cerebral carbohydrate metabolism during acute hypoxia and recovery

Abstract— The levels of ATP, ADP, AMP and phosphocreatine, of four amino acids, and of 11 intermediates of carbohydrate metabolism in mouse brain were determined after: (1) various degrees of hypoxia; (2) hypoxia combined with anaesthesia; and (3) recovery from severe hypoxia. Glycogen decreased and lactate rose markedly in hypoxia, but levels of ATP and phosphocreatine were normal or near normal even when convulsions and respiratory collapse appeared imminent. During 30 s of complete ischaemia (decapitation) the decline in cerebral ATP and phosphocreatine and the increase in AMP was less in mice previously rendered hypoxic than in control mice. From the changes we calculated that the metabolic rate had decreased by 15 per cent or more during 30 min of hypoxia. Hypoxia was also associated with decreases of cerebral 6-phosphogluconate and aspartate, and increases in alanine, γ-aminobutyrate, α-ketoglutarate, malate, pyruvate, and the lactate :pyruvate ratio. Following recovery in air (10 min), increases were observed in glucose (200 per cent), glucose-6-phosphate, phosphocreatine and citrate, and there was a fall in fructose-1, 6-diphosphale. Similar measurements were made in samples from cerebral cortex, cerebellum, midbrain and medulla. Severe hypoxia produced significant increases in lactate and decreases in glycogen in all areas; γ-aminobutyrate levels increased in cerebral cortex and brain stem, but not in cerebellum. No significant changes occurred in ATP and only in cerebral cortex was there a significant fall in phosphocreatine. Phosphocreatine, ATP and glycogen were determined by quantitative histochemical methods in four areas of medulla oblongata, including the physiological respiratory centre of the ventromedial portion. After hypoxia, ATP was unchanged throughout and the changes (decreases) in phosphocreatine and glycogen were principally confined to dorsal medulla, notably the lateral zone. Thus there is no evidence that respiratory failure is caused by a ‘power’ failure in the respiratory centre. It is suggested that in extremis a protective mechanism may cause neurons to cease firing before high-energy phosphate stores have been exhausted.     

GLYCOGEN AND GLYCOGEN PHOSPHORYLASE IN THE CEREBRAL CORTEX OF MICE UNDER THE INFLUENCE OF METHIONINE SULPHOXIMINE

Abstract— Glucose and glycogen levels in the mouse cerebral cortex in vivo were studied after recovery from methionine sulphoximine seizures. The animals appeared normal 24 h after methionine sulphoximine administration but both glucose and glycogen still persisted at higher levels 72 h after injection (by 64 and 275 per cent, respectively). When seizures were prevented by methionine, the increase in glucose and glycogen at the longer time intervals was significantly smaller than in animals treated with methionine sulphoximine only; glucose reached normal values at 48 or 72 h; the accumulation of glycogen was reduced by about three to five times, but after 72 h the levels were still significantly higher than in control animals (67 or 32 per cent increase, depending on the administered dose of methionine). In contrast to the considerable accumulation of glycogen after administration of methionine sulphoximine in vivo, it had no effect on the level of glycogen in brain cortex slices in vitro. After 3 h incubation in the absence of methionine sulphoximine, glycogen was resynthesized to a level of about 4 μmol/g wet tissue and this value was not significantly affected by the presence of various concentrations of methionine sulphoximine in the incubation medium (10^-5 to 10^-2 M). The total (a+b forms) phosphorylase activity of mouse cerebral cortex in vivo after methionine sulphoximine administration was not affected. The fraction of active phosphorylase was reduced by about 50 per cent at the time of seizures. When seizures were prevented by methionine, the decrease in active phosphorylase was also completely prevented. In the preconvulsive period (1-2 h) and after recovery from the seizures (48 h after methionine sulphoximine administration) active phosphorylase was normal. The possible mechanisms involved in the increased accumulation of glycogen after methionine sulphoximine administration are discussed.     

Metabolic profile of hippocampal regions after bilateral ischemia and recovery

Microanalysis methods were used to determine the effect of bilateral carotid occlusion on net levels of energy metabolites in discrete cellular regions of the hippocampus and dentate gyrus of the Mongolian gerbil. Glucose, glycogen, ATP and phosphocreatine levels were not decreased after one minute of bilateral occlusion. Three minutes of ischemia, however, produced a dramatic fall in net levels with no further decrease observed at fifteen minutes. Re-establishment of blood flow for five minutes after a fifteen minute ischemic episode resulted in replenishment of metabolites to pre-ischemic levels. Glucose was increased two to three times in sham-operated animals as compared to control (non-operated) animals. The increase was the result of the Na-pentobarbital anesthetic employed. The present data indicate that regions of the hippocampus and dentate gyrus respond in a uniform manner to bilateral occlusion of the carotid arteries. Further, most cells maintained enough viability to resume production of high-energy phosphate and carbohydrate metabolites.     

Quinolinic Acid-induced Seizures Stimulate Glutamate Uptake into Synaptic Vesicles from Rat Brain: Effects Prevented by Guanine-based Purines

Glutamate uptake into synaptic vesicles is a vital step for glutamatergic neurotransmission. Quinolinic acid (QA) is an endogenous glutamate analog that may be involved in the etiology of epilepsy and is related to disturbances on glutamate release and uptake. Guanine-based purines (GBPs) guanosine 5′-monophosphate (GMP and guanosine) have been shown to exert anticonvulsant effects against QA-induced seizures. The aims of this study were to investigate the effects of in vivo administration of several convulsant agents on glutamate uptake into synaptic vesicles and investigate the role of MK-801, guanosine or GMP (anticonvulsants) on glutamate uptake into synaptic vesicles from rats presenting QA-induced seizures. Animals were treated with vehicle (saline 0.9%), QA 239.2 nmoles, kainate 30 mg/kg, picrotoxin 6 mg/kg, PTZ (pentylenetetrazole) 60 mg/kg, caffeine 150 mg/kg or MES (maximal transcorneal electroshock) 80 mA. All convulsant agents induced seizures in 80–100% of animals, but only QA stimulated glutamate uptake into synaptic vesicle. Guanosine or GMP prevented seizures induced by QA (up to 52% of protection), an effect similar to the NMDA antagonist MK-801 (60% of protection). Both GBPs and MK-801 prevented QA-induced glutamate uptake stimulation. This study provided additional evidence on the role of QA and GBPs on glutamatergic system in rat brain, and point to new perspectives on seizures treatment.