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At least 667 records · Page 37Linked to original sources
PubMed1989

Rolipram induces c-fos protein-like immunoreactivity in ependymal and glial-like cells in adult rat brain.

We tested the effects of the cyclic AMP-dependent phosphodiesterase inhibitor 4- (3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (rolipram) on c-fos protein-like immunoreactivity (FOS-IR) in adult rat brain. Rolipram (25-100 mg/kg, i.p.) did not detectability alter basal FOS-IR in neurons but induced FOS-IR in glial-like cells scattered in white matter regions and in ependymal cells lining the lateral and third ventricles. This induction was observed at 1 and 4 h after injection but was not detectable 10 min or 24 h after rolipram injection.

Animals↗
PubMed1991

The influence of strychnine-insensitive glycine receptor agonists and antagonists on generalized seizure thresholds.

We have examined the influence of strychnine-insensitive glycine (gly2) receptor agonists and antagonists on the expression of generalized seizure activity (generalized seizure threshold (GST), afterdischarge duration and motor seizure response) in fully amygdala kindled rats. Intra-amygdaloid administration of the selective gly2 receptor antagonist, 7-chlorokynurenic acid (7-C1KYN) (10-50 nmol) dose-dependently raised GSTs in a glycine-reversible manner. The same doses had no significant effect on other parameters of seizure expression. (+/-)-3-Amino-1-hydroxy-2-pyrrolidone (HA-966), a proposed low-efficacy partial agonist at the gly2 receptor17, showed similar but weaker anticonvulsant activity in this model. The active, R-(+)-enantiomer of HA-966 showed greater anticonvulsant efficacy than the racemic mixture, but was still clearly less active than 7-C1KYN. The gly2 receptor agonists glycine (10-50 nmol), D-serine (50 nmol) and D-alanine (50 nmol) failed to influence any of the parameters of the seizure response, suggesting that gly2 receptors in the basolateral amygdala are fully saturated in vivo. The behavioural impairment induced by high doses of 7-C1KYN did not appear to be associated with gly2 receptor blockade. These results support the concept that potent and selective gly2 receptor antagonists may provide a useful, novel class of anticonvulsant agents.

Alanine↗
PubMed1993

MK-801, but not drugs acting at strychnine-insensitive glycine receptors, attenuate methamphetamine nigrostriatal toxicity.

Repeated administration of methamphetamine (METH) results in damage to nigrostriatal dopaminergic neurons. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists and use-dependent cation channel blockers attenuate METH-induced damage. The objectives of the present study were to examine whether comparable reductions in METH-induced damage could be obtained by compounds acting at strychnine-insensitive glycine receptors on the NMDA receptor complex. Four injections of METH (5 mg/kg i.p.) resulted in a approximately 70.9% depletion of striatal dopamine (DA) and approximately 62.7% depletion of dihydroxyphenylacetic acid (DOPAC) content, respectively. A significant protection against METH-induced DA and DOPAC depletion was afforded by the use-dependent channel blocker, MK-801. The competitive glycine antagonist 7-chlorokynurenic acid (7-Cl-KA), the low efficacy glycine partial agonist (+)-3-amino-1-hydroxy-2-pyrrolidone ((+)-HA-966), and the high efficacy partial glycine agonist 1-aminocyclopropane-carboxylic acid (ACPC) were ineffective against METH-induced toxicity despite their abilities to attenuate glutamate-induced neurotoxicity under both in vivo and in vitro conditions. These results indicate that glycinergic ligands do not possess the same broad neuroprotective spectrum as other classes of NMDA antagonists.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Desensitization of the NMDA receptor complex by glycinergic ligands in cerebellar granule cell cultures.

Glutamate neurotoxicity was examined in cultured cerebellar granule neurons following both prolonged (20-24 h) and brief (45 min) exposure to compounds acting at strychnine-insensitive glycine receptors. Glutamate neurotoxicity was reduced in a concentration-dependent fashion by brief exposure to the glycine partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and (+-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966) and the competitive antagonist, 7-chlorokynurenic acid (7-CK) with a rank order efficacy: 7-CK > HA-966 > ACPC. Neither D-cycloserine (D-CS) nor glycine affected neurotoxicity produced by maximum glutamate concentrations, while glycine but not D-CS augmented the effects of submaximum glutamate concentrations. Prolonged exposure of cultures to either full (glycine) or partial agonists (ACPC, D-CS, HA-966) abolished the neuroprotective effects of ACPC and significantly diminished the neuroprotective effects of HA-966. In contrast, the neuroprotective effects of 7-CK were only marginally reduced by prolonged exposure to glycinergic ligands, while the neuroprotection afforded by compounds acting at other loci on the NMDA receptor complex (e.g. 2-amino-5-phosphonopentanoate (APV) and dizocilpine (MK-801)) were unaltered. These effects may represent homologous desensitization of the NMDA receptor complex at its strychnine-insensitive glycine receptor induced by prolonged exposure to glycinergic agonists and partial agonists. Nonetheless, levels of the NMDA receptor subunit zeta 1 mRNA were unaffected by prolonged exposure to ACPC, indicating the apparent desensitization could involve a post-translational modification of the NMDA receptor complex.

2-Amino-5-phosphonovalerate↗
PubMed1996

The glycine/NMDA receptor antagonist HA-966 impairs visual recognition memory in rhesus monkeys.

Recent studies have shown that strychnine-insensitive glycine binding sites positively modulate the N-methyl-D-asparate (NMDA) subclass of glutamate receptors, which are important in neural pathways involved in cognitive function. We examined the effect of (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), a highly specific antagonist of this glycine modulatory site on the NMDA receptor, on visual recognition memory in four rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample (DNMS) with a list length of 20 trial-unique graphic symbols. In addition, the effect of HA-966 was compared with that of (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (dizocilpine; MK-801), a noncompetitive NMDA channel blocker. Administration of HA-966 (0.1-10 mg/kg, i.m.) 30 min before testing impaired DNMS performance dose-dependently, starting at doses of 3.2 mg/kg; the memory deficity following the highest dose (10 mg/kg) was associated with prolonged response latencies. Similar impairments in recognition memory were observed following treatment with MK-801, though at much lower doses (3.2-32 micrograms/kg) than those at which HA-966 was effective. Administration of low doses of HA-966 (1 mg/kg) and MK-801 (10 micrograms/kg), each of which had no significant effect on performance when given alone, also failed to impair performance when given concurrently. Combined administration of both drugs, each at amnesia-producing doses (3.2 mg/kg of HA-966 plus 32 micrograms/kg of MK-801), markedly impaired performance in an additive, not a synergistic, manner. From these results, we propose that the recognition memory impairment observed in our monkeys following HA-966 administration is via an action on the glycine modulatory site of the NMDA receptor complex.

Animals↗
PubMed1984

The haemolytic reactions of 1-acetyl-2-phenylhydrazine and hydrazine: a spin trapping study.

Free radical production from the reaction of hydrazine and 1-acetyl-2-phenylhydrazine (AcPhHZ) with oxyhaemoglobin and with human red blood cells, has been observed by the electron spin resonance technique of spin trapping. Using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), the free radical intermediates detected depended on the hydrazine derivative, oxyhaemoglobin and the oxyhaem/hydrazine derivative concentration ratio. The reaction of hydrazine with oxyhaemoglobin in the presence of DMPO gave a nitroxide which was identified as a reduced dimer of DMPO. Whereas hydrazine-treated red blood cells, in the presence of DMPO, gave a nitroxide spin adduct which was identified as the hydroxyl radical spin adduct of DMPO, 5,5-dimethyl-1-pyrrolidino-1-oxyl (DMPO-OH). The reaction of AcPhHZ with oxyhaemoglobin, in the presence of DMPO, gave DMPO-OH, the phenyl radical spin adduct of DMPO, 5,5-dimethyl-2-phenylpyrrolidino-1-oxyl (DMPO-Ph) and an oxidised derivative of DMPO, 5,5-dimethyl-2-pyrrolidone-1-oxyl (DMPOX). The amounts of DMPO-Ph, DMPO-OH and DMPOX observed depended on the 1-acetyl-2-phenyl-hydrazine/oxyhaemoglobin concentration ratio; DMPOX replaced DMPO-OH as the concentration of AcPhHZ was decreased. DMPOX production has been previously associated with the production of highly oxidised haem iron-oxygen intermediates. AcPhHZ treated red blood cells gave DMPO-Ph and DMPO-OH spin adducts in the presence of DMPO. DMPO had little to no effect on the rate of oxygen consumption by oxyhaemoglobin with hydrazine and AcPhHZ. Moreover, the rate of oxyhaemoglobin oxidation induced by hydrazine, was not decreased by DMPO whereas the rate of oxyhaemoglobin oxidation induced by AcPhHZ was decreased approx. 40% by DMPO. DMPO (10 mM) gave a small decrease in haemolysis and lipid peroxidation induced by 1 mM hydrazine and AcPhHZ in a 1% suspension of red blood cells.

Carboxyhemoglobin↗
PubMed1976

Studies on gamma-glutamyl transpeptidase of human urine.

A simple and rapid method suitable for clinical laboratories, for the removal of the inhibitors in urine of gamma-glutamyl transpeptidase activity, using an ion-retardation resin, is described. Gel chromatography of urine resulted in appreciable loss of the enzyme activity. Freezing at -5 degrees C and thawing, did not affect the activity of the enzyme. Dimethyl sulfoxide and polyvinyl pyrrolidone up to a creatinine and NaCl at levels found in normal urine did not inhibit the transpeptidase.

Chlorides↗
PubMed1996

Comparative spermicidal performance of iodinated and non-iodinated contraceptive formulations of nonoxynol-9 co-precipitated with polyvinylpyrrolidone.

The objective of this study was to evaluate the spermicidal qualities of various combinations of nonoxynol-9 (N-9; whole molecule = oligomers 1-18) and its isolated fractions (oligomers 8-10, 4-6 and 1-3), co-precipitated with non-iodinated and/or iodinated (Io) polyvinylpyrrolidone (PVP) as possible vaginal contraceptives. Spermicidal qualities of known equimolar concentrations of various combinations of PVP/N-9 and PVP-Io/N-9 were tested via a modified Sander-Cramer test (SCT) using human spermatozoa. Spermicidal agents and semen samples were mixed 1:1 (v/v) and evaluated for sperm viability. Spermicidal activity was reported as the minimal concentration (microgram/mL) of spermicide capable of killing all spermatozoa within 20 sec after exposure to the spermicide. The spermicidal activity of PVP/N-9 and PVP-Io/N-9 preparations containing N-9 oligomers 1-18 and/or 8-10 was similar, and these preparations were more efficient in killing the spermatozoa than the ones containing N-9 oligomers 4-6 and 1-3. Polyvinyl-pyrrolidone proved to be an effective vehicle for PVP/N-9 and PVP-Io/N-9 preparations, especially those containing N-9 oligomers 4-6 and 1-3. Incorporation of Io into the spermicidal preparations brought about additional efficacy. The current findings could be of clinical significance in future studies when preparing and delivering those selected co-precipitates vaginally.

Cell Survival↗
PubMed1986

The effects of nonpenetrating cryoprotectants added to TEST-yolk-glycerol extender on the post-thaw motility of ram spermatozoa.

The effects of adding five different concentrations of 17 polymeric compounds to TEST-yolk-glycerol extender on ram spermatozoa survival was studied. These were Aquacide (I, II, and III); dextran (0.8-1.6, 1.9, 15-20, 70, and 200-300 kDa); three types of Dri-Sweet; hydroxyethyl starch; methylcellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, and Supercol 912. All the compounds tested except the Dri-Sweet compounds and hydroxyethyl starch significantly (P less than 0.05) decreased percentages of motile cells in unfrozen samples. The use of dextran (0.8-1.6 kDa; hydrolyzed dextran separated by ethanol) and Aquacide II significantly (P less than 0.05) increased post-thaw motility of spermatozoa frozen in pellets. Dextran (15-20 kDa), dextran (0.8-1.6 kDa), Aquacide II, and hydroxyethyl starch significantly (P less than 0.05) increased the percentages of post-thaw motility of ram spermatozoa frozen in the presence of glycerol and egg yolk.

Animals↗
PubMed1986

Filaggrin breakdown to water binding compounds during development of the rat stratum corneum is controlled by the water activity of the environment.

Filaggrin is a specific epidermal protein which is the precursor of the free amino acids, urocanic acid and pyrrolidone carboxylic acid which are largely responsible for the ability of the stratum corneum of the skin to remain hydrated at low environmental humidity. The distribution of filaggrin shown by immunofluorescence in the stratum corneum of the rat changed dramatically during the first hours of postnatal life. During late foetal development, filaggrin accumulated through the entire thickness of the stratum corneum, indicating that there was a block on the subsequent processing of the protein which normally would convert it to free amino acids. Immediately after birth this block was lifted and normal proteolysis of the filaggrin took place in the outer part of the stratum corneum, leaving the normal adult pattern of a thin zone of cells containing filaggrin at the bottom of the stratum corneum. This activation of filaggrin proteolysis was dependent on the drop in external water activity caused by the transition from an aqueous environment in utero to a dryer environment after birth and it could be blocked by maintaining a 100% humidity atmosphere around the newborn rat after birth. In isolated stratum corneum in vitro, filaggrin proteolysis took place only between 80 and 95% relative humidity, both higher and lower relative humidity blocked the proteolysis. Application of occlusive patches to adult rats prevented the normal proteolysis of filaggrin, indicating that this mechanism controls not only the massive filaggrin proteolysis occurring after birth but also the proteolysis occurring during normal stratum corneum maturation. The stratum corneum therefore has the ability to respond to changes in external humidity by altering the level of the stratum corneum where it converts its reserves of filaggrin into water binding amino acids, such that under humid conditions water binding components will be produced in only the most superficial stratum corneum, or even not produced at all.

Aging↗
PubMedDate not supplied

The effect of blocking dopamine release on synthesis rate of dopamine in the striatum of the rat.

Two experiments were carried out in rats to investigate the mechanisms by which dopamine (DA) synthesis is regulated. First, a unilateral lesion was made in the substantia nigra, thus interrupting the nervous impulse flow of the nigro-striatal pathway. Secondly, the release of DA in the striatum was blocked by means of 1-hydroxy-3-amino-pyrrolidone-2 (HA-966). In both experiments the synthesis rate of DA was accelerated as was shown by analysing the time course of the specific activity of striatal DA after an i.v. injection of 3,5-3H-tyrosine. Furthermore the influence of apomorphine on the rate of DA synthesis, accelerated by HA-966 or by lesion, was investigated. Apomorphine appeared to block the increase of DA synthesis. The results are discussed in the light of a transsynaptic feedback mechanism.

Animals↗
PubMed1976

Absence of a 'cholinergic link' in the apomorphine-induced feedback inhibition of dopamine synthesis in rat striatum.

The blocking effect of apomorphine on the rise in striatal dopamine (DA) content, induced by 1-hydroxy-3-amino-pyrrolidone-2 (HA-966) was taken as a measure for the intrastriatal feedback inhibition of DA synthesis. The effects of cholinergic drugs on this feedback system were assessed in order to verify the hypothesis that this mechanism is mediated via an intrastriatal cholinergic link. We presumed that DA receptors were located on a cholinergic neuron, while the cholinergic terminals in turn made direct or indirect axon-axonal contact with the dopaminergic nigro-striatal pathway (N.S.P.). Although cholinergic agents could modify the effect of HA-966 on striatal DA content, it proved to be impossible to counteract the blocking effect of apomorphine with cholinergic drugs as was to be expected. Therefore we concluded that the effect of apomorphine was not brought about in the way which had been postulated.

Animals↗
PubMed1978

Electrical stimulation of the nigrostriatal pathway after HA-966 block of triatal dopamine release.

Striatal dopamine (DA) of rats increased twofold 1 h after blockade of DA release by either an electrolytic lesion of the substantia nigra (SN) or systemic administration of 1-hydroxy-3-amino-pyrrolidone-2 (HA-966). If the treatments were combined, no further increase was observed. The decrease in DA induced by alpha-methyl-p-tyrosine (alphaMT) in otherwise untreated animals was not enhanced by a 20 min electrical stimulation of nigrostriatal fibres. If, however, in addition to synthesis blockade by alphaMT, DA release was interrupted by a lesion of the SN and/or by HA-966, electrical stimulation caused a significant decrease in striatal DA. It is assumed that HA-966 exerts its action in the dopaminergic nigrostriatal system by way of blockade of the nerve impulse flow at the level of the SN.

Animals↗
PubMed1982

The pharmacological assessment of a new, potent oxotremorine analogue in mice and rats.

Some of the central and peripheral effects of oxotremorine (OT) and its azetidine analogue, N-[4-azetidinyl)-2-butynyl]-2-pyrrolidone (BM 120), were compared in mice and rats. BM 120 was found to be about twice as potent as OT and to have a somewhat longer duration of action. All its effects were antagonized by pretreatment with atropine sulphate. BM 120 acted as powerful muscarinic agonist on the isolated guinea pig ileum.

Animals↗
PubMed1988

Repeated administration of HA-966 and haloperidol to rats: similar tolerance to striatal dopamine accumulation after HA-966 challenge, but dissimilar effects on striatal [3H]spiperone binding.

Repeated administration of 1-hydroxy-3-amino-pyrrolidone-2 (HA-966) to rats induces tolerance, as shown by a decreased, drug-stimulated accumulation of dopamine (DA) in the striatum. In the present study we compared the adaptive response of the striatal dopaminergic system to repeated administration of HA-966 with the adaptive response observed after repeated haloperidol. These treatments deprive dopamine (DA) receptors from their agonist and cause a blockade of DA receptors, respectively. Tolerance to HA-966 was not accompanied by a change in the specific binding of [3H]spiperone to striatal membranes. This is in contrast to the well-documented up-regulation of DA receptors that occurs with tolerance to haloperidol. Repeated haloperidol pretreatment also diminished DA accumulation following a challenge dose of HA-966, to a similar extent as that caused by repeated pretreatment with HA-966. These similar effects of pretreatment with HA-966 or haloperidol on the response to the HA-966 challenge are in line with, and strengthen, the idea that an increased sensitivity of presynaptic DA receptors is responsible for the decreasing effect of HA-966 after its repeated administration. Haloperidol and HA-966 clearly have different effects on postsynaptic DA receptors, as is shown by their differential effects on striatal [3H]spiperone binding.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Evidence for a role of glycine in area tempestas for triggering convulsive seizures.

An epileptogenic region of the deep prepiriform cortex, area tempestas (AT), triggers convulsive seizures in response to the focal application of GABA antagonists, muscarinic agonists and excitatory amino acid agonists. In all cases, activation of N-methyl-D-aspartate (NMDA)-sensitive receptors in AT is required for triggering convulsions from this site. To determine whether glycine is involved in the activation of NMDA-sensitive receptors in AT, we evaluated the effects of 7-chlorokynurenic acid (7-CLKYN); kynurenic acid (KYN) and 3-amino-1-hydroxy-2-pyrrolidone (HA-966) on convulsions evoked by focal application of bicuculline methiodide (118 pmol) into AT. Significant anticonvulsant effects were obtained with 1.25 nmol of 7-CLKYN, 6.25 nmol of KYN and 60 nmol of HA-966 in AT. 7-CLKYN in AT also blocked the convulsant effects of carbachol (273 pmol) and kainic acid (117 pmol) injected into AT. When injected into the lateral ventricle, high doses (50-100 nmol) of 7-CLKYN were required in order to attenuate AT-evoked convulsions and these doses produced marked ataxia. In contrast, no ataxia was observed following 7-CLKYN application into AT at anticonvulsant doses. Our results implicate glycine antagonism as a mechanism for preventing convulsions triggered via NMDA receptor activation in AT and demonstrate that a different anatomical site of action is responsible for the motor impairment produced by glycine antagonism.

Animals↗
PubMed1992

Antinociceptive actions of different classes of excitatory amino acid receptor antagonists in mice.

Intrathecal (i.t.) injection of the competitive and selective N-methyl-D-aspartate (NMDA) receptor antagonists DL-2-amino-5-phosphonopentanoic acid (AP5), D-2-amino-7-phosphonoheptanoic acid (AP7), beta-D-aspartylaminomethyl phosphonic acid (Asp-AMP), 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and gamma-D-glutamylaminomethyl phosphonic acid (Glu-AMP) produced dose-dependent and reversible analgesic effects in the mouse hot-plate and formalin tests of nociception. They were slightly more potent in the formalin test but had no or negligible effects in the tail-flick test. The non-selective or non-NMDA receptor antagonists 6-cyano-7-nitro-quinoxalinedione (CNQX), 6,7-dinitro-quinoxalinedione (DNQX), gamma-D-glutamylglycine (gamma DGG), gamma-glutamylaminomethyl sulphonic acid (GAMS), kynurenic acid, cis-2,3-piperidine dicarboxylic acid (cis-PDA; partial agonist) and p-bromobenzoyl piperazine dicarboxylic acid (pBB-PzDA) had the same efficacy in the mouse hot-plate, tail-flick and formalin tests (gamma DGG and pBB-PzDA were not tested in the formalin test). This heterogeneous group of antagonists was somewhat more potent in the tail-flick test and slightly less potent in the formalin test than in the hot-plate test. Of the two glycine site antagonists tested, 7-chlorokynurenic acid (7-Cl-Kyn) and (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), the effect of the latter was compatible with selective action at the NMDA receptor complex while the action of the former was comparable to those of non-selective excitatory amino acid (EAA) receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1993

Binding characteristics of remoxipride and its metabolites to dopamine D2 and D3 receptors.

The substituted benzamide, remoxipride, is a new atypical antipsychotic agent with good clinical efficacy and low extrapyramidal side-effect potential. In the present study, the in vitro receptor binding properties of remoxipride and several of its metabolites to rat striatal dopamine D2 and cloned human dopamine D2A and D3 receptors were investigated. Remoxipride bound to [3H]raclopride-labelled dopamine D2 receptors in rat striatum with an affinity (Ki) of 113 nM. The significantly lower affinities of remoxipride reported when [3H]spiperone was used as a radioligand are suggested to be due to methodological problems associated with the use of very high-affinity radioligands. Some of the phenolic metabolites of remoxipride found mainly in rat exhibited considerably higher affinities to dopamine D2 and D3 receptors than remoxipride itself. The pyrrolidone metabolites found mainly in the human had very low dopamine D2 and D3 affinities. The present in vitro results suggest that the behavioural effects of remoxipride in rats may reflect the effect of remoxipride and some of its high-affinity metabolites.

Animals↗