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Robert Schwarcz - One of the best experts on this subject based on the ideXlab platform.
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ultrastructure and immunocytochemical distribution of gaba in layer iii of the rat medial entorhinal cortex following Aminooxyacetic Acid induced seizures
Experimental Brain Research, 1999Co-Authors: Robert Schwarcz, Ole Petter OttersenAbstract:Layer III of the entorhinal cortex (EC) is lesioned in patients with temporal lobe epilepsy (TLE). A similar neuropathology is also present in different animal models of TLE. For example, injection of the ”indirect” excitotoxin Aminooxyacetic Acid (AOAA) into the EC of rats causes behavioral seizures and preferential loss of neurons in layer III of the medial EC. The animals also develop hyperexcitability of the EC and the hippocampal region CA1. To further explore the neuropathological changes within the EC, the ultrastructure and distribution of GABA-like immunoreactivity were assessed in layer III, 28 days after an intraentorhinal AOAA injection. At this time point, light microscopic preparations revealed that a large proportion of pyramidal (putative excitatory) neurons in layer III of the medial EC had degenerated, whereas GABA-immunoreactive neurons had survived. In immunogold-labeled ultrathin sections, the lesioned neuropil was found to contain morphologically intact GABA-containing neurons and nerve terminals. Pathologically swollen dendrites and electron-dense neuronal profiles were present in the lesioned sector as well. The majority of the electron-dense profiles was identified as degenerating dendritic spines that were closely apposed to strongly glutamate-immunopositive axon terminals. Thus, the entorhinal chemoarchitecture is dramatically altered following an episode of AOAA-induced epileptic seizures. One possible consequence of this pathology is a reduced ”drive” of the surviving layer III GABA neurons, which in turn may cause hyperexcitability of the EC and the hippocampus. These findings may be of relevance for the genesis and spread of temporal lobe seizures.
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Aminooxyacetic Acid causes selective neuronal loss in layer iii of the rat medial entorhinal cortex
Neuroscience Letters, 1992Co-Authors: Fu Du, Robert SchwarczAbstract:Abstract Aminooxyacetic Acid (AOAA) was used to produce a selective lesion in the rat entorhinal cortex (EC). As assessed 7 days following the injection of AOAA ( 75 μ g 0.75 μ l ) into the EC, neuronal loss in layer III of the medial EC, particularly in its ventral portion, was consistently observed in Nissl-stained horizontal sections. This selective neurodegeneration was seen even when AOAA was injected laterally or in deeper layers. Behavioral seizures occurred between 2 and 4 h after the AOAA injection. AOAA-induced EC lesions may provide experimental models for the study of human diseases in which the EC, particularly layer III neurons, is involved.
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focal injection of Aminooxyacetic Acid produces seizures and lesions in rat hippocampus evidence for mediation by nmda receptors
Experimental Neurology, 1991Co-Authors: Owen G Mcmaster, Fu Du, Edward D French, Robert SchwarczAbstract:Abstract Aminooxyacetic Acid (AOAA), a potent yet nonspecific transaminase inhibitor, is known to cause convulsions when administered at high doses to experimental animals. The present study was designed to explore the mechanism(s) underlying the epileptogenic properties of AOAA. To this end, the drug was injected into the hippocampus of unanesthetized rats. Injection of 1.8 to 450 nmol AOAA produced dose-dependent EEG abnormalities including, at the higher doses, limbic seizures. Coadministration of the selective NMDA receptor antagonist d -2-amino-7-phosphonoheptanoic Acid (APH) at doses of 45 and 225 nmol caused an almost complete inhibition of seizures produced by 225 nmol AOAA. At 225 and 450 nmol, AOAA also caused selective neuronal damage, which was restricted to the CA1 region at the lower dose and also affected the CA 3 CA 4 area in two of six rats injected with the higher dose. Co-injection of 225 nmol APH completely protected the hippocampus from AOAA-induced damage. In separate experiments, microiontophoretic application of AOAA to CA1 pyramidal neurons failed to increase the firing rate of each of the 10 cells tested, thus indicating that the drug does not directly activate NMDA receptors. These experiments suggest that seizures and neurotoxicity produced by AOAA are mediated indirectly via NMDA receptor activation.
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determination of extracellular kynurenic Acid in the striatum of unanesthetized rats effect of Aminooxyacetic Acid
Neuroscience Letters, 1990Co-Authors: Carmela Speciale, Waldemar A Turski, Huiqiu Wu, Jan Bert P Gramsbergen, Urban Ungerstedt, Robert SchwarczAbstract:Abstract Kynurenic Acid (KYNA) production from its bioprecursor l -kynurenine (KYN) was assessed in vivo by intrastriatal microdialysis in freely moving rats. In the absence of KYN, the extracellular concentration of KYNA was below the limit of assay sensitivity (i.e. μ l). In the presence of KYN (50–2000 μM), KYNA concentration in the dialysate increased continuously to reach steady-state levels after 2 h of perfusion. Introduction of the unspecific transaminase inhibitor Aminooxyacetic Acid (AOAA) through the dialysis probe caused a progressive decrease of extracellular KYNA, which reached dose-dependent minimal levels within 2 h. One mM AOAA caused an almost complete depletion of KYNA in the dialysate. These data demonstrate that extracellular KYNA can be assessed by microdialysis and that AOAA can be used as a tool to examine the neurobiology of KYNA in awake, freely moving animals.
Waldemar A Turski - One of the best experts on this subject based on the ideXlab platform.
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quinolinate like neurotoxicity produced by Aminooxyacetic Acid in rat striatum
Amino Acids, 1992Co-Authors: Waldemar A Turski, Ewa M Urbanska, M Sieklucka, Chrysanthy IkonomidouAbstract:The endogenous tryptophan metabolite quinolinic Acid elicits in rodent brain a pattern of neuronal degeneration which resembles that caused by L-glutamate. Its qualities as a neurotoxic agent raised the hypothesis that quinolinic Acid might be involved in the pathogenesis of human neurodegenerative disorders. Kynurenic Acid, another endogenous tryptophan metabolite and preferential N-methyl-D-aspartate (NMDA) antagonist, has been shown to block quinolinic Acid neurotoxicity. Here we report that microinjections of Aminooxyacetic Acid (AOAA), an inhibitor of kynurenine transaminase and of other pyridoxal phosphate-dependent enzymes, into the rat striatum produce neuronal damage resembling that caused by quinolinic Acid. AOAA-induced striatal lesions can be prevented by kynurenic Acid and the selective NMDA antagonist 2-amino-7-phosphonoheptanoic Acid. These results suggest that AOAA produces excitotoxic lesions by depleting brain concentrations of kynurenic Acid (inhibition of synthetic enzyme) or due to impairment of intracellular energy metabolism (depletion of cell energy resources). The concept of deficient neuroprotection due to metabolic defects might help to clarify the pathogenesis of human neurodegenerative disorders and to develop strategies that may be useful in their treatment.
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age dependency of the susceptibility of rats to Aminooxyacetic Acid seizures
Developmental Brain Research, 1992Co-Authors: Waldemar A Turski, Marek Dziki, Jolanta Parada, Z Kleinrok, Esper A CavalheiroAbstract:Abstract Immature rats are more susceptible to clonic seizures induced by Aminooxyacetic Acid (AOAA) than mature and senile rats. Highest susceptibility to AOAA seizures was observed in 7–14-day-old rat pups. The lowest susceptibility was recorded in 10–20 month-old rats. AOAA seizures in 14-day-old rats were blocked by clonazepam and valproate, but not by phenobarbital, carbamazepine, diphenylhydantoin, trimethadione or ethosuximide. Morphological analysis of brains from 14-day- and 3-month-old rats which experienced AOAA seizures did not reveal epilepsy-related damage. These observations suggest that immature rat brain is highly prone to convulsions induced by AOAA and that such convulsions are difficult to control by available antiepileptic treatment.
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Aminooxyacetic Acid produces excitotoxic lesions in the rat striatum
Synapse, 1991Co-Authors: Ewa M Urbanska, M Sieklucka, Chrysanthy Ikonomidou, Waldemar A TurskiAbstract:The neuropathological, biochemical, and behavioral effects of intrastriatal injection of Aminooxyacetic Acid (AOAA), a non-specific transaminase inhibitor, were examined in rats. AOAA, 0.1–1 μmol, produced neuronal damage when injected into the striatum of adult rats but failed to damage the striatum of 6-d-old or decorticated rats. AOAA-induced (0.25 μmol-1 μmol) striatal lesions in adult rats displayed excitotoxic characteristics and could be prevented by the N-methyl-D-aspartate (NMDA) receptor antagonists (–)-2-amino-7-phosphono-heptanoate (AP7; 0.25 μmol) or kynurenate (KYNA; 0.5 μmol), but not by the non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX; 0.25 μmol). AOAA produced a dose-dependent reduction in striatal L-glutamate decarboxylase activity, as measured 14 d following intrastriatal injection, which could also be prevented by AP7 or KYNA, but not by NBQX. These findings suggest that AOAA-induced lesions are preferentially mediated by activation of the NMDA subtype of excitatory amino Acid receptors. Behavioral studies revealed that the cataleptic response to haloperidol, 2 mg/kg, was decreased whereas the cataleptic response to arecoline, 15 mg/kg, and morphine, 15 mg/kg, was potentiated in AOAA lesioned animals 14 d following bilateral intrastriatal injections of AOAA, 0.25 and 1 μmol. In rats which received unilateral intrastriatal injection of AOAA, 0.1–1 μmol, apomorphine, 0.5 mg/kg, induced circling towards the lesioned side. Rats which received AP7, 0.25 μmol, or KYNA, 0.5 μmol, coadministered with AOAA, 0.25 μmol, behaved as vehicle-treated controls, while those which received NBQX, 0.25 μmol, and AOAA, 0.25 μmol, had behavioral patterns similar to those subjected to AOAA alone. γ-Vinyl-GABA (4-amino-5-hexenoate; 1 μmol), an inhibitor of the γ-aminobutyrate (GABA) transaminase, and 3-mercaptoproprionate (1 μmol), a preferential inhibitor of L-aspartate transaminase, caused no damage when injected into the striatum of adult rats. Therefore we propose that inhibition of endogenous KYNA synthesis might be responsible for the neurotoxic properties of AOAA. Our findings are consistent with the hypothesis on the existence of a sensitive balance between endogenous excitotoxins and endogenous antagonists in the adult rat brain and suggest that blockede of the synthesis of the latter may result in excitotoxic cell death.
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seizures induced by Aminooxyacetic Acid in mice pharmacolgical characteristics
Synapse, 1991Co-Authors: Waldemar A Turski, Marek Dziki, Ewa M Urbanska, Lineu S Calderazzofilho, Esper A CavalheiroAbstract:: Systemic (s.c.) administration of Aminooxyacetic Acid (AOAA) in mice triggered clonic convulsions with a CD50 (convulsive dose) of 68 mg/kg (range 54-86). AOAA also induced clonic convulsions in mice subjected to intracerebroventricular administration of the drug with a CD50 of 0.04 mumols (range 0.028-0.06). At the onset of convulsions induced by systemic AOAA (CD97;150 mg/kg), the GAD activity in the frontal cortex and hippocampus was not affected. GABA mimetic drugs, progabide and gabaculine, had no effect on convulsions induced by AOAA. Convulsions induced by systemic administration of AOAA were blocked by diazepam, phenobarbital, and valproate. Ethosuximide, trimethadione, acetazolamide, diphenylhydantoin, and carbamazepine remained ineffective. L-Phenylisopropyladenosine was also found to protect mice against AOAA-induced convulsions, whereas atropine and baclofen had no effect. The seizures induced by intracerebroventricular administration of AOAA (CD97; 0.1 mumols) were blocked by coadministration of preferential N-methyl-D-aspartate antagonists, D-(-)-2-aminophosphonoheptanoic (AP7), 3-[+/-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic (CPP), and kynurenic Acid (KYNA); preferential quisqualate/kainate antagonists, 6-cyano-7-nitro-quinoxaline-2,3-dione and gamma-D-glutamylaminomethylsulphonic Acid, remained inactive in the range of dosages sufficient to block seizures induced by quisqualic Acid or kainic Acid. The antagonistic action of antiepileptic drugs effective against seizures induced by excitatory amino Acids (diazepam and valproate), and drugs acting on excitatory amino Acid receptors (AP7, CPP, and KYNA) upon seizures induced by AOAA suggests an involvement of excitatory neurotransmission in the convulsant action of the drug.
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determination of extracellular kynurenic Acid in the striatum of unanesthetized rats effect of Aminooxyacetic Acid
Neuroscience Letters, 1990Co-Authors: Carmela Speciale, Waldemar A Turski, Huiqiu Wu, Jan Bert P Gramsbergen, Urban Ungerstedt, Robert SchwarczAbstract:Abstract Kynurenic Acid (KYNA) production from its bioprecursor l -kynurenine (KYN) was assessed in vivo by intrastriatal microdialysis in freely moving rats. In the absence of KYN, the extracellular concentration of KYNA was below the limit of assay sensitivity (i.e. μ l). In the presence of KYN (50–2000 μM), KYNA concentration in the dialysate increased continuously to reach steady-state levels after 2 h of perfusion. Introduction of the unspecific transaminase inhibitor Aminooxyacetic Acid (AOAA) through the dialysis probe caused a progressive decrease of extracellular KYNA, which reached dose-dependent minimal levels within 2 h. One mM AOAA caused an almost complete depletion of KYNA in the dialysate. These data demonstrate that extracellular KYNA can be assessed by microdialysis and that AOAA can be used as a tool to examine the neurobiology of KYNA in awake, freely moving animals.
H E Scharfman - One of the best experts on this subject based on the ideXlab platform.
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hyperexcitability of entorhinal cortex and hippocampus after application of Aminooxyacetic Acid aoaa to layer iii of the rat medial entorhinal cortex in vitro
Journal of Neurophysiology, 1996Co-Authors: H E ScharfmanAbstract:1. Injection of Aminooxyacetic Acid (AOAA) into the entorhinal cortex in vivo produces acute seizures and cell loss in medial entorhinal cortex. To understand these effects, AOAA was applied direct...
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hyperexcitability of entorhinal cortex and hippocampus after application of Aminooxyacetic Acid aoaa to layer iii of the rat medial entorhinal cortex in vitro
Journal of Neurophysiology, 1996Co-Authors: H E ScharfmanAbstract:1. Injection of Aminooxyacetic Acid (AOAA) into the entorhinal cortex in vivo produces acute seizures and cell loss in medial entorhinal cortex. To understand these effects, AOAA was applied directly to the medial entorhinal cortex in slices containing both the entorhinal cortex and hippocampus. Extracellular and intracellular recordings were made in both the entorhinal cortex and hippocampus to study responses to angular bundle stimulation and spontaneous activity. 2. AOAA was applied focally by leak from a micropipette or by pressure ejection. Evoked potentials increased gradually within 5 min of application, particularly the late, negative components. Evoked potentials continued to increase for up to 1 h, and these changes persisted for the remainder of the experiment (up to 5 h after drug application). 3. Paired pulse facilitation (100-ms interval) was also enhanced after AOAA application. Increasing stimulus frequency to 1-10 Hz increased evoked potentials further, and after several seconds of such s...
Esper A Cavalheiro - One of the best experts on this subject based on the ideXlab platform.
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age dependency of the susceptibility of rats to Aminooxyacetic Acid seizures
Developmental Brain Research, 1992Co-Authors: Waldemar A Turski, Marek Dziki, Jolanta Parada, Z Kleinrok, Esper A CavalheiroAbstract:Abstract Immature rats are more susceptible to clonic seizures induced by Aminooxyacetic Acid (AOAA) than mature and senile rats. Highest susceptibility to AOAA seizures was observed in 7–14-day-old rat pups. The lowest susceptibility was recorded in 10–20 month-old rats. AOAA seizures in 14-day-old rats were blocked by clonazepam and valproate, but not by phenobarbital, carbamazepine, diphenylhydantoin, trimethadione or ethosuximide. Morphological analysis of brains from 14-day- and 3-month-old rats which experienced AOAA seizures did not reveal epilepsy-related damage. These observations suggest that immature rat brain is highly prone to convulsions induced by AOAA and that such convulsions are difficult to control by available antiepileptic treatment.
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seizures induced by Aminooxyacetic Acid in mice pharmacolgical characteristics
Synapse, 1991Co-Authors: Waldemar A Turski, Marek Dziki, Ewa M Urbanska, Lineu S Calderazzofilho, Esper A CavalheiroAbstract:: Systemic (s.c.) administration of Aminooxyacetic Acid (AOAA) in mice triggered clonic convulsions with a CD50 (convulsive dose) of 68 mg/kg (range 54-86). AOAA also induced clonic convulsions in mice subjected to intracerebroventricular administration of the drug with a CD50 of 0.04 mumols (range 0.028-0.06). At the onset of convulsions induced by systemic AOAA (CD97;150 mg/kg), the GAD activity in the frontal cortex and hippocampus was not affected. GABA mimetic drugs, progabide and gabaculine, had no effect on convulsions induced by AOAA. Convulsions induced by systemic administration of AOAA were blocked by diazepam, phenobarbital, and valproate. Ethosuximide, trimethadione, acetazolamide, diphenylhydantoin, and carbamazepine remained ineffective. L-Phenylisopropyladenosine was also found to protect mice against AOAA-induced convulsions, whereas atropine and baclofen had no effect. The seizures induced by intracerebroventricular administration of AOAA (CD97; 0.1 mumols) were blocked by coadministration of preferential N-methyl-D-aspartate antagonists, D-(-)-2-aminophosphonoheptanoic (AP7), 3-[+/-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic (CPP), and kynurenic Acid (KYNA); preferential quisqualate/kainate antagonists, 6-cyano-7-nitro-quinoxaline-2,3-dione and gamma-D-glutamylaminomethylsulphonic Acid, remained inactive in the range of dosages sufficient to block seizures induced by quisqualic Acid or kainic Acid. The antagonistic action of antiepileptic drugs effective against seizures induced by excitatory amino Acids (diazepam and valproate), and drugs acting on excitatory amino Acid receptors (AP7, CPP, and KYNA) upon seizures induced by AOAA suggests an involvement of excitatory neurotransmission in the convulsant action of the drug.
Ewa M Urbanska - One of the best experts on this subject based on the ideXlab platform.
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quinolinate like neurotoxicity produced by Aminooxyacetic Acid in rat striatum
Amino Acids, 1992Co-Authors: Waldemar A Turski, Ewa M Urbanska, M Sieklucka, Chrysanthy IkonomidouAbstract:The endogenous tryptophan metabolite quinolinic Acid elicits in rodent brain a pattern of neuronal degeneration which resembles that caused by L-glutamate. Its qualities as a neurotoxic agent raised the hypothesis that quinolinic Acid might be involved in the pathogenesis of human neurodegenerative disorders. Kynurenic Acid, another endogenous tryptophan metabolite and preferential N-methyl-D-aspartate (NMDA) antagonist, has been shown to block quinolinic Acid neurotoxicity. Here we report that microinjections of Aminooxyacetic Acid (AOAA), an inhibitor of kynurenine transaminase and of other pyridoxal phosphate-dependent enzymes, into the rat striatum produce neuronal damage resembling that caused by quinolinic Acid. AOAA-induced striatal lesions can be prevented by kynurenic Acid and the selective NMDA antagonist 2-amino-7-phosphonoheptanoic Acid. These results suggest that AOAA produces excitotoxic lesions by depleting brain concentrations of kynurenic Acid (inhibition of synthetic enzyme) or due to impairment of intracellular energy metabolism (depletion of cell energy resources). The concept of deficient neuroprotection due to metabolic defects might help to clarify the pathogenesis of human neurodegenerative disorders and to develop strategies that may be useful in their treatment.
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Aminooxyacetic Acid produces excitotoxic lesions in the rat striatum
Synapse, 1991Co-Authors: Ewa M Urbanska, M Sieklucka, Chrysanthy Ikonomidou, Waldemar A TurskiAbstract:The neuropathological, biochemical, and behavioral effects of intrastriatal injection of Aminooxyacetic Acid (AOAA), a non-specific transaminase inhibitor, were examined in rats. AOAA, 0.1–1 μmol, produced neuronal damage when injected into the striatum of adult rats but failed to damage the striatum of 6-d-old or decorticated rats. AOAA-induced (0.25 μmol-1 μmol) striatal lesions in adult rats displayed excitotoxic characteristics and could be prevented by the N-methyl-D-aspartate (NMDA) receptor antagonists (–)-2-amino-7-phosphono-heptanoate (AP7; 0.25 μmol) or kynurenate (KYNA; 0.5 μmol), but not by the non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX; 0.25 μmol). AOAA produced a dose-dependent reduction in striatal L-glutamate decarboxylase activity, as measured 14 d following intrastriatal injection, which could also be prevented by AP7 or KYNA, but not by NBQX. These findings suggest that AOAA-induced lesions are preferentially mediated by activation of the NMDA subtype of excitatory amino Acid receptors. Behavioral studies revealed that the cataleptic response to haloperidol, 2 mg/kg, was decreased whereas the cataleptic response to arecoline, 15 mg/kg, and morphine, 15 mg/kg, was potentiated in AOAA lesioned animals 14 d following bilateral intrastriatal injections of AOAA, 0.25 and 1 μmol. In rats which received unilateral intrastriatal injection of AOAA, 0.1–1 μmol, apomorphine, 0.5 mg/kg, induced circling towards the lesioned side. Rats which received AP7, 0.25 μmol, or KYNA, 0.5 μmol, coadministered with AOAA, 0.25 μmol, behaved as vehicle-treated controls, while those which received NBQX, 0.25 μmol, and AOAA, 0.25 μmol, had behavioral patterns similar to those subjected to AOAA alone. γ-Vinyl-GABA (4-amino-5-hexenoate; 1 μmol), an inhibitor of the γ-aminobutyrate (GABA) transaminase, and 3-mercaptoproprionate (1 μmol), a preferential inhibitor of L-aspartate transaminase, caused no damage when injected into the striatum of adult rats. Therefore we propose that inhibition of endogenous KYNA synthesis might be responsible for the neurotoxic properties of AOAA. Our findings are consistent with the hypothesis on the existence of a sensitive balance between endogenous excitotoxins and endogenous antagonists in the adult rat brain and suggest that blockede of the synthesis of the latter may result in excitotoxic cell death.
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seizures induced by Aminooxyacetic Acid in mice pharmacolgical characteristics
Synapse, 1991Co-Authors: Waldemar A Turski, Marek Dziki, Ewa M Urbanska, Lineu S Calderazzofilho, Esper A CavalheiroAbstract:: Systemic (s.c.) administration of Aminooxyacetic Acid (AOAA) in mice triggered clonic convulsions with a CD50 (convulsive dose) of 68 mg/kg (range 54-86). AOAA also induced clonic convulsions in mice subjected to intracerebroventricular administration of the drug with a CD50 of 0.04 mumols (range 0.028-0.06). At the onset of convulsions induced by systemic AOAA (CD97;150 mg/kg), the GAD activity in the frontal cortex and hippocampus was not affected. GABA mimetic drugs, progabide and gabaculine, had no effect on convulsions induced by AOAA. Convulsions induced by systemic administration of AOAA were blocked by diazepam, phenobarbital, and valproate. Ethosuximide, trimethadione, acetazolamide, diphenylhydantoin, and carbamazepine remained ineffective. L-Phenylisopropyladenosine was also found to protect mice against AOAA-induced convulsions, whereas atropine and baclofen had no effect. The seizures induced by intracerebroventricular administration of AOAA (CD97; 0.1 mumols) were blocked by coadministration of preferential N-methyl-D-aspartate antagonists, D-(-)-2-aminophosphonoheptanoic (AP7), 3-[+/-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic (CPP), and kynurenic Acid (KYNA); preferential quisqualate/kainate antagonists, 6-cyano-7-nitro-quinoxaline-2,3-dione and gamma-D-glutamylaminomethylsulphonic Acid, remained inactive in the range of dosages sufficient to block seizures induced by quisqualic Acid or kainic Acid. The antagonistic action of antiepileptic drugs effective against seizures induced by excitatory amino Acids (diazepam and valproate), and drugs acting on excitatory amino Acid receptors (AP7, CPP, and KYNA) upon seizures induced by AOAA suggests an involvement of excitatory neurotransmission in the convulsant action of the drug.