Peroxisomes and peroxisomal functions in hyperpipecolic acidaemia.
Explore the source record for details and available documents.
Acyltransferases↗
SEARCH · Search PubMed
Results for “Pipecolic Acids”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Caudal anaesthesia with bupivacaine (Marcaine) for anal surgery: a clinical trial.
Explore the source record for details and available documents.
Adolescent↗
Can the "state-dependency" hypothesis explain prevention of amphetamine sensitization in rats by NMDA receptor antagonists?
Many laboratories have reported that coadministration of N-methyl-D-aspartate (NMDA) receptor antagonists with psychomotor stimulants prevents the development of behavioral sensitization and therefore concluded that NMDA receptor transmission is necessary for sensitization. According to an alternative "state-dependency" interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response, i.e., it is only elicited in response to combined administration of the NMDA receptor antagonist and the stimulant. This hypothesis is supported by progressive augmentation of the locomotor response to the drug combination during the induction phase, and expression of sensitization when challenged with the combination but not the stimulant alone. To test this hypothesis, rats were treated during a 6-day induction phase with amphetamine (Amph) alone or in combination with the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg) or the non-competitive NMDA receptor antagonist MK-801 (0.05, 0.1 and 0.25 mg/kg). When CGS 19755 was coadministered with Amph, there was no progressive augmentation of response to the drug combination. When challenged with Amph alone, rats did not exhibit the biphasic pattern of locomotor activity characteristic of Amph sensitization. No sensitization of stereotyped behaviors was evident, although the ambulatory response was greater than that exhibited by naive rats. Results with MK-801 were complex, but progressive augmentation of response to the drug combination appeared to in part reflect sensitization to MK-801 and could be dissociated from the ability of MK-801 to prevent the development of sensitization as assessed by response to challenge with Amph alone. Many of these findings are inconsistent with predictions of the "state-dependency" hypothesis. Moreover, the ability of NMDA receptor antagonists to prevent biochemical and electrophysiological correlates of sensitization is difficult to reconcile with the idea that sensitization develops in the presence of NMDA receptor blockade but cannot be expressed. Together, these findings suggest that the ability of NMDA receptor antagonists to prevent Amph sensitization reflects a requirement for NMDA receptor transmission during its induction.
Amphetamine↗
Selective activation of synapses near the tip of drug-ejecting microelectrode, and effects of antagonists of excitatory amino acids in the hippocampus.
A technique was developed to selectively facilitate transmission through synapses near the tip of a drug-ejecting micropipette by increasing Ca2+ concentration in a small space surrounding the tip. By means of this technique, we found that antagonists of excitatory amino acids, cis-2,3-piperidine dicarboxylic acid, gamma-D-glutamylglycine and glutamic acid diethylester, blocked excitation induced in CA3 neurons by glutamate and by mossy fiber stimulation in thin hippocampal sections of the guinea pig.
Amino Acids↗
NMDA-but not AMPA-receptor antagonists augment scopolamine-induced spatial cognitive deficit of rats in a radial maze task.
The effect of NMDA and AMPA receptor antagonists on a scopolamine-induced spatial cognitive deficit was investigated in rats using an 8-arm radial maze. The NMDA antagonists, MK801 and CGS19755, robustly augmented scopolamine-induced deficits but had no effect on spatial cognition when administered alone. In contrast, augmentation of the scopolamine-induced deficits was not observed when the selective AMPA antagonist, YM90K, was administered with scopolamine. These results suggest that the NMDA but not AMPA subtypes of the ionotropic glutamate receptors play important roles in regulation of the central cholinergic function related to the spatial learning and memory processes.
Animals↗
Identification of kainic and quisqualic acid receptors on inner retinal cells of the salamander Ambystoma mexicanum.
The presence of kainic (KA) and quisqualic acid (QA) receptors on inner retinal neurones of the axolotl Ambystoma mexicanum has been studied using intracellular recording techniques. In the presence of CoCl2, which blocks neurotransmitter release, KA and QA depolarized the membrane. The minimum concentration of KA that induced a response was 1 microM and a maximum response was obtained with 10 microM (EC50: 3 microM). The operating range of QA was between 0.5 and 5 microM with an EC50 of 1 microM. These data show that inner retinal cells of the axolotl are sensitive to KA and QA. Cis-2,3-piperidine dicarboxylic acid (PDA, 3 mM) completely blocked responses to 5 microM KA, but not those induced by 2 microM QA. This suggests that the KA- and QA-sensitive receptors on inner retinal cells of the salamander are pharmacologically different and that PDA can be a valuable tool in distinguishing KA- and QA-sensitive receptors on these neurones.
Ambystoma↗
The mutagenicity of N-nitrosopiperidines for Salmonella typhimurium.
Explore the source record for details and available documents.
DNA Repair↗
Protection by MK-801 against hypoxia-, excitotoxin-, and depolarization-induced neuronal damage in vitro.
Exposure of rat hippocampal slices to 12-min hypoxia produced only mild neuronal damage, as 72% of all slices recovered their CA1-evoked population spike following a 30-min recovery period. However, when this hypoxic insult was administered in the presence of 2.5 microM kainate or AMPA, only 6 and 15% of the slices, respectively, recovered their neuronal function. This enhancement of hypoxic damage by kainate could be attenuated in a dose-dependent fashion by the kainate/AMPA antagonist GYKI 52466 but not by the competitive NMDA antagonist APV. Unexpectedly, the noncompetitive NMDA antagonist MK-801 also attenuated the kainate- and AMPA-enhanced hypoxic neuronal damage and was more efficacious than GYKI 52466. Considering (1) the ability of MK-801 to antagonize hypoxic neuronal damage in the absence or the presence of NMDA, kainate or AMPA; (2) the antihypoxic effect of MK-801 in the presence of APV + 7-chlorokynurenate, a pairing that supposedly blocks MK-801 binding to the NMDA receptor; (3) the ability of MK-801 to protect hippocampal slices against brain damage induced by depolarization + excitotoxin (50 mM KCl + mM glutamate for 60 min); and (4) the ability of diltiazem, an L-type calcium channel blocker, to protect hippocampal slices against hypoxic neuronal damage, we conclude that the mode of action of MK-801 cannot be explained by its NMDA receptor antagonistic properties alone. A possible blockade of Ca2+ channels, most likely of the L-type, by MK-801 should be considered along with other mechanisms.
2-Amino-5-phosphonovalerate↗
Effects of aging and chronic nimodipine on hippocampal binding of [3H]CGS 19755.
Previous studies have suggested that aging is associated with impaired behavioral performance and with decrements of N-methyl-D-aspartate (NMDA) receptors in the rat hippo-campus. Other studies have indicated that chronic treatment with nimodipine, a Ca2+ channel antagonist, prevents the age-related decline in performance by rats in behavioral tasks. Therefore, we tested whether nimodipine altered binding of [3H]CGS 19755 to hippocampal NMDA receptors in rats whose performance on a 14-unit T maze had been tested previously (14). No significant age difference was observed in [3H]CGS 19755 binding in hippocampi from old Fischer-344 rats (27 months) as compared with mature but not senescent rats (9 months); however, old rats that received chronic treatment with a low dose of nimodipine (20 mg pellets implanted subcutaneously twice during 70 days of treatment) showed higher levels of binding. A high dose of nimodipine (40 mg pellets implanted by the same route and at the same times as the low dose) was without effect on [3H]CGS 19755 binding, although aged rats given this treatment performed better in the maze than rats that received no nimodipine or the low dose. In a second experiment comparing hippocampi of young (4 months) and old (24 months) rats, saturation studies confirmed the lack of an age difference in [3H]CGS 19755 binding. The findings suggest that neither the age-related decline in maze performance nor the enhancement of behavior by nimodipine depend upon changes in hippocampal NMDA receptors.
Aging↗
Pretreatment with NMDA antagonists limits release of excitatory amino acids following traumatic brain injury.
After central nervous system (CNS) trauma, there are marked elevations in the extracellular levels of excitatory amino acids (EAA), which are believed to contribute to delayed tissue damage. Administration of N-methyl-D-aspartate (NMDA) receptor antagonists reduces injury severity after brain or spinal cord trauma, presumably by blocking the postsynaptic NMDA receptor. In the present studies, levels of extracellular amino acids were monitored by microdialysis during, and after, a moderately severe fluid-percussion brain injury to rats. Pretreatment (15 min prior to injury) with the non-competitive NMDA antagonist dextrorphan or the competitive NMDA antagonist CGS 19755 significantly attenuated the post-traumatic increase in extracellular glutamate. Pretreatment with dextrorphan attenuated the post-traumatic increase in extracellular levels of aspartate; although these differences did not reach significance when examined as absolute values, they were significant when analyzed as percent increase over pre-trauma baseline levels. These results are consistent with recent experiments and suggest that NMDA antagonists may limit the release of glutamate and aspartate after trauma through a presynaptic mechanism.
Amino Acids↗
An investigation of the mechanisms of delayed neurodegeneration caused by direct injection of quinolinate into the rat striatum in vivo.
Injection of the N-methyl-D-aspartate receptor agonist quinolinate, or N-methyl-D-aspartate itself, into the rat brain produces neurodegeneration which can be prevented by N-methyl-D-aspartate receptor antagonists administered up to 5 h after excitotoxin injection. The present study was designed to investigate aspects of the mechanisms involved in this delayed form of neurodegeneration. Following its injection into the rat striatum, extracellular levels of [3H]quinolinate were monitored using a microdialysis probe located 1 mm from the site of injection. Peak concentrations were observed 10-20 min after injection and [3H]quinolinate levels decayed in a biexponential fashion, the initial component having an apparent t1/2 of 13.7 +/- 5.2 min (n = 3). Estimations of the extracellular concentrations of quinolinate after an injection of 200 nmol indicated a peak level of 13.7 +/- 6.0 mM (n = 3) at 10-20 min which declined to 1.2 +/- 0.13 mM (n = 3) by 2 h and substantial levels were present up to 5 h, the period over which N-methyl-D-aspartate receptor antagonists are effective in this model. Administration of dizocilpine at 1, 2, 3 or 5 h after injection of 100, 200 or 400 nmol quinolinate resulted in a similar temporal profile of neuroprotection, as assessed by measuring the activities of choline acetyltransferase and glutamate decarboxylase in striatal homogenates, which was independent of the degree of neurodegeneration produced by the different excitotoxin doses. Overall, these results suggest that the neuronal degeneration caused by quinolinate in vivo is critically dependent upon events occurring after the initial peak of excitoxin levels in the extracellular space.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Antagonists↗
Syntheses, activity and modeling studies of 3- and 4-(sulfo- and sulfonamidoalkyl)pyridine and piperidine-2-carboxylic acid derivatives as analogs of NMDA receptor antagonists.
A series of 3- and 4-(sulfo- and sulfonamidoalkyl)pyridine and piperidine-2-carboxylic acid derivatives as analogs of NMDA receptor antagonists was prepared. Affinity for the NMDA receptor was determined by binding assays using the specific radioligand [3H] (2SR,4RS)-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS-19755). The 3-alkylsulfonyl moiety was introduced by selective reduction of a carboxylic acid function followed by bromination, substitution by Na2SO3 and catalytic reduction. For the 4-alkylsulfonic derivatives the crucial step was the introduction of the 2-cyano function and its further conversion to 2-carboxylic acid. The most potent compound of the series was the pyridine (11a) [4-(sulfomethyl)pyridine-2-carboxylic acid] with a modest IC50 of 40 microM. A molecular modeling study has been undertaken to understand the pharmacological results. In a first step, a comparative modeling study of the active pyridine and the poorly active piperidine sulfonic acid derivatives 11a and 10a [4-(sulfomethyl)piperidine-2-carboxylic acid] and of the phosphonic homologues was performed. We propose that the binding geometry of the sulfonic moiety within the NMDA receptor is different from that of the phosphonic containing antagonists. In order to test this assumption, we have made, in a second step, a complete conformational analysis of the sulfonic acid derivatives, as well as some analogs taken from the literature, either active or inactive as NMDA antagonists. A preferred conformation of the sulfonic acids is proposed.
Binding, Competitive↗
Acute D2/D3 dopaminergic agonism but chronic D2/D3 antagonism prevents NMDA antagonist neurotoxicity.
BACKGROUND: Antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor, most likely by producing disinhibtion in complex circuits, acutely produce psychosis and cognitive disturbances in humans, and neurotoxicity in rodents. Studies examining NMDA Receptor Hypofunction (NRHypo) neurotoxicity in animals, therefore, may provide insights into the pathophysiology of psychotic disorders. Dopaminergic D2 and/or D3 agents can modify psychosis over days to weeks, suggesting involvement of these transmitter system(s). METHODS: We studied the ability of D2/D3 agonists and antagonists to modify NRHypo neurotoxicity both after a one-time acute exposure and after chronic daily exposure. RESULTS: Here we report that D2/D3 dopamine agonists, probably via D3 receptors, prevent NRHypo neurotoxicity when given acutely. The protective effect with D2/D3 agonists is not seen after chronic daily dosing. In contrast, the antipsychotic haloperidol does not affect NRHypo neurotoxicity when given acutely at D2/D3 doses. However, after chronic daily dosing of 1, 3, or 5 weeks, haloperidol does prevent NRHypo neurotoxicity with longer durations producing greater protection. CONCLUSIONS: Understanding the changes that occur in the NRHypo circuit after chronic exposure to dopaminergic agents could provide important clues into the pathophysiology of psychotic disorders.
Animals↗
Homocysteine, a risk factor for atherosclerosis, biphasically changes the endothelial production of kynurenic acid.
Increased serum level of homocysteine is an independent risk factor for vascular disease. The effect of DL-homocysteine on the endothelial production of kynurenic acid, an antagonist of alpha7-nicotinic and N-methyl-D-aspartate (NMDA) glutamate receptors, has been evaluated in vitro and in vivo. In rat aortic rings, DL-homocysteine at 40-100 microM enhanced, whereas at >or=400 microM decreased the synthesis of kynurenic acid. S-adenosylhomocysteine mimicked the biphasic action of DL-homocysteine. On the contrary, thiol-containing compounds, L-cysteine and L-methionine, were only inhibiting kynurenic acid production. L-kynurenine uptake blockers, L-phenylalanine and L-leucine, reversed the stimulatory effect of S-adenosylhomocysteine. L-glycine, co-agonist of NMDA receptor, and cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), an antagonist of NMDA receptor, have not influenced kynurenic acid formation. In vivo, DL-homocysteine (1.3 mmol, i.p.) increased the level of kynurenic acid in rat serum from 23.7+/-7.1 to 60.7+/-14.2 (15 min, P<0.01) and 55.7+/-13.6 (60 min, P<0.01) pmol/ml, respectively; the endothelial content of kynurenic acid was also increased (51.6+/-5.8 vs. 73.2+/-9.4 fmol/microg of protein; 15 min; P<0.01). DL-homocysteine seems to modulate the production of kynurenic acid both directly and indirectly, possibly following the conversion to S-adenosylhomocysteine. The obtained data suggest a potential contribution of altered formation of kynurenic acid to the endothelial changes induced by hyperhomocysteinemia.
Animals↗
Cognitive effects of dopaminergic and glutamatergic blockade in nucleus accumbens in pigeons.
In earlier studies it was found that glutamatergic transmission within the nucleus accumbens septi is involved in the performance of a learned visual shape discrimination in pigeons. This study examines what effects several kinds of glutamate and dopamine antagonists have on the same task. Pigeons were trained with the relevant discrimination, bilaterally implanted with cannulas into the nucleus accumbens and tested after various transmission blockers had been administered intracerebrally. SCH-23390, a D1 dopamine antagonist, at the dose used, had no effect, and Spiperone, a D2-dopamine and 5HT2a-serotonine antagonist, significantly decreased the error repeat trials. CNQX, a non-NMDA glutamate receptor antagonist, and Cycloleucine, an antagonist of the glycine allosteric site of NMDA receptors, had no effect. CGS-19755, a selective competitive NMDA antagonist, significantly impaired performance by significantly decreasing the percent correct trials and increasing the error repeat trials. CPPG, a II/III metabotropic glutamate antagonist, remarkably improved performance. MMPG, a III/II metabotropic glutamate antagonist, at the dose used, did not have any significant effect. The preparation employed may be a useful animal model of perceptual disturbances in schizophrenia.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
NMDA receptor antagonists prevent conditioned activation of intracranial self-stimulation in rats.
Rats with bipolar electrodes implanted unilaterally into the ventral tegmental area were trained to lever-press for response contingent electrical stimulation (continuous reinforcement). After preliminary lever-press training, two types of daily sessions were held on 10 consecutive days: type T+, during which current intensity was set at the Threshold level and each response was accompanied by the visual signal (stimulus lights above the lever briefly went off); and type ST-, during which current was set at the SubThreshold level and there were no visual stimuli. On day 11, combination of the subthreshold current intensities and stimulus lights previously associated with the threshold stimulation (session type ST+) resulted in significantly elevated response rates compared to the performance under the subthreshold current without visual stimuli (session type ST-). This effect was dose dependently blocked by competitive NMDA receptor antagonist (+/-)-CPP ((+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) and CGS 19755 (cis-4-(phosphonomethyl) piperidine-2-carboxylic acid). The present findings suggest that the activation of intracranial self-stimulation induced by a conditioned visual stimulus is dependent on the NMDA receptor functioning.
Animals↗
Competitive NMDA and strychnine-insensitive glycine-site antagonists disrupt prepulse inhibition.
Prepulse inhibition (PPI) is thought to reflect the operation of a sensorimotor gating system in the brain. Sensorimotor gating abnormalities have been identified in schizophrenic patients, and various neural systems are involved in this function. To study the modulation of the sensorimotor gating system by the N-methyl-D-aspartate (NMDA) receptor channel complex, the effects of noncompetitive and competitive NMDA antagonists on PPI were examined in rats. PPI was not disrupted by CGS 19755, a competitive NMDA antagonist, at 30 min after subcutaneous (s.c.) administration. However, CGS 19755 (40 mg/kg s.c.) decreased PPI at 120 min after administration with a marked decrease of startle amplitude. Late onset of the effect of CGS 19755 was also observed in the increase of spontaneous locomotor activity (SLA). On the other hand, phencyclidine, a noncompetitive NMDA antagonist, disrupted PPI at 30 min after administration and increased SLA from 20 min after administration. PPI was also disrupted by bilateral intracerebroventricular administration of 5,7-dichlorokyn urenate (10 and 20 micrograms/side X 2), an antagonist at the strychnine-insensitive glycine receptor, which is an allosteric binding site in the NMDA receptor-channel complex. It is concluded that the NMDA receptor-channel complex plays an important role in regulation of PPI.
Acoustic Stimulation↗
The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord.
Racemic (dl)-methadone has antagonist activity at the N-methyl-D-aspartate (NMDA) receptor. We evaluated dl-methadone, the opioid active (l-) and the opioid inactive (d-) isomers in competition binding assays. dl-Methadone and its d- and l- isomers exhibited low micromolar affinities for the [3H]MK-801-labeled non-competitive site of the NMDA receptor in both rat forebrain and spinal cord synaptic membranes, with Ki values and displacement curves similar to those of dextromethorphan, an established NMDA receptor antagonist. They lacked affinity at the [3H]CGS-19755-labeled competitive site of the NMDA receptor. Therefore, both methadone and its the d- and l- isomers differ from morphine, hydromorphone, and naltrexone in that they have non-competitive antagonist activity at the NMDA receptor. A non-opioid NMDA receptor antagonist, such as d-methadone, may improve the efficacy of morphine by attenuating the development of tolerance.
Animals↗