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At least 487 records · Page 27Linked to original sources
PubMed1986

Non-cholinergic synaptic excitation in neostriatum: pharmacological evidence for mediation by a glutamate-like transmitter.

We studied the synaptic pharmacology of an excitatory pathway in the neostriatum using electrophysiological techniques in tissue slices from rats. In response to single electrical stimuli, two negative, extracellular potentials (N-1 and N-2) were recorded through micropipette electrodes within 150-450 micron of the stimulating cathode. N-2 was reversibly reduced or abolished by reducing the concentration of calcium in the bathing medium, while N-1 was unaffected. Both N-1 and N-2 were reversibly abolished by the local anaesthetic procaine. Single-unit, extracellular action potentials were, at times, associated with either N-1 or N-2. Intracellular recordings showed action potentials at N-2 latency arising from graded, monophasic, depolarizing potentials. Bath-applied cholinoceptor and dopamine receptor antagonists failed to reduce N-2. By contrast, antagonists of excitatory amino acid transmitters reversibly reduced or abolished N-2. gamma-D-Glutamylglycine (GG), (+/-)-cis-2,3-piperidine dicarboxylic acid (PDA) and DL-2-amino-4-phosphonobutyric acid (APB) blocked N-2 with ED50S of 0.79 mM, 1.0 mM and 1.1 mM, respectively. (-)-Baclofen reversibly blocked N-2 with an ED50 of 0.79 microM; (+)-baclofen was 330 times less potent. The results suggest that N-1 results from direct activation of fibre tracts or cell bodies, while N-2 is a population spike mediated by excitatory synapses whose natural transmitter pharmacologically resembles glutamate.

Animals↗
PubMed1983

An excitatory amino acid antagonist blocks cone input to sign-conserving second-order retinal neurons.

cis-2,3-Piperidinedicarboxylic acid (PDA), an excitatory amino acid antagonist, reversibly blocked cone input to OFF bipolars and horizontal cells, whereas ON bipolars were relatively unaffected. Kainic acid effects were also blocked, indicating a postsynaptic mechanism of action. The use of PDA helps to characterize one of two classes of excitatory amino acid synaptic receptors that mediate cone influence in the outer retina.

Amino Acids↗
PubMed1998

An alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist and an N-methyl-D-aspartate (NMDA) channel blocker synergistically impair spatial memory in rats.

The interaction of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist YM90K with the competitive N-methyl-D-aspartate (NMDA) antagonist CGS19755 or with the NMDA channel blocker MK801 on the spatial memory of rats was examined by the 4-arm-baited radial maze task. When administered alone, these drugs had no effect on the spatial memory. The combination of YM90K and MK801 synergistically disrupted working and reference memories, whereas the combination of YM90K and CGS19755 had no effect. These results indicate that the blockade of the AMPA receptor and NMDA channels produces a synergistic impairment of spatial memory and suggest that interaction between the AMPA and NMDA receptors plays a role in cognitive function.

Animals↗
PubMed1996

Pharmacological properties of acquired excitotoxicity in Chinese hamster ovary cells transfected with N-methyl-D-aspartate receptor subunits.

The cytotoxicity induced by the transient expression of functional N-methyl-D-aspartate (NMDA) receptors has been examined with the use of a luciferase reporter assay in Chinese hamster ovary cells. Various NMDA receptor antagonists, in a dose-dependent manner, prevented a loss of luciferase activity 24 to 48 hr post-transfection of either the NR1/NR2A or NR1/ NR2B subunit receptor configurations, likely correlating to the time required to express functionally these receptors. Both glutamate and NMDA were potently cytotoxic to transfected cells previously protected by antagonists. The novel ifenprodil analog (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP101,606-27) protected cells expressing NR1/NR2B, but not those cells expressing either NR1/NR2A or, putatively, NR1/NR2A/NR2B. Decreased cytotoxicity was observed when a mutated NR1 subunit (N616R) with reduced Ca++ permeability was used in coexpression studies with NR2A or NR2B. In contrast to our results with NR1/NR2A or NR1/NR2B, cells expressing NR1/NR2C did not perish. Our studies suggest that expression of functional NMDA receptors in non-neuronal cells leads to a form of excitotoxicity similar to that observed in mammalian neurons in vitro.

Animals↗
PubMed1998

Effect of glutamate analogues and inhibitory neurotransmitters on the electroretinograms elicited by random sequence stimuli in rabbits.

OBJECTIVE: To study the origin of the different components of the electroretinogram (ERG) elicited by a random binary m-sequence stimulus. METHODS: Electroretinograms were recorded from pigmented rabbits before and after the injection of glutamate analogues (2-amino-4-phosphono-butyric acid [APB; DL form] and cis-2,3-piperidine-dicarboxylic acid [PDA]) and inhibitory neurotransmitters (glycine and gamma-aminobutyric acid [GABA]) to abolish the contribution of different cell types to the ERG. Two types of stimuli were used: conventional full-field stimulation with short- and long-duration flashes and a random binary m-sequence of flashes designed to mimic the pseudorandom binary m-sequence stimulation used in the multifocal ERG technique. RESULTS: The effects of APB and PDA on the first-order kernel of the random ERGs were similar to those on the photopic short-flash ERG. Glycine and GABA minimized the oscillatory potentials (OPs) of the photopic ERGs, and also reduced the amplitude of the positive wave of the first-order kernel slightly but caused a large reduction in the amplitude of the second-order kernel. CONCLUSIONS: The data suggest that the ON and OFF bipolar cells contribute significantly to the photopic short-flash ERG, as previously shown, and to the first-order kernel of the responses elicited by the pseudorandom binary sequence stimuli. The second-order kernel and the OPs receive a strong contribution from the cells of the inner retinal layers.

Aminobutyrates↗
PubMed1998

Neurological deterioration as a potential alternative endpoint in human clinical trials of experimental pharmacological agents for treatment of severe traumatic brain injuries. Executive Committee of the International Selfotel Trial.

OBJECTIVE: A recently improved understanding of the pathophysiological features of head injuries has led to the development of new drug therapies. Accurate human clinical trials remain necessary to document the efficacy and safety of new agents. It would be helpful to decrease the time from drug development to clinical use and general availability for drugs found to be effective. Conversely, ineffective agents could be abandoned in a timely fashion. RATIONALE: A new endpoint measure, defined as neuroworsening (NW), is an objective observable event that is identifiable during hospitalization. This may enable the efficacy of drugs to be demonstrated or disproved much earlier than with 6-month outcome assessments. The prospective, double-blind, multicenter trial of the N-methyl-D-aspartate receptor antagonist Selfotel was used to acquire data on the efficacy of NW in predicting neurological outcomes. The 6-month Glasgow Outcome Scale scores, which were the primary endpoints of that trial, were compared with the frequency of NW. NW was an observable event that could be objectively defined after head injuries. Patients who suffered one or more episodes of NW demonstrated significantly higher morbidity and mortality rates than did patients who did not. CONCLUSION: Future trials should consider the use of NW as an outcome measure that can be included with more traditional measures in the study design. If the strong correlation demonstrated between NW and 6-month Glasgow Outcome Scale scores can be prospectively demonstrated in a successful trial, the time to approval of future agents could be decreased.

Adult↗
PubMed2000

Argatroban as an anticoagulant for both hematologic and chemical tests.

Argatroban possesses strong antithrombin-like activity. We evaluated the usefulness of argatroban in anticoagulating specimens for routine laboratory tests. Results using blood anticoagulated with argatroban corresponded well with the results of blood treated with ethylendiamine tetra-acetic acid (EDTA) in the complete blood count (CBC), including the WBC differential count and morphology of blood cells, when the CBC was performed within 2 hr of blood collection. Clinical chemistry results from argatroban-treated samples were similar to results obtained with serum specimens. Thus, argatroban may be a useful anticoagulant for emergency laboratory medicine.

Anticoagulants↗
PubMed1988

Effects of kynurenate and other excitatory amino acid antagonists as blockers of light- and kainate-induced retinal rod photoreceptor disc shedding.

Photoreceptor disc shedding in the retina involves detachment of discs from distal outer segments and phagocytosis of those discs by adjacent pigment epithelial cells. The disc-shedding process balances the continuous renewal of photosensitive membrane. In amphibians, rod disc shedding normally is light-stimulated. However, excitatory amino acids such as kainate stimulate disc shedding independent of a dark-light transition. Excitatory amino acid-induced disc shedding is accompanied by toxic changes within the retina. To evaluate the possible role of an endogenous excitatory amino acid in the regulation of light-evoked disc shedding, we examined the effects of excitatory amino acid antagonists on kainate-induced and light-evoked disc shedding and on retinal toxicity. Using eyecups from Rana pipiens, we found that kynurenate, D-O-phosphoserine, and cis-2,3-piperidine dicarboxylic acid (cis-PDA) all block both the neurotoxic and disc-shedding effects of kainate. Kynurenate and D-O-phosphoserine, but not cis-PDA, also block light-evoked disc shedding. Our analysis suggests that kynurenate blocks the mechanism by which light "triggers" disc shedding rather than directly inhibiting disc detachment and phagocytosis. The observation that cis-PDA antagonizes the effects of kainate, but not light, suggests that the receptor mediating the kainate effect on disc shedding may not be involved in the normal initiation of the response by light. In contrast, our data on kynurenate suggest that it antagonizes an endogenous mechanism involved in the normal control of disc shedding. Thus, analysis of the differences between cis-PDA and kynurenate as antagonists in the retina may yield important insight into the mechanism by which light initiates disc shedding.

Animals↗
PubMed1996

Concurrent locomotor stimulation and decrease in dopamine release in rats and mice after treatment with the competitive NMDA receptor antagonists D-CPPene and CGS 19755.

The present study was aimed at investigating the effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonists D-CPPene (3-(2-carboxypiperazine-4-yl)-propenyl-1-phosphonic acid) and CGS 19755 (cis-4-(phosphonomethyl)piperidine-2-carboxylic acid) on dopamine (DA) transmission and motor activity in mice and rats. As measures of DA release we used mouse brain 3-methoxytyramine (3-MT) levels, and indirect estimate of DA release, and striatal dialysate measures of DA in conscious and freely moving rats by means of microdialysis. To obtain additional information about monoaminergic neurotransmission, brain tissue levels of DA, DOPAC, HVA, 5-HT and 5-HIAA were measured in both mice and rats. The animals were sacrificed at the time when NMDA antagonist-induced locomotor stimulation was maximal. In mice, D-CPPene and CGS 19755 decreased striatal 3-MT levels, whereas, in general, 3-MT levels in the limbic forebrain were not significantly altered. Treatment with CGS 19755 decreased rat striatal dialysate levels of DA but increased 5-HIAA at time points when locomotor activity was increased. D-CPPene and CGS 19755 have been observed to produce psychotic symptoms in man. The present study suggests that these symptoms are not a result of an increase in central dopamine release.

Animals↗
PubMed1985

Identification of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oic acid, an intermediate in cholic acid synthesis, in the plasma of patients with infantile Refsum's disease.

The plasma bile acid profiles of three children with the inherited metabolic disorder, infantile Refsum's disease, were found to contain 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oic acid. This intermediate in the synthesis of cholic acid was identified by combined gas-liquid chromatography-mass spectrometry and accounted for approximately 25% of the total bile acids which were present at elevated concentrations in plasma. Infantile Refsum's disease appears to share several biochemical features with the cerebro-hepato-renal syndrome (Zellweger's disease), including abnormal bile acid metabolism.

Bile Acids and Salts↗
PubMed1995

Dissociation between cognitive and motor/motivational deficits in the delayed matching to position test: effects of scopolamine, 8-OH-DPAT and EAA antagonists.

The effects of the muscarinic antagonists scopolamine HBr and MeBr, the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the N-methyl-d-aspartate (NMDA) antagonists MK-801 and CGS-19755 on performance of rats in a delayed matching-to-position task were examined. Pretreatment with scopolamine HBr (0.05 and 0.1 mg/kg), resulted in a delay-dependent decrease in the percentage of correct responses and discriminability (log d), but had no effect on either the latency to complete trials, or the rate of trial completion during the fixed duration session. Scopolamine MeBr (0.1 mg/kg) did not impair percent correct or increase the response latency but did decrease the rate of trial completion. 8-OH-DPAT (up to 0.3 mg/kg), had no effect on percent correct, but did induce a small decrease in discriminability. The impairment in discriminability occurred only at a dose that substantially reduced the rate of trial completion. Both MK-801 (0.05 mg/kg) and CGS 19755 (10 mg/kg) induced a delay-independent impairment in percent correct, discriminability and a reduction in the rate of trial completion without affecting latency. A lower dose of CGS 19755 (5.0 mg/kg) induced a slight impairment in discriminability without significantly affecting the other measures. Taken together, these results demonstrate some dissociation between drug-induced cognitive and motor/motivational deficits in the DMTP test. However, the data question the specificity of putative cognitive impairments reported in many previous studies with the 5-HT1A agonist 8-OH-DPAT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2003

Neuroprotective effects of N-methyl-D-aspartate receptor antagonist on aspartate induced neurotoxicity in the spinal cord in vivo.

OBJECTIVE: Much evidence has been gathered to show that neurotoxicity of excitatory amino acids is mainly activated through an N-methyl-D-aspartate (NMDA) receptor cascade. We evaluated the protective effects of NMDA receptor antagonists, MK-801 and CGS19755 on spinal cord neurons using the NMDA receptor mediated neurotoxicity model in vivo. METHODS: New Zealand white rabbits underwent an infrarenal aortic isolation. Group A animals (n = 7) received segmental aspartate (50 mM) infusion for 10 minutes. Group B animals (n = 6) were pretreated with MK-801 (6mg/kg), a noncompetitive NMDA receptor antagonist, that was administrated intravenously for 3 hours beginning 1 hour before the segmental infusion of aspartate (50 mM) of 10 minutes. Group C animals (n = 6) received pretreatment with CGS19755 (30mg/kg), a competitive NMDA receptor antagonist, that was administrated in the same fashion as group B, followed by the segmental infusion of aspartate (50 mM). Neurologic status was scored at 12, 24, and 48 hours after operation using the Tarlov score. All the animals were sacrificed for histologic assessment at 48 hours. RESULTS: Group A animals exhibited paraplegia or paraparesis with marked neuronal necrosis. Group B and C animals showed significantly better neurologic function compared with group A (p = 0.0013, A vs. B) (p = 0.0011, A vs. C). Pathohistological change was not observed in group B and C animals. CONCLUSIONS: NMDA receptor antagonists can have protective effects on spinal cord neurons against aspartate induced neurotoxicity. This model may be useful in assaying protective agents in the spinal cord against neuronal injury mediated by NMDA receptors in vivo.

Animals↗
PubMed1996

Structure-activity relationships of competitive NMDA receptor antagonists.

The interaction of structurally constrained competitive NMDA receptor antagonists, (+/-)-cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), (2-amino-4,5-(1,2-cyclohexyl))-7-phosphonoheptanoic acid (NPC 12626), (+/-)-6-phosphonomethyl-de-cahydroisoquinoline-3-carboxylic acid (LY 274614), (S)-alpha-amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid (SDZ EAB-515) and (S)-alpha-amino-5-phosphonomethyl[1,1':4',1"-terphenyl]-3-propa noi c acid (SDZ 215-439), with their receptor was assessed using radioligand binding, protection against neurotoxicity in cortical neuronal cultures and computerised molecular modelling. All compounds inhibited the specific binding of [3H]CGS 19755 and/or [3H]CGP 39653 (inhibition constants 40-2000 nM), and protected neuronal cultures from NMDA-mediated injury (IC50 values 1.3-5.6 microM). Quantitative conformational analyses indicated that the molecules fitted well to a NMDA receptor model. Our results draw attention to a deep hydrophobic pocket, defined by the bi- and terphenyl containing antagonists (SDZ EAB-515, SDZ 215-439), which may influence potency and selectivity.

Amino Acids↗
PubMed1993

Development of dopamine and N-methyl-D-aspartate systems in rat brain: the effect of prenatal phencyclidine exposure.

Phencyclidine (PCP) inhibits the uptake of the neurotransmitter dopamine (DA), and blocks N-methyl-D-aspartate (NMDA) receptor-regulated ion channels. PCP also binds to sigma receptors in vivo and in vitro in rat brain. Prolonged exposure to PCP in adults has been observed to reduce the number of PCP binding sites in brain. We designed these experiments to evaluate whether prolonged prenatal exposure to PCP produces alterations in the development of DA and NMDA systems in brain. To do so, we characterized the normal course of development of basal and stimulated DA release in striatal slices, the ontogeny of striatal DA concentrations, and the development of NMDA receptor channels and associated glutamate binding sites in frontal cortex. We compared these developmental profiles to those in rats exposed to prenatal PCP, in an attempt to characterize the effect of prenatal PCP exposure on the pattern of brain development. Pregnant CD rats were injected s.c. with either 0, 10 or 20 mg/kg PCP daily on gestational days 8 through 20. On postnatal days (PND) 8, 21, 45, or 100, rats were sacrificed and brain tissues isolated for in vitro assessment. In vitro [3H]DA release from striatal slices evoked by either 40 microM glutamate or 15 mM K+ increased over 250% from PND 8 to PND 45, and glutamate-stimulated release was still significantly below adult levels at PND 45. In contrast, D-methamphetamine (D-METH)-evoked [3H]DA release, frontal cortical glutamate binding sites and NMDA channels developed early, reaching adult levels on or before PND 21.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Antiepileptic action of excitatory amino acid antagonists in the photosensitive baboon, Papio papio.

Antagonists of excitation induced by dicarboxylic amino acids have been evaluated for acute anticonvulsant activity in baboons, Papio papio, with photosensitive epilepsy. 2-Amino-7-phosphonoheptanoic acid, 1 mmol/kg, i.v., abolishes myoclonic responses for 5 h. Less prolonged protection is seen after cis-2,3-piperidine-dicarboxylic acid, 1-3.3 mmol/kg; 2-amino-5-phosphonovaleric acid, 1-3.3 mmol/kg; or glutamic acid diethyl ester, 1-3.3 mmol/kg. Toxic side-effects are prominent after the latter two compounds. Antagonists of excitation due to N-methyl-D-aspartate possess acute anticonvulsant activity in a wider range of models epilepsy.

2-Amino-5-phosphonovalerate↗