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M Plotkine

Publications and source records attributed to M Plotkine.

At least 19 recordsLinked to original sources
PubMed1995

Striatal dopamine participates in glutamate-induced hydroxyl radical generation.

Using a microdialysis technique we showed that the exposure of the rat striatum to glutamate yields hydroxyl radicals and results in striatal damage. We postulated that dopamine release is enhanced by glutamate perfusion and that the enzymatic metabolism of dopamine may account for this hydroxyl radical formation. The inhibition of monoamine oxidases by i.p. co-administration of clorgy-line and deprenyl reduced hydroxyl radical production induced by glutamate perfusion, but significantly increased the striatal damage. Our results suggest that the enzymatic metabolism of dopamine participates in glutamate-induced hydroxyl radical generation but that other by-products of dopamine may be responsible for the aggravation of the striatal injury.

Animals↗
PubMed1995

Blockers of NMDA-operated channels decrease glutamate and aspartate extracellular accumulation in striatum during forebrain ischaemia in rats.

Brain microdialysis was used to study changes in the glutamate and aspartate extracellular concentrations in the striatum of conscious rats submitted to 30 minutes cerebral ischaemia, using the four-vessel occlusion model. Perfusion of the N-methyl-D-aspartate (NMDA) receptor channel blockers, dizocilpine (MK-801; 75 microM) and Mg2+ (2.5 mM), inhibited the ischaemia-induced accumulation of glutamate and aspartate. The AMPA/kainate receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamylbenzo (F) quinoxaline (NBQX; 15 microM and 450 microM) had no effect on glutamate and aspartate levels during ischaemia. On the other hand, omission of Ca2+ from the perfusing solution did not alter the increases in glutamate and aspartate induced by ischaemia. These results suggest that the glutamate and aspartate accumulation in four-vessel occlusion ischaemia is mediated by activation of NMDA receptors in a Ca2+ independent manner.

Animals↗
PubMed1994

L-NAME modulates glutamate accumulation induced by K(+)-depolarization but not by forebrain ischaemia in the rat striatum.

The accumulation of extracellular glutamate and aspartate in the striatum of rats during ischaemia was examined by perfusion with Ca(+)-free medium and treatment with the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Male Wistar rats were subjected to 30 min ischaemia using the 4-vessel occlusion model or high K(+)-depolarization. Extracellular glutamate and aspartate were monitored by in vivo microdialysis. Perfusion with Ca(2+)-free medium and systemic administration or local perfusion of L-NAME reduced the K(+)-evoked glutamate accumulation but not the ischaemia-induced glutamate accumulation. The aspartate concentration was unaffected in both conditions. Our data suggest that the extracellular glutamate and aspartate originates from a Ca(2+)-independent pool during forebrain ischaemia and is not modulated by nitric oxide. In high K(+)-depolarization the accumulated glutamate may arise, at least in part, from enhanced vesicular release and is modulated by nitric oxide.

Amino Acid Oxidoreductases↗
PubMed1992

Inhibition of glutamate release in rat hippocampus by kynurenic acid does not protect CA1 cells from forebrain ischemia.

We assessed the effect of a broad spectrum glutamatergic receptor antagonist, kynurenic acid (500 mg/kg) on ischemia-induced hippocampal glutamate release and neuronal damage. Kynurenic acid significantly decreased glutamate release during ischemia but had no effect on the hippocampal lesion. Some protection was observed in the cortex and in the striatum. These data suggested that the extracellular accumulation of glutamate during forebrain ischemia does not play a major role in the hippocampus.

Animals↗
PubMed1992

Concomitant increases in the extracellular concentrations of excitatory and inhibitory amino acids in the rat hippocampus during forebrain ischemia.

The extracellular concentrations of aspartate, glutamate, glutamine, taurine and gamma-aminobutyric acid in the hippocampus were determined during and after forebrain ischemia (4-vessel model) in the unanaesthetized rat. Ischemia led to a large increase in both inhibitory (taurine and gamma-aminobutyric acid) and excitatory amino acids (aspartate, glutamate). These results suggest that in this model, as previously proposed in other models of ischemia, the large increase of inhibitory amino acids could counterbalance the excitotoxicity due to aspartate and glutamate.

Amino Acids↗
PubMed1992

Striatal protection induced by lesioning the substantia nigra of rats subjected to focal ischemia.

Unilateral 6-hydroxydopamine lesion of the substantia nigra reduced the volume of striatal necrosis and suppressed the increase in extracellular glutamate concentration in the striatum induced by middle cerebral artery occlusion in rats. These results indicate that the dopaminergic nigrostriatal pathway is highly involved in the vulnerability of the striatum to ischemia and suggest that glutamate-dopamine interactions may play a key role in the striatal ischemic insult.

Animals↗
PubMed1992

The neuroprotective effect of a nitric oxide inhibitor in a rat model of focal cerebral ischaemia.

Recent data showed that glutamate toxicity in primary cortical cultures is mediated by nitric oxide. In order to investigate the effect of inhibition of NO synthase on focal cerebral ischaemia in rats, we studied the histological consequences of a middle cerebral artery (MCA) occlusion after post-operative treatment with NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. We found a significant reduction of cortical (-43%) and striatal (-25%) necrotic volumes induced by MCA occlusion, indicating that NO synthesis plays an important role in the neurotoxic cascade leading to neuronal damage after focal cerebral ischaemia in rats.

Amino Acid Oxidoreductases↗
PubMed1992

Neurological and behavioral outcomes of focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: The aim of this study was to investigate the neurobehavioral consequences of focal ischemia in rats. METHODS: We induced permanent occlusion of the left middle cerebral artery in 14 Sprague-Dawley rats, and used 13 sham-operated rats as controls. During surgery, brain temperature and body temperature were kept at normothermia. Neurobehavioral studies (neurological examination, passive avoidance task, Y maze test, and modified open-field test) were carried out 4 days after ischemia before killing the rats to evaluate histological damage. RESULTS: Ischemia induced large infarcts in the cortex (138.6 +/- 8.5 mm3) and caudate-putamen (48.8 +/- 2.6 mm3) and, compared with sham-operated rats, produced a dramatic neurological deficit (p less than 0.001) characterized by sensorimotor dysfunctions and hemiplegia. Memory retention was significantly (p less than 0.05) impaired in the passive avoidance task, but neither vigilance and exploratory behavior measured in the modified open-field test nor working memory evaluated in the Y maze test were disturbed. Infarct size was not correlated with the neurological or behavioral deficits. CONCLUSIONS: This lack of correlation indicates the necessity of carrying out parallel histological, neurological, and behavioral studies in any assays of new drugs using this model of focal ischemia.

Animals↗
PubMed1992

[Experimental antithrombotic activity of oral isosorbide dinitrate].

The activity of isosorbide dinitrate (ISDN) a nitrate derivative with platelet anti-aggregant properties, was studied on a model of arterial thrombosis by electric stimulation of the rat carotid arteries. In control animals, occlusive thrombosis occurred in 15.3 +/- 1.0 minutes. When administered orally in dosages of 1 to 30 mg/kg, 30 minutes before stimulation, ISDN prolonged the time to arterial occlusion by a factor of 2 to 3 times. This effect was significant from doses of 1 mg/kg. This anti-thrombotic activity was unchanged by pretreatment of 100 mg/kg I.V. of acetylsalicylic acid, a dose sufficient to inhibit prostacycline synthesis. On the other hand, its activity was completely blocked by the administration of an inhibitor of NO-synthetase, L-nitroarginine methylester (1 mg/kg I.V.). These results show that ISDN is active on a model of arterial thrombosis in the rat by a mechanism independent of prostacycline production but implying a stimulation of the formation of nitric oxide.

Administration, Oral↗
PubMed1991

Enhancement of endogenous excitatory amino acids by theophylline does not modify the behavioral and histological consequences of forebrain ischemia.

The neuroprotective role of endogenous adenosine during forebrain ischemia elicited by 4-vessel occlusion in rats was assessed using the adenosine antagonist, theophylline (32 mg/kg). Despite an increase in the release of glutamate in the hippocampus during ischemia, theophylline did not alter the neurological and histological outcomes. These results indicate that endogenous adenosine does not act as an endogenous neuroprotector by modulating glutamate release in this model.

Adenosine↗
PubMed1991

Nigrostriatal pathway modulates striatum vulnerability to quinolinic acid.

This study evaluates the modulation of striatum vulnerability to quinolinic acid (QA) by the nitrostriatal projection. Unilateral lesioning of the substantia nigra with 6-hydroxydopamine markedly reduced the volume of striatal necrosis observed 3 days after local injection of quinolinic acid (150 nmol). This result is consistent with the concept that the nigrostriatal pathway potentiates the vulnerability of striatum to excitotoxic damage.

Animals↗
PubMed1991

Oral administration of isosorbide dinitrate inhibits arterial thrombosis in rats.

The effect of isosorbide dinitrate, a nitrovasodilator known to inhibit platelet function, was examined in a model of electrically induced carotid artery thrombosis in rats. In the dose range of 1-30 mg/kg isosorbide dinitrate, administered orally, significantly delayed carotid occlusion. These results demonstrate that isosorbide dinitrate has antithrombotic activity and it is suggested that this antithrombotic activity is due to the generation of nitric oxide.

Administration, Oral↗
PubMed1990

Kynurenic acid antagonizes hippocampal quinolinic acid neurotoxicity: behavioral and histological evaluation.

In the present study, we evaluate the ability of kynurenic acid to protect hippocampal neurons from the neurotoxicity of the N-methyl-D-aspartate (NMDA) agonist quinolinic acid. Bilateral intrahippocampal injection of quinolinic acid (120 nmol) led to severe behavioral disturbances and total loss of hippocampal neurons. Intrahippocampal co-injection of kynurenic acid (360 nmol) completely prevented cell loss and behavioral disturbances. However, the protection was incomplete when kynurenic acid was intraperitoneally injected (500 mg/kg, repeated during 4 days). These above results indicate that kynurenic acid can antagonize the neuronal degeneration mediated by excessive stimulation of NMDA receptors in vivo.

Animals↗
PubMed1990

Effects of transient cerebral ischemia on the hippocampal dentate theta (theta) profile in the acute rat: a study 4-5 months following recirculation.

This study mainly describes the long-term effects of 20 min of cerebral ischemia on the profile of the presumed cholinergic theta rhythm in the rat dorsal hippocampal formation during ether anesthesia and injection of the muscarinic agonist agent arecoline. The experimental data were collected 4-5 months after ischemia. They show that ischemia results in a statistically significant reduction in both superficial and deep theta recorded from the CA1 area of the hippocampus and the dentate gyrus, respectively. Amplitude reduction is similar for both rhythms and co-varies positively with the extent of CA1 stratum pyramidale damage which, from light microscope observation, appeared to be the major neuroanatomical consequence of ischemic insult in the dorsal hippocampal formation. The medial septal nucleus-diagonal band of Broca complex involved in theta generation did not suffer visible anatomical damage. Moreover, no significant alteration in the spatial distribution and the density of hippocampal dentate acetylcholinesterase reaction product was seen in ischemic animals. These histological data were statistically confirmed by computerized image analysis. Finally, this is the first investigation to show that transient interruption of cerebral blood flow results in a long-lasting alteration of theta rhythm which is probably the major aspect of the basic activity of the hippocampal formation. Thus, the present findings obtained in the acute rat at 4-5 months postischemia confirm and extend, in most respects, our previous results collected in the chronic animal 2-29 days following 4-vessel occlusion. Possible significance of these findings for the hypothesis of the dependent generation sites of superficial and deep thetas in the hippocampus assumed to be crucial in learning and memory, is discussed.

Acetylcholinesterase↗
PubMed1990

Effect on cerebral blood flow of orally administered indomethacin-loaded poly(isobutylcyanoacrylate) and poly(DL-lactide) nanocapsules.

Nanocapsules, containing indomethacin, were prepared either by interfacial polymerization of isobutylcyanoacrylate monomers or by interfacial deposition of a performed (DL-lactide) polymer. In-vitro release of indomethacin from nanocapsules was dependent on the pH of the sink solution and was enhanced by addition of albumin. A decrease in cerebral blood flow was noted 15 min after oral administration to rats of indomethacin nanocapsules (5 mg kg-1) and lasted over 3 h. Empty nanocapsules had no effect. Since release of indomethacin from nanocapsules is unlikely to occur in the lumen of the stomach, due to unsuitable pH conditions, and nanocapsules have been previously shown to be able to cross the intestinal barrier, to reach the villi vessels intact and to protect against the ulcerating effect of the free drug, it is suggested that the rapid onset of the pharmacological effect was sufficiently induced by free indomethacin released in the plasma following absorption of the intact nanocapsules.

Administration, Oral↗
PubMed1988

Investigations on the role of arachidonic acid metabolism pathways in the antithrombotic activity of nafazatrom and molsidomine.

The activity of nafazatrom and molsidomine, two antithrombotic drugs claimed to increase prostacycline level, was investigated in an electrically-induced carotid thrombosis model in the conscious rat. Both nafazatrom (5 mg/kg, i.v.) and molsidomine significantly delayed thrombus formation, an activity that was shared by prostacyclin (100 ng/kg/min, i.v.). Acetylsalicylic acid, at a dosage devoided of antithrombotic activity (100 mg/kg, i.v.) abolished the effect of nafazatrom but not of molsidomine. These results indicate that a cyclooxygenase-dependent compound (prostacyclin ?) play a major role in the antithrombotic effect of nafazatrom but not of molsidomine. Moreover, since compounds inhibiting the lipoxygenase pathway, i.e., BW755c (10 and 25 mg/kg, i.v.) and nordihydroguaiaretic acid (10 and 25 mg/kg, i.v.) were unable to show any antithrombotic effect, the activity of molsidomine can unlikely be due to its lipoxygenase inhibitory property.

Animals↗