Neuroactive Amino Acids in Focally Epileptic Human Brain: A Review

Studies of neuroactive amino acids and their regulatory enzymes in surgically excised focally epileptic human brain are reviewed. Concentrations of glutamate, aspartate and glycine are significantly increased in epileptogenic cerebral cortex. The activities of the enzymes, glutamate dehydrogenase and aspartate aminotransferase, involved in glutamate and aspartate metabolism are also increased. Polyamine synthesis is enhanced in epileptogenic cortex and may contribute to the activation of N-methyl-D-aspartate (NMDA) receptors. Nuclear magnetic resonance spectroscopy (NMRS) reveals that patients with poorly controlled complex partial seizures have a significant diminution in occipital lobe gamma aminobutyric acid (GABA) concentration. The activity of the enzyme GABA-aminotransaminase (GABA-T) which catalyzes GABA degredation is not altered in epileptogenic cortex. NMRS studies show that vigabatrin, a GABA-T inhibitor and effective antiepileptic, significantly increases brain GABA. Glutamate decarboxylase (GAD), responsible for GABA synthesis, is diminished in interneurons in discrete regions of epileptogenic cortex and hippocampus. In vivo microdialysis performed in epilepsy surgery patients provides measurements of extracellular amino acid levels during spontaneous seizures. Glutamate concentrations are higher in epileptic hippocampi and increase before seizure onset reaching potentially excitotoxic levels. Frontal or temporal cortical epileptogenic foci also release aspartate, glutamate and serine particularly during intense seizures or status epilepticus. GABA in contrast, exhibits a delayed and feeble rise in the epileptic hippocampus possibly due to a reduction in the number and/or efficiency of GABA transporters.     

Evidence Disputing the Link Between Seizure Activity and High Extracellular Glutamate

Abstract: As seizures in experimental models can be induced by the activation and suppressed by the inhibition of glutamate receptors, it is often proposed that a high extracellular glutamate level subsequent to excessive presynaptic release and/or altered glutamate uptake is epileptogenic. The purpose of this study was to ascertain the link between seizure activity and high extracellular glutamate. To assist the detection of any putative rise in extracellular glutamate during seizures, microdialysis was coupled to enzyme-amperometric detection of glutamate, which provides maximal sensitivity and time resolution. Electrical activity and field potential were also recorded through the dialysis membrane to confirm that epileptic activity was present at the sampling site. No increase in dialysate glutamate content was detected during picrotoxin-induced seizures, even when the K⁺ concentration in the perfusion medium was raised to 50% above that measured previously during paroxysmal activity. In addition, sustained inhibition of glutamate uptake by l - trans -pyrrolidine-2,4-dicarboxylate increased the extracellular glutamate level >20-fold but did not produce electrophysiological changes indicative of excessive excitation. These findings indicate that seizures are not necessarily accompanied by an increased extracellular glutamate level and that increased glutamatergic excitation in epilepsy may result from other abnormalities such as increased density of glutamate receptors, enhanced activation subsequent to reduced modulation, or sprouting of glutamatergic synapses.     

Changes in extracellular amino acid concentrations in the rat hippocampus after in vivo actin depolymerization with latrunculin A

The effect of latrunculin A microperfusion on hippocampal extracellular concentrations of glutamate, aspartate, glycine and GABA, as measured by in vivo microdialysis, was investigated. Latrunculin A (4 microg/ml) was perfused for three consecutive days (8h a day) to promote in vivo F-actin depolymerization. Intrahippocampal latrunculin A microdialysis induced seizures during the second and third day of perfusion, and the animals started showing spontaneous seizures 1 month after lartrunculin A administration. Hippocampal glutamate levels were significantly increased during the first day of latrunculin A microperfusion without significant changes during the second and third day of perfusion. Aspartate levels were significantly increased during the first and second days of treatment. The rise on glutamate and asparate levels was partially reversed by perfusion of NMDA antagonist MK-801. Glycine concentrations were significantly increased during the 3 days of latrunculin A microdialyis, but no significant effect was observed on baseline GABA levels. One month after latrunculin A microperfusion, no significant differences in glutamate and aspartate extracellular concentrations were detected as compared to controls, however, significant increases in glycine and GABA extracellular concentrations were observed. The immediate increases in glutamate, aspartate and glycine levels indicate a modulatory effect of the F-actin cytoskeleton on extracellular concentrations of glutamate, aspartate and glycine. The chronic elevations in GABA and glycine levels are more likely to be related with long-term epileptogenesis processes. Our results suggest that the in vivo biochemical study of actin-dependent processes seems to be a promising approach to the neuropathology and neuropharmacology of epileptic seizures.     

Excitatory aminoacids and epileptic seizures in immature brain

Data on convulsant and anticonvulsant action of drugs influencing excitatory amino acid receptors in developing rats are reviewed. Agonists of NMDA type of receptors NMDA and homocysteic acid, elicited an age-related seizure pattern--flexion, emprosthotonic seizures--in the first three postnatal weeks of rats. Generalized clonic-tonic seizures appeared only after a longer latency. Kainic acid administration resulted in epileptic automatisms and later in minimal, clonic seizures followed by generalized tonic-clonic seizures. A decrease of sensitivity to convulsant action with age is a general rule for all agonists tested. Different anticonvulsant action of NMDA and nonNMDA antagonists was demonstrated in a model of generalized tonic-clonic seizures induced by pentetrazol, whereas their action against epileptic afterdischarges elicited by electrical stimulation of cerebral cortex was similar. Again, higher efficacy in younger animals was a rule. As far as metabotropic glutamate receptors are concerned, agonists of groups II and III were shown to protect against convulsant action of homocysteic acid in immature rats and an antagonist of group I receptors MPEP suppressed the tonic phase of generalized tonic-clonic seizures induced by pentetrazol more efficiently in younger than in more mature rat pups. Unfortunately, a higher sensitivity to the action of antagonists of ionotropic glutamate receptors was demonstrated also for unwanted side effects (motor functions were compromized). In contrast, glutamate metabotropic receptor antagonist MPEP did not exhibit any serious side effects in rat pups.     

Disturbance of motivated behavior in rats by epileptic afterdischarges

Nearly all epileptic seizures in patients are characterized by deranged consciousness. We started to study changes in motivated behavior (drinking in thirsty rats) as a possible analogue of compromised consciousness during and after epileptic seizures. Epileptic afterdischarges (ADs) were elicited by stimulation of the dorsal hippocampus and/or thalamus. Rats with implanted electrodes (deprived of water for 24 hours) were trained to lick water from a narrow tube. After pretraining ADs were elicited eight times in each animal and access to water was allowed during different phases of the AD. Stimulation did not affect licking if no AD was induced. If stimulation was successful, licking was stopped in nearly 70 % of stimulations and modified (biting the tube) in 30 %. Hippocampal ADs (characterized by serrated waves in the EEG and by an arrest of behavior with subsequent automatisms) completely blocked licking, signs of recovery appeared during the interval between the AD and recurrent AD and it progressed during recurrent ADs. Thalamic ADs abolished licking in 82% of cases and immediately after ADs normal licking reappeared in 49 % of these observations. Our results suggest that changes in motivated behavior might serve as an analogue of compromised human consciousness.     

2 types of chronic epileptogenesis in rabbits during kindling stimulation of the hippocampus

The development of convulsant readiness in rabbits during kindling electrical stimulation of the hippocamp was studied as was the dependence of the motor seizure pattern on the degree of epileptiform activity generalization in the CNS. The kindling electrical stimulation of the hippocamp gave rise to the formation in different rabbits of the two main types of afterdischarges. One of them was characterized by high-frequency and high-amplitude spikes (total duration 8-30 s) and the other one by continuous, rather long (50-100 s) hypersynchronous paroxysms. In the interictal period, the animals with the first type demonstrated the occurrence of spontaneous spikes (in all the brain structures under study) that sometimes progressed to a more or less prolonged seizure discharges. At the same time in the animals with the second type of afterdischarges the EEG in the interictal period was slightly different from normal. Despite this fact the seizures induced by electrical stimulation ran a milder course (short-term clonic seizures) in animals with the first type of afterdischarges as compared to those with the second type (long-term clonicotonic seizures). It is assumed that the severity of the motor seizure does not depend on the degree of epileptic activity generalization in the CNS.     

Epilepsy, Neurodegeneration, and Extracellular Glutamate in the Hippocampus of Awake and Anesthetized Rats Treated with Okadaic Acid

We have previously shown that the intrahippocampal microinjection of okadaic acid (OKA), a potent inhibitor of serine/threonine protein phosphatases, induces epileptic seizures, neuronal death, and the hyperphosphorylation of the NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor. We administered OKA by reverse microdialysis in the hippocampus of awake and halothane-anesthetized rats, with simultaneous collection of microdialysis fractions and recording of the EEG activity, and subsequent histological analysis. OKA produced intense behavioral and persistent EEG seizure activity in the awake rats but not in the anesthetized animals, and did not significantly alter the extracellular concentration of glutamate and aspartate detected in the microdialysis fractions. One day after the experiment a remarkable neurodegeneration of CA1 hippocampal region was observed in both the awake and the anesthetized rats. We conclude that the OKA-induced epilepsy cannot be ascribed to increased extracellular glutamate, but to an increased sensitivity of NMDA receptor. We propose that halothane protected against the epilepsy because it blocks NMDA receptor overactivation, and that the neurodegeneration of CA1 region is independent of this overactivation and due probably to alterations of cytoskeletal proteins consequent to the OKA-induced hyperphosphorylation.     

Extracellular GABA in the Ventrolateral Thalamus of Rats Exhibiting Spontaneous Absence Epilepsy: A Microdialysis Study

Abstract: There is compelling evidence that excessive GABA-mediated inhibition may underlie the abnormal electrical activity, initiated in the thalamus, associated with epileptic absence seizures. In particular, the GABA_B receptor subtype seems to play a critical role, because its antagonists are potent inhibitors of absence seizures, whereas its agonists exacerbate seizure activity. Using a validated rat model of absence epilepsy, we have previously found no evidence of abnormal GABA_B receptor density or affinity in thalamic tissue. In the present study, we have used in vivo microdialysis to monitor changes in levels of extracellular GABA and other amino acids in this brain region. We have shown that basal extracellular levels of GABA and, to a lesser extent, taurine are increased when compared with values in nonepileptic controls. However, modifying GABAergic transmission with the GABA_B agonist (−)-baclofen (2 mg/kg i.p.), the GABA_B antagonist CGP-35348 (200 mg/kg i.p.), or the GABA uptake inhibitor tiagabine (100 µ M ) did not produce any further alteration in extracellular GABA levels, despite the ability of these compounds to increase (baclofen and tiagabine) or decrease (CGP-35348) seizure activity. These findings suggest that the increased basal GABA levels observed in this animal model are not simply a consequence of seizure activity but may contribute to the initiation of absence seizures.     

Effects of Retigabine on the Neurodegeneration and Extracellular Glutamate Changes Induced by 4-Aminopyridine in Rat Hippocampus <Emphasis Type="Italic">In Vivo</Emphasis>

We have previously shown that microdialysis perfusion of the K⁺ channel blocker 4-aminopyridine (4-AP) in rat hippocampus induces convulsions and neurodegeneration, due to the stimulation of glutamate release from synaptic terminals. Retigabine is an opener of the KCNQ2/Q3-type K⁺ channel that possesses antiepileptic action and may be neuroprotective, and we have therefore studied its effect on the hyperexcitation, the neuronal damage and the changes in extracellular glutamate induced by 4-AP. Retigabine and 4-AP were co-administered by microdialysis in the hippocampus of anesthetized rats, with simultaneous recording of the EEG, and the extracellular concentration of glutamate was measured in the microdialysis fractions. In 70–80% of the rats tested retigabine reduced the 4-AP-induced stimulation of glutamate release and prevented the neuronal damage observed at 24 h in the CA1 hippocampal region. However, retigabine did not block the EEG epileptic discharges and their duration was reduced in only 20–25% of the tested animals. We conclude that the neuroprotective action of retigabine is probably due to the blockade of the 4-AP-induced stimulation of glutamate release. This inhibition, however, was not sufficient to block the epileptic activity. Special issue dedicated to Dr. Simo S. Oja     

Implication of Gamma Band in Soman-Induced Seizures

Soman, an anticholinesterasic neurotoxic drug, induces epileptic seizures during severe intoxication. Their trigger conditions still remain unknown and a great variability between animals is observed. The butterfly model in the catastrophe theory has been used to explain these triggering conditions.We have developed a technique allowing, in freely moving rats, the « in vivo » determination of three sets of neurophysiological data, followed before and during a soman intoxication. For the same rat, we associated cortical acetylcholinesterase (AChE) activity by microdialysis with both the assay of extracellular acetylcholine (ACh) concentrations and electroencephalographic (EEG) recording and power spectrum analysis (gamma band). Data have been analysed to define the critical parameters which lead to the epileptic fit.Although we found thresholds for seizure occurrence, AChE inhibition having to be over 65% and ACh over 200 fold the baseline, these two criteria are not sufficient to predict the appearance of seizures. Only animals with no increase of energy in the gamma band early after soman poisoning will then exhibit an epileptic fit.The butterfly model provides an original interpretation of these results and gives a particular role of the energy in gamma band as a survival attractor.     

Glutamate uptake in blood platelets from epileptic patients

Glutamate, the major excitatory amino acid neurotransmitter, is involved in epileptogenesis and initiation and spread of seizures. We studied glutamate uptake into blood platelets from patients with distinct epileptic syndromes: included were 20 patients with temporal lobe epilepsy and hippocampal sclerosis (TLE+HS), 20 with juvenile myoclonus epilepsy (JME) and 20 healthy volunteers matched for age and sex. The affinity of glutamate for the transporters was highest in patients with TLE+HS, but the maximal velocity of transport was highest in controls. There were no differences in the plasma levels of glutamate. Carbamazepine (CBZ), valproate (VPA) and lamotrigine (LTG) did not affect the uptake in vitro. The alterations observed in the uptake of glutamate in TLE+HS patients may reflect an up-regulated uptake of glutamate in the brain.     

Effect of ionotropic glutamate receptors antagonists on the modifications in extracellular glutamate and aspartate levels during picrotoxin seizures: a microdialysis study in freely moving rats

Our previous studies have shown a local decrease in glutamate and aspartate levels during seizures, induced by picrotoxin microdialysis in the hippocampus of chronic freely moving rats. In this paper, we study the effect of continuous hippocampal microperfusion of the NMDA, AMPA and kainate glutamate receptor inhibitors 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (MK-801); 6,7-dinitroquinoxaline-2,3-dione (DNQX), and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466). We also examine the action of L(-)-threo-3-hydroxyaspartic acid (THA), a glutamate and aspartate reuptake blocker, on the modification of extracellular glutamate and aspartate levels induced by picrotoxin, using the microdialysis method in freely moving rats. We found that changes in extracellular hippocampal concentrations in both amino acids are prevented by NMDA, AMPA and kainate receptor inhibitors. Seizures elicited under DNQX also induce a transient increase in aspartate extracellular levels coincident with seizure time. L(-)-threo-3-hydroxyaspartic acid increased the basal extracellular concentrations of both amino acids, but did not prevent the seizure-related decrease. Our results suggest that glutamate, the major neurotransmitter at the synaptic level, may also play an important role in non-synaptic transmission during seizures.     

Midazolam suppresses spike-and-wave rhythm accompanying three different models of epileptic seizures

The action of a water-soluble benzodiazepine midazolam (0.1 and 1 mg/kg i.p.) was tested against three models of spike-and-wave rhythm in rats: rhythmic metrazol activity (a model of human absence seizures), minimal metrazol seizures, and epileptic afterdischarges induced by low-frequency cortical stimulation (probably models of human myoclonic seizures). Midazolam was able to reduce spike-and-wave activity in all three models, but there were quantitative differences: the lower dose was effective only against rhythmic metrazol activity, but its action against two other models was negligible, whereas the higher dose of midazolam resulted in significant effects in all three models. These quantitative differences are not sufficient to prove our hypothesis that the spike-and-wave rhythm represents different phenomena in various models. A spread of epileptic activity into brain structures other than the thalamocortical system determines the type of epileptic seizures.     

Sepsis inhibits reduction of dehydroascorbic acid and accumulation of ascorbate in astroglial cultures: intracellular ascorbate depletion increases nitric oxide synthase induction and glutamate uptake inhibition

Sepsis is associated with oxidative stress and impaired glutamatergic transmission in brain. We investigated whether sepsis impairs accumulation of the antioxidant, ascorbate, and uptake of glutamate by astrocytes. Bacterial endotoxin (Escherichia coli lipopolysaccharide, LPS) and the inflammatory cytokine, interferon-gamma (IFNgamma), were applied to primary astrocyte cultures to model sepsis. In the absence of ascorbate, the combination of LPS and IFNgamma (LPS + IFNgammay) up-regulated inducible nitric oxide synthase (iNOS) and decreased the initial rate of glutamate uptake by 50% within 24 h. Cell viability and facilitated glucose transport activity were not affected at 24 h. Pre-treatment with ascorbate-2-O-phosphate increased intracellular ascorbate concentration and attenuated the induction of iNOS and inhibition of glutamate uptake caused by LPS + IFNgamma. Subsequent experiments examined the mechanisms by which cells accumulate ascorbate. LPS + IFNy decreased slightly the initial rate of uptake of ascorbate and inhibited markedly the rate with which intracellular dehydroascorbic acid (DHAA) was reduced to ascorbate. We conclude that septic insult impairs astrocytic clearance of DHAA from the extracellular fluid and decreases intracellular ascorbate concentration. Furthermore, sepsis induces iNOS and inhibits glutamate uptake by astrocytes through mechanisms that can be modulated by intracellular ascorbate. These results indicate treatments that increase intracellular ascorbate concentration may be beneficial for patients at risk for neurologic complication in sepsis.     

Cell-selective effects of ammonia on glutamate transporter and receptor function in the mammalian brain

Increased brain ammonia concentrations are a hallmark feature of several neurological disorders including congenital urea cycle disorders, Reye's syndrome and hepatic encephalopathy (HE) associated with liver failure. Over the last decade, increasing evidence suggests that hyperammonemia leads to alterations in the glutamatergic neurotransmitter system. Studies utilizing in vivo and in vitro models of hyperammonemia reveal significant changes in brain glutamate levels, glutamate uptake and glutamate receptor function. Extracellular brain glutamate levels are consistently increased in rat models of acute liver failure. Furthermore, glutamate transport studies in both cultured neurons and astrocytes demonstrate a significant suppression in the high affinity uptake of glutamate following exposure to ammonia. Reductions in NMDA and non-NMDA glutamate receptor sites in animal models of acute liver failure suggest a compensatory decrease in receptor levels in the wake of rising extracellular levels of glutamate. Ammonia exposure also has significant effects on metabotropic glutamate receptor activation with implications, although less clear, that may relate to the brain edema and seizures associated with clinical hyperammonemic pathologies. Therapeutic measures aimed at these targets could result in effective measures for the prevention of CNS consequences in hyperammonemic syndromes.     

局部高频电刺激海马对海人酸致痫大鼠海马细胞外谷氨酸和γ-氨基丁酸释放的影响

目的：通过高频电刺激海人酸癫痫模型大鼠海马,观察海马细胞外谷氨酸（Glu）和γ-氨基丁酸（GABA）的动态变化。方法：将SD大鼠分成4大组（n=10）：①空白组;②海人酸组;③假刺激组：植入刺激电极未予电刺激;④电刺激组：海人酸注射后予130 Hz电刺激。利用微透析技术收集不同时段海马细胞外液,应用高效液相-荧光检测法测定收集液Glu、GABA的浓度。结果：注射海人酸后Glu明显升高,并持续至第14天,电刺激使Glu明显下降;而注射海人酸后GABA呈短暂性升高,后逐渐下降于第4天后保持稍高于正常水平,电刺激并无明显改变GABA的水平。结论：海马细胞外Glu下降在海马电刺激治疗癫痫中起到重要作用;高频电刺激海马选择性地减少谷氨酸能神经元活动,但不影响GABA的释放。     

Hippocampal afterdischarges and localization of the stimulating electrodes

Electrically evoked hippocampal afterdischarges are used as a model of partial epileptic seizures with a complex symptomatology and for testing anticonvulsants and toxic substances. Stimulating electrodes were implanted in the dorsal hippocampus of 16 laboratory rats and when the animals had recovered they were stimulated (15-s series, 8 Hz, pulse length 1 ms) with a voltage double the threshold value for a tissue response. The following features of the evoked afterdischarge were evaluated: the duration of the first phase of the afterdischarge, the duration of the non-active interphase, the duration of the second phase and the number of "wet dog shakes" (a constant accompaniment of hippocampal afterdischarges). Localization of the electrodes in the CA1 (n = 7) and CA3 (n = 7) region of the hippocampus made no difference to these parameters and in both cases the measured and evaluated data were the same. The afterdischarges were always accompanied by a marked orientation reaction. The study showed that when using macroelectrodes to stimulate the dorsal hippocampus, their localization in the CA1/CA3 is not of critical importance.     

The Search for New Screening Models of Pharmacoresistant Epilepsy: Is Induction of Acute Seizures in Epileptic Rodents a Suitable Approach?

Epilepsy, a prevalent neurological disease characterized by spontaneous recurrent seizures (SRS), is often refractory to treatment with anti-seizure drugs (ASDs), so that more effective ASDs are urgently needed. For this purpose, it would be important to develop, validate, and implement new animal models of pharmacoresistant epilepsy into drug discovery. Several chronic animal models with difficult-to-treat SRS do exist; however, most of these models are not suited for drug screening, because drug testing on SRS necessitates laborious video-EEG seizure monitoring. More recently, it was proposed that, instead of monitoring SRS, chemical or electrical induction of acute seizures in epileptic rodents may be used as a surrogate for testing the efficacy of novel ASDs against refractory SRS. Indeed, several ASDs were shown to lose their efficacy on acute seizures, when such seizures were induced by pentylenetetrazole (PTZ) in epileptic rather than nonepileptic rats, whereas this was not observed when using the maximal electroshock seizure test. Subsequent studies confirmed the loss of anti-seizure efficacy of valproate against PTZ-induced seizures in epileptic mice, but several other ASDs were more potent against PTZ in epileptic than nonepileptic mice. This was also observed when using the 6-Hz model of partial seizures in epileptic mice, in which the potency of levetiracetam, in particular, was markedly increased compared to nonepileptic animals. Overall, these observations suggest that performing acute seizure tests in epileptic rodents provides valuable information on the pharmacological profile of ASDs, in particular those with mechanisms inherent to disease-induced brain alterations. However, it appears that further work is needed to define optimal approaches for acute seizure induction and generation of epileptic/drug refractory animals that would permit reliable screening of new ASDs with improved potential to provide seizure control in patients with pharmacoresistant epilepsy.     

Physiological Elevations of Glucocorticoids Potentiate Glutamate Accumulation in the Hippocampus

Abstract: Glucocorticoids (GCs) are secreted during stress and can damage the hippocampus over the course of aging and impair the capacity of hippocampal neurons to survive excitotoxic insults. Using microdialysis, we have previously observed that GCs augment the extracellular accumulation of glutamate and aspartate in the hippocampus following kainic acid-induced seizures. In that study, adrenalectomized rats maintained on minimal GC concentrations were compared with those exposed to GCs elevated to near-pharmacological levels. We wished to gain insight into the physiological relevance of these observations. Thus, we have examined the effects of GCs over the normal physiological range on glutamate and aspartate profiles; this was done by implanting adrenalectomized rats with GC-secreting pellets, which produce stable and controllable circulating GC concentrations. We observe that incremental increases in GC concentrations cause incremental increases in glutamate accumulation before the kainic acid insult, as well as in the magnitude of the glutamate response to kainic acid. Elevating GC concentrations from the circadian trough to peak doubled cumulative glutamate accumulation, whereas a rise into the stress range caused a fourfold increase in accumulation. Similar, although smaller, effects also occurred with aspartate accumulation (as well as with taurine but not glutamine accumulation). These data show that the highly elevated GC concentrations that accompany neurological insults such as seizure or hypoxia-ischemia will greatly exacerbate the glutamate accumulation at that time. Furthermore, stress levels of GCs augmented glutamate accumulation even in the absence of an excitotoxic insult, perhaps explaining how sustained stress itself damages the hippocampus. Finally, even the moderately ?levated basal GC concentrations that typically occur in aged rats augmented glutamate accumulation, perhaps explaining how GCs damage the hippocampus over the course of normal aging.     

Carnitine pretreatment can partially change the excitability of the immature nervous tissue

The possible protective action of L-carnitine on neuronal excitability was studied in 21-day-old male Wistar rats with implanted electrodes. Administration of L-carnitine did not change the elicitation and duration of the epileptic seizures (cortical afterdischarges, ADs) in rats under normobaric oxygen atmosphere conditions. However, in animals exposed to 30 min hypobaric hypoxia the duration of the ADs was shortened after the second, fourth and sixth stimulation (in comparison with the first evoked ADs) while carnitine-treated rats retained their neuronal excitability and the duration of ADs was shortened only after the third stimulation.