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ABSTRACT: In vitro and in vivo brain slice techniques were used to examine phencyclidine (PCP) effects on the lateral propagation of epileptiform field potentials (EFP) across adjacent areas of rat frontal neocortex. Epileptiform activity was induced by perfusing slices with Mg 2+-free artificial cerebrospinal fluid. Simultaneous field potential recordings of EFP were obtained from four microelectrodes placed 2-3 mm apart across coronal slices in the third layer. PCP, applied focally between recording sites, blocked rapid propagation across treated areas and resulted in the emergence of spatially separate, independent pacemakers. The characteristics of paroxysmal depolarization shifts did not change significantly by the blockade of lateral propagation of EFP. The same asynchronized pattern of EFP conduction was observed after local application of the N-methyl-D-aspartate (NMDA)-receptor antagonist DL-2-amino-5-phosphono-valeric acid. Local administration of haloperidol as well as NMDA before PCP application reversibly prevented appearance of multiple pacemakers. Focal application of dopamine produced an abnormal pattern of lateral conduction of EFP in 50 % of tested slices. Pacemaker failure as an indicator of functional impairment of cortical integration is the proposed mechanism for developing of schizophrenia-like psychosis associated with epilepsy. Abbreviations. APV: DL-2-amino-5-phosphono-valeric acid EEG:electroencephalogram EFP:epileptiform field potentials NMDA:N-methyl-D-aspartate PCP:phencyclidine SLPE:Schizophrenialike psychosis associated with epilepsy
Pharmacopsychiatry 06/2003; 36(3):113-20. · 2.07 Impact Factor
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ABSTRACT: Spreading depressions (SD) occur in association with ischaemia, epilepsy and migraine. Intracellular calcium oscillations have been suggested to be involved in the generation and propagation of SD. The present study was performed to study the mechanism of conditioning guinea pig hippocampal slices by the T-type calcium channel blockers NiCl2 and amiloride. SD-like fluctuations of DC potential were recorded by inserting microelectrodes into the CA1 and CA3 regions. The SD occurrence was significantly greater with 10 micromol/l NiCl2 as well as with 25 and 50 micromol/l amiloride than with other concentrations of these substances. The concentration response curve was inversely U-shaped with the maximum repetition rates of SDs being achieved at 10 micromol/l NiCl2 as well as at 25 and 50 micromol/l amiloride. SD occurrence could be completely blocked by the NMDA antagonist APV (10 micromol/l) in all cases. These data demonstrate that modulation of the Ca2+ dynamics conditioned guinea pig hippocampal slices and increased their susceptibility to generate SD.
Cephalalgia 11/2000; 20(8):740-7. · 3.43 Impact Factor
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ABSTRACT: Cerebral taurine acts as neurotransmitter, as neuromodulator, or as osmoregulator. To investigate its release mechanisms in vivo, we combined the microdialysis technique with a variety of experimental paradigms. Taurine release was stimulated by either NMDA, NO or a hypotonic solution locally with or without the addition of the NMDA antagonists APV or Ketamine, or the NO synthase inhibitor L-NAME. Alternatively, the neuroprotective drug lubeluzole was applied i.v. NMDA, NO or the hypotonic solution stimulated the release of taurine. NMDA-mediated taurine release was inhibited by either APV, Ketamine or the NO synthase inhibitor L-NAME. Lubeluzole had no effect. Under the hypotonic conditions only lubeluzole was effective. These data confirm in vivo that the NMDA-induced taurine release is mediated via the NO cascade. By contrast, the release after a hypotonic stimulus is not related to the NO cascade. Instead, Na(+)- and/or Ca(2+)-mediated events might have been attenuated by lubeluzole.
Neurochemical Research 07/2000; 25(6):801-7. · 2.24 Impact Factor
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ABSTRACT: Taurine and glutamate were monitored by microdialysis technique during various cerebral insults: a. Application of K+ triggered a cortical spreading depression (CSD). Taurine and glutamate increased concomitantly but recovery of glutamate was faster than that of taurine. b. Application of NMDA induced also CSD but only taurine increased. c. Induction of an infarct triggered repetitive CSDs. Taurine increased rapidly whereas glutamate rose slowly starting with some delay. d. After induction of ischemia, taurine and glutamate increased after onset of depolarisation. The increase of glutamate occurred late after a small, transient increase in parallel with the depolarisation. These data suggest a close functional relationship between the changes of both amino acids. Therefore, they should be monitored together especially in clinical settings: during excitation, only taurine will increase; during overexcitation, taurine will also increase but to a higher maximum followed by a moderate rise of glutamate; after energy failure, taurine will accumulate to its highest level followed by a continuous rise of glutamate.
Amino Acids 02/2000; 19(3-4):571-83. · 3.25 Impact Factor
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ABSTRACT: The present study was performed in order to determine the oxygen consumption of a rat brain perfused with an artificial oxygen carrier. Measurements were performed prior to and 2 or 30 min after an ischemic period of 5 min. In addition, the energy-related metabolites were determined. Basal oxygen consumption and energy state were comparable to in vivo conditions. The tissue concentration of the energy metabolites decreased during ischemia and completely recovered during 30 min of reperfusion. The oxygen consumption was higher in the early phase of reperfusion than under pre-ischemic conditions. However, the oxygen consumption in the later phase of reperfusion was lower than the basal consumption. The data demonstrate that the addition of an artificial oxygen carrier to the perfusate provides sufficient amounts of oxygen to the in vitro preparation and that the measurement of the oxygen consumption during the post-ischemic reperfusion is a more sensitive parameter for the detection of emerging deficits than the measurement of the tissue levels of the energy metabolites.
Neurological Research 02/1998; 20 Suppl 1:S37-9. · 1.52 Impact Factor
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ABSTRACT: The K+-channel blocker tetraethylammonium (TEA) was applied to study its effects in self-sustaining, circling spreading depression in the chicken retina (RSD). Extracellular K+ (Ke+ activities and the direct-current (DC) signal were recorded using double-barrelled microelectrodes. Superfusion of TEA-concentrations of 10 to 250 microM for 4 to 7 min reduced the RSD-associated DC amplitude (by 9 to 45%) and the maximum of the K+ concentration (by 9 to 34%) in a dose-dependent manner. Propagation velocity of the RSD was lowered by 24%. At concentrations higher than 250 microM TEA (0.5 to 10 mM), the propagation was slowed by more than 60%, after which the RSD disappeared. Recovery upon reperfusion with Ringer was immediate. These observations illustrate: 1) TEA affects the Ke+ changes during RSD at very low concentrations. 2) The reduced Ke+ transients are accompanied by a reduction of the DC shifts. 3) These changes of the electrical properties of the RSDs are paralleled by a reduction of the propagation velocity. 4) The effects of TEA are reversible. 5) The changes of these parameters occur dose-dependently. These data suggest a close relationship between the amplitudes of the ionic/electric changes during RSDs and the mechanisms of propagation.
Journal of Neuroscience Research 02/1998; 51(1):85-9. · 2.74 Impact Factor
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ABSTRACT: Lubeluzole is a neuroprotective compound that has been shown to stereoselectively rescue sensorimotor function and reduce infarct size in a photochemical stroke model in rats. Tissue swelling, which occurs in the peri-infarct zone, is accompanied by a compensatory taurine release. Therefore, using a microdialysis technique, we aimed at measuring changes of extracellular concentrations of taurine in the peri-infarct zone and the effects of lubeluzole and its R-isomer. Lubeluzole blocked the increase of taurine in tissue immediately surrounding a photochemically induced thrombotic neocortical infarct. By contrast, the R-isomer was completely inactive. We hypothesize that lubeluzole may reduce osmoregulatory stress in peri-infarct tissue.
Acta neurochirurgica. Supplement 02/1997; 70:185-7.
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ABSTRACT: The measurement of cerebral extracellular lactate levels has been suggested to be used to monitor cerebral function in intensive care However, although an increase of extracellular lactate levels is a sensitive parameter for increased cellular activity in general, it will be shown that its prognostic value is limited in regard to the severity of the impairment of cellular function. As an alternative the measurement of the extracellular levels of inorganic phosphate (IP) or adenosine is proposed here: Whereas extracellular lactate levels increased rapidly to about the same extents during ischemia (IS) and spreading depression (SD), IP rose during IS only. Adenosine, on the other hand, increased during both events to a different degree. If, therefore, lactate was the only parameter to be monitored after a cerebral insult, the results would not allow to discriminate between a transient, spontaneously recovering event as a SD and a long lasting or an irreversible loss of cell function as in persisting ischemia/hypoxia. The measurement of IP, therefore, seems to be more suitable than that of lactate or adenosine since IP will appear within the extracellular space only after a sustained failure of membrane function. Thus, the measurement of IP changes turned out to be the more useful parameter for intensive care supervision.
Acta neurochirurgica. Supplement 02/1996; 67:28-30.
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ABSTRACT: The chicken retina is an accessible piece of intact gray matter in which a self-sustained form of the 'Spreading Depression' (SD) wave can be easily elicited and recorded for many hours with double barrel ion-sensitive electrodes in the extracellular space. The blockade of glial (Müller) cell potassium channels with barium chloride added to the perfusing Ringer depressed both the negative potential shift typical of SDs and the velocity of spread. Moreover, there was separation of the extracellular increase of potassium and the drop in the extracellular potential: the peak of the potassium wave was increased, as well as its duration whereas the potential wave could be depressed to zero or even inverted to positive. By contrast the transient extracellular calcium drop could not be separated from the extracellular potential wave but appeared related to it: no transient calcium drop was observed when the negative potential was completely depressed or inverted. Both, the amplitude of the extracellular potential and extracellular calcium activity appeared to be important factors controlling the velocity of spread.
Brain Research 07/1993; 614(1-2):45-51. · 2.73 Impact Factor
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ABSTRACT: Tissue levels of inorganic phosphate (iP-) and lactate (lac) increase during cerebral ischemia and cortical spreading depression (SD). Since cell membranes become leaky during these insults, iP- and lac were expected to leak into the extracellular space (ECS). In order to find out whether this occurs or does not, a microdialysis (MD) fiber was implanted into the cortex of anesthetized rats and extracellular lactate (lac(e)) and extracellular iP- (iPe-) were determined during various insults. Extracellular lactate increased to about the same extent during ischemia and SD. In contrast, iPe- increased during ischemia but not during SD. Instead, iPe- started to rise after SD and reached its maximum about 45 min later. The distinct pattern of iPe- in comparison to lac(e) during the above mentioned insults points to a qualitative difference of the underlying mechanisms: whereas lac appears within the ECS at any stressful situation, elevation of iP- within the ECS indicates depletion of energy stores in parallel to the lack of control of ion homeostasis.
Neuroscience Letters 08/1992; 141(2):269-72. · 2.11 Impact Factor
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ABSTRACT: pH sensitive microcelectrodes were used in combination with microdialysis (MD) technique to measure extracellular pH (pHe) and extracellular lactate (lace) within the cortex of rat brains during cortical spreading depression (SD). SD was induced by local K(+)-application and identified by DC recordings. It was accompanied by an extracellular acidification of 0.34 +/- 0.06 pH units and by a 2.8 +/- 0.80 fold increase of lace; the recovery of pHe took place within three phases, that of lace within 2 phases. The recovery of both parameters was complete about 45 min after the onset of SD. We conclude that the changes of lace and pHe are closely related. This indicates both lactate and protons to be transported in parallel.
Neuroscience Letters 02/1992; 135(1):83-6. · 2.11 Impact Factor
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ABSTRACT: In microdialysis experiments, 'recovery' estimations are required to calculate extracellular concentrations of the compounds determined. Generally, relative recovery (RR) is determined in vitro as: RR = cd/cs, with (cd) being the concentration of a compound in a dialysate fraction and (cs) its known concentration within a sample solution. To determine recoveryin vivo, relative loss (RL) was defined RL = (cp-cd)/cp with (cp-cd) being the loss of a compound from the perfusate and (cp) its perfusate concentration. RL was determined in vitro and in vivo by adding an 'internal reference compound' to the perfusate. Here, 14C-labelled lactate was used as the compound of interest. Comparing RL and RR in vitro, we found both to be similar. In vivo, however, RL was 34% of RL(in) vitro (CSF) and 46% of RL(in) vitro in agar-containing CSF. During ischaemia, RL of lactate even decreased to only 35% of the pre-ischaemic control level. We conclude that RL and RR represent inverse measurements of 'recovery.' Whereas RR can only be determined in vitro, RL can be determined in vivo. We found recoveryin vivo to be different from recoveryin vitro. Moreover, recoveryin vivo decreased during ischaemia. By means of the measured recoveryin vivo extracellular lactate concentrations prior and during ischaemia were calculated. The results, therefore, validate the 'internal reference technique' as a practical method for estimating recoveryin vivo and for controlling dialysis efficacy in vivo even continuously.
Journal of Neuroscience Methods 12/1991; 40(1):31-8. · 1.98 Impact Factor
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ABSTRACT: 1. The aim of this study was to examine the rapid changes in extracellular hydrogen ion activity [( H+]o or pHo) which are associated with depolarization and repolarization subsequent to cerebral ischemia reperfusion. Two parallel studies were performed with different rat models of ischemia: repetitive severe ischemia produced in anesthetized animals by occlusion of the vertebral and carotid arteries and temporary interruption of blood flow in isolated brain. [H+]o and direct current potential (DC potential) were recorded simultaneously in all experiments. Examination of these two parameters was supplemented by recording tissue concentration of carbon dioxide (PtCO2) in the four-vessel occlusion model and assaying major metabolites involved in energy production in experiments with isolated brains. 2. Measurements of [H+]o during ischemia consistently revealed a steady increase of [H+]o on which was superimposed an abrupt and transient fall in [H+]o closely related to the occurrence of the fast negative shift of DC potential characterizing brain-cell depolarization. Analysis of the relationship between the magnitude of the transient fall in H+ and the level of [H+]o at which this occurred showed that the amplitude of the transient fall in H+ increased with tissue acidosis. 3. We propose that this phenomenon is indirect evidence that rapid transfer of acid equivalents occurs across the plasmalemma, concomitantly to its depolarization. Both events probably result from a common cause, i.e., nonspecific increase of the cell-membrane permeability to ions subsequent to opening of membrane channels. 4. Early on during recirculation, an acidotic [H+]o shift associated with membrane repolarization was clearly visible whenever the ionic gradients recovered rapidly.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Neurophysiology 11/1990; 64(4):1125-33. · 3.32 Impact Factor
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ABSTRACT: The effects of complete ischemia on cerebral arachidonic acid (AA) metabolism were investigated in the isolated perfused rat brain. During 12.5 min of ischemia, AA, 5-hydroxy-6,8,11,14-eicosatetraenoic acid, and 15-hydroxy-5,8,11,13-eicosatetraenoic acid increased 129-, 4-, and 10-fold, respectively, while subsequent reperfusion for 30 min resulted in normalized levels independently of the duration of preceding ischemia. Prostaglandin (PG) F2 alpha, PGE2, PGD2, 6-keto-PGF1 alpha, and thromboxane (Tx) B2 remained at preischemic levels during 12.5 min of complete ischemia. However, at the end of subsequent reperfusion for 30 min, the levels of the prostanoids PGF2 alpha, PGE2, PGD2, 6-keto-PGF1 alpha, and TxB2 increased according to the preceding ischemic time. The levels reached a maximum after 7.5 min of ischemia and were elevated by 7-, 14-, 48-, 3-, and 30-fold, respectively. A prolongation of ischemia of up to 12.5 min was not associated with further increases of prostanoids at the end of reperfusion. The mechanisms underlying the metabolism of eicosanoids are discussed in relation to the changes of cortical direct current potential.
Journal of Cerebral Blood Flow & Metabolism 06/1990; 10(3):358-64. · 5.01 Impact Factor
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Acta physiologica Scandinavica. Supplementum 02/1989; 582:54.
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ABSTRACT: Isolated perfused rat brains were subjected to complete ischemia. Reperfusion was started 10 min after the negative DC-shift. In control brains, recovery of flow was retarded and, after 10 min of reperfusion, a delayed hypoperfusion developed. In flunarizine-treated brains, recovery of flow was considerably steeper, complete and without reduction during the further course of reperfusion. Additionally, restoration of energy metabolism and mitochondrial function was significantly improved. The effect on the energetic state of the brains was at least partly independent of the improvement of flow. This could be concluded from experiments in which reperfusion was commenced simultaneously with DC-negativation. In these experiments, flow recovery was prompt and complete in control as well as in treated brains. Nevertheless, treated brains exhibited after reperfusion significantly better ratios of ATP to ADP and normalized levels of lactate and succinate.
Biomedica biochimica acta 02/1989; 48(2-3):S161-5.
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ABSTRACT: The cerebral effects of subeluzole have been studied using the following methods: hypobaric hypoxia in mice, complete ischemia by decapitation in mice, anoxic hypoxia in mice, hemic hypoxia in rats, incomplete ischemia by bilateral carotid ligation in rats, anoxic hypoxia in rats and asphyxic hypoxia in cats. Sabeluzole was active in all the models used: it increased the survival time in hypobaric hypoxia (maximum at 40 mg/kg--by 92.0%, p less than 0.001), survival time in anoxic hypoxia in mice (maximum at 40 mg/kg--by 27.2%, p less than 0.001), gasping in decapitation model (maximum at 20 mg/kg--by 155.4%, p less than 0.001) and survival in hemic hypoxia (maximum at 2.5 mg/kg--by 21.1%, p less than 0.05). The duration of the effect as evaluated in the decapitation model was about 6 h. In incomplete ischemia in rats, however, it showed a weak effect. In anoxic hypoxia in rats, sabeluzole (5 mg/kg i.v.) increased the time latency between onset of anoxia and negative DC-shift by 20.5% and the K+e-threshold by 25.7%. In asphyxic hypoxia in cats, sabeluzole (0.5 mg/kg i.v.) counteracted the hypoxia-induced decrease of the fast-wave amplitudes during the cortical resistance period and the hypoxia-induced decrease of the slow-wave and increase of the fast wave amplitudes during the cortical recovery period.
Methods and Findings in Experimental and Clinical Pharmacology 13(6):385-90. · 0.93 Impact Factor
