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Biomedical subjects

A Reches

Publications and source records attributed to A Reches.

At least 37 records · Page 2Linked to original sources
PubMed1991

Preserved striatal tyrosine hydroxylase activity, assessed in vivo, following neonatal hypoxia-ischemia.

Previous in vitro studies have shown that biochemical indices of striatal dopaminergic systems are preserved following neonatal hypoxia-ischemia. There has been no previous assessment of these systems in vivo. Using the accumulation of striatal dopa following administration of a dopa decarboxylase inhibitor as an in vivo measure of tyrosine hydroxylase (TH) activity, we have found that baseline TH activity, and its regulation by both neuronal activity and presynaptic autoreceptors are also preserved following hypoxia-ischemia.

Animals↗
PubMed1991

In vitro release and intestinal absorption of physostigmine salicylate from submicron emulsions.

The in vitro release of physostigmine salicylate (PS) from a submicron emulsion and an aqueous solution was studied using the dialysis bag method. These formulations were then perfused to various locations along the rat small intestine (proximal, mid, and distal jejunum), and two lengths (10 and 55 cm). The disappearance of PS from the luminal compartment and its appearance in the blood compartment was monitored. In the in vitro drug release from emulsion experiments, a biphasic appearance of PS in the sink solution was observed, suggesting a possible sustained release from the emulsion. However, absorption data from perfusion studies did not correlate with this in vitro observation. No significant difference was found in absorption from emulsion versus solution in the mid jejunum where PS absorption was maximal. The difference between the two liquid formulations was observed only in those intestinal segments where the absorption was relatively low [absorption rate values of 4.6 +/- 0.86 and 9.98 +/- 2.04 (log%/min) x 10(-3) in the proximal and distal parts of the small intestine, respectively, as compared with 14.0 +/- 1.2-14.8 +/- 1.1 (log%/min) x 10(-3) in the mid jejunum]. In the distal part of the rat small intestine, PS was absorbed significantly better from solution than from the submicron emulsion. Cholinesterase activity in blood samples collected after intestinal perfusion with emulsion or solution revealed lower enzyme activity following emulsion administration.

Acetylcholinesterase↗
PubMed1990

Effect of nitecapone (OR-462) on the pharmacokinetics of levodopa and 3-O-methyldopa formation in cynomolgus monkeys.

3-O-Methyldopa (OMD) is the principal circulating metabolite formed from exogenously administered levodopa. We studied the effect of nitecapone (OR-462), a novel inhibitor of catechol-O-methyltransferase (COMT), on OMD formation in cynomolgus monkeys following intravenous levodopa administration. The drug does not cross the blood-brain barrier, and therefore inhibits only peripheral OMD formation. At a dose of 5 mg/kg, nitecapone reduced the area under the OMD concentration-time curve by 50%. Inhibition of OMD production was maximal at 65% following a dose of 10 mg/kg. A dose of 15 mg/kg produced no further inhibition. The plasma pharmacokinetics of carbidopa, levodopa, and OMD in the monkeys were similar to those in humans. No adverse physiological effects of nitecapone were observed. In single-dose studies, OR-462 is an effective peripheral COMT inhibitor.

Animals↗
PubMed1987

Effect of intrastriatal and intranigral administration of synthetic neuromelanin on the dopaminergic neurotoxicity of MPTP in rodents.

Previous studies showed that the neurotoxin MPTP and its toxic metabolites bind with high affinity to neuromelanin (NM). Therefore, the presence of NM in human and primate but not in rodent substantia nigra, theoretically may be responsible for the species-selective dopaminergic (DA) toxicity of MPTP. We measured DA levels in rodent striatum 7 days after an acute single challenge with MPTP (40 mg/kg, s.c.) given alone or 24 h following unilateral intrastriatal injections of synthetic DA-NM in mice and intrastriatal or intranigral pigment administration in rats. Ipsilateral striatal DA levels were unaffected in control rodents treated with unilateral intrastriatal or intranigral DA-NM. In mice, systemic MPTP produced marked striatal DA depletions which were mildly increased in the striata given prior DA-NM injections. In rats, a species resistant to MPTP, administration of toxin did not affect striatal DA levels. However, after pretreatment with unilateral intrastriatal DA-NM, MPTP induced mild DA falls in ipsilateral striata. By contrast, intranigral administration of DA-NM followed by MPTP, did not alter ipsilateral striatal DA in rats. The findings suggest that intrastriatal DA-NM in mice and rats may augment or initiate, respectively. MPTP-induced damage to sensitive DA-nerve-terminals perhaps by its action as a depot for binding and protracted release and action of the toxin. Lack of effect of intranigral DA-NM which is retained extraneuronally suggests that role of NM in the toxicity of MPTP may depend on its location within DA cell bodies in the nigra.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Effect of hypothalamic lesions on experimental autoimmune diseases in rats.

The development of experimental autoimmune encephalomyelitis (EAE) was prevented in rats immunized with encephalitogenic antigen two weeks, but not twelve weeks, after stereotaxic electrolytic destruction of the anterior hypothalamus. Serum antibody level to the antigen myelin basic protein was decreased, and in vitro lymphocyte transformation response to a mitogen was increased. On the other hand, incidence and intensity of chronic experimental autoimmune myasthenia gravis (EAMG) induced by acetylcholine receptor immunization were higher in rats with anterior hypothalamic lesion. In addition, expression of EAE in rats was inhibited when dopamine and norepinephrine in brain were depleted due to intraventricular injection of 6-hydroxydopamine or subcutaneous injection of reserpine. The study indicates hypothalamic modulatory effects on autoimmune response as well as possible involvement of neurotransmitters in this kind of neuroimmunomodulation.

Animals↗
PubMed1986

Reserpine-induced up-regulation of dopamine D2 receptors in the rat striatum is enhanced by denervation but not by chronic receptor blockade.

Compensatory increases in the density of dopamine (DA) D2 receptors in the rat striatum occur following chronic interruption of dopaminergic neurotransmission. Substantia nigra lesions, DA depletion with reserpine and D2 receptor blockade by neuroleptics increase the number of striatal D2 receptors as identified with the D2 ligand, [3H]spiperone [( 3H]SPIP). Chronic administration of haloperidol to substantia nigra-lesioned rats causes an additive increase in binding over levels obtained with one treatment alone. In this study we have found a similar response when lesioned animals are treated with reserpine. However, compensatory increases in the number of [3H]SPIP binding sites found after combined administration of reserpine and haloperidol to intact rats do not exceed levels obtained following administration of either drug alone. The data suggest that up-regulation of striatal D2 binding sites occurring after substantia nigra lesions is unique relative to other forms of up-regulation and may involve the loss of a presynaptic regulatory factor other than DA.

Animals↗
PubMed1986

Parkinson's disease in monozygotic twins.

Recent studies of twins have demonstrated an unexpectedly low concordance of Parkinson's disease in monozygotic twins. Only two monozygotic twin pairs concordant for it have been reported. However, both pairs were atypical because of an early age at onset and other unusual features. We studied a monozygotic twin pair concordant for typical Parkinson's disease. The brothers have lived apart for forty years. The onset of tremor occurred three months apart, at age 71. The progression of the symptoms has been identical. Although one of the twins is more severely affected, both have typical manifestations of Parkinson's disease that respond well to dopaminergic medication. The occurrence of Parkinson's disease in these monozygotic twins suggests that genetic susceptibility is important in the tremor-dominant variety of Parkinson's disease.

Aged↗
PubMed1986

Pharmacologic evaluation of dopaminergic receptor blockade by metoclopramide.

The occurrence of adverse extrapyramidal effects following metoclopramide (MCP) therapy has been well documented in humans. In rats, MCP produced catalepsy and inhibited apomorphine-induced stereotypy, locomotor activity, and rotational behavior. MCP also accelerated dopamine turnover, potently stimulated prolactin release, and, at high concentrations, inhibited [3H]spiperone binding to striatal membranes. These behavioral and biochemical effects induced by MCP were similar to those observed with haloperidol. We conclude that MCP possesses most of the pharmacological properties of neuroleptic agents.

Animals↗
PubMed1986

Clonazepam-induced up-regulation of serotonin1 and serotonin2 binding sites in rat frontal cortex.

Chronic administration of the benzodiazepine clonazepam increased the number of [3H]5-HT (5-HT1) and [3H]SPIP (5-HT2) binding sites in rat frontal cortex. In each instance, binding changes reflected increases in the maximum densities of binding sites (Bmax) with no change in ligand affinities (KD). Increases in binding required continued clonazepam exposure (10 days) at high doses. [3H]5-HT binding was significantly elevated at daily dose levels (i.p.) of 5.0 mg/kg but not 2.5 mg/kg. [3H]SPIP binding was significantly increased at drug doses of 2.5 mg/kg but not 1.0 mg/kg. Binding changes were regional in that they occurred in membranes from frontal cortex but not brainstem. A second benzodiazepine, diazepam, did not affect either binding site at daily doses of 30 mg/kg. These data suggest that serotonin receptor changes seen after chronic clonazepam may occur as a compensatory response to decreases in the presynaptic release of serotonin.

Animals↗
PubMed1985

Presynaptic inhibition of dopamine synthesis in rat striatum: effects of chronic dopamine depletion and receptor blockade.

These studies assessed the effects of dopamine (DA) depletion and receptor blockade on presynaptic inhibition of DA synthesis in the rat striatum. Chronic reserpine administration significantly decreased striatal DA levels but did not affect in vivo tyrosine hydroxylase activity, as determined by following dihydroxyphenylalanine (DOPA) accumulations. Both reserpine and haloperidol increased the sensitivity of presynaptic striatal DA response as determined by the ability of apomorphine (APO) to inhibit DOPA accumulation in NSD-1015-treated rats. The effect of concurrent administration of reserpine plus haloperidol on presynaptic response was additive. Additivity occurred at doses of reserpine and haloperidol which induced maximum sensitivity when administered singularly. The data suggest that increases in sensitivity of presynaptic DA response following DA depletion and receptor blockade are mediated by separate regulatory mechanisms.

Animals↗
PubMed1985

Serotonin depletion induced by reserpine is attenuated by prophylactic administration of lithium.

Prophylactic administration of lithium significantly attenuated the serotonin depleting effects of reserpine. In rat brain, lithium did not change the capacity of the storage protein, serotonin binding protein to bind the amine either in vivo or in vitro nor did it change its sensitivity to reserpine. However, the chronic administration of lithium significantly decreased reserpine levels in plasma and brain tissue of treated rats compared with rats which were treated only with reserpine. It is concluded that the antagonism between reserpine and lithium does not involve the serotonin binding protein but may be due to the lithium-induced reduction of reserpine levels.

Animals↗
PubMed1985

Tetrabenazine induces acute dystonic reactions.

Four patients suffered acute dystonic reactions caused by tetrabenazine. Because dystonic reactions have previously been reported only after dopamine receptor blockade and not with dopamine depletion, it is likely that the ability of tetrabenazine to induce acute dystonia is due to its dopamine receptor blocking properties. Because tetrabenazine can induce acute dystonia even when combined with alpha-methyl-p-tyrosine, presynaptic dopamine stores may not be necessary for these reactions to occur.

Acute Disease↗
PubMed1985

Attenuation by electroshock treatment of the haloperidol-induced rise in the binding of 3H-imipramine to rat brain membranes.

Studies were conducted in rats to investigate whether chronic haloperidol treatment, electroshock treatment (EST), or a combination of both affects the high-affinity binding of 3H-imipramine to cerebral membranes. Chronic haloperidol (2 mg/kg SC daily for 28 days) resulted in a significant decrease in the density of binding sites in animals killed 1 h after the last treatment, but binding was markedly enhanced after a "washout" period of 5 days. In animals subjected to EST (20-30 mA, 1.5 s, 60 Hz; three times a week for 4 weeks) and killed 1 h after the last treatment, there were no apparent changes, but when animals were allowed a recovery period of 5 days there appeared to be a slight increase in binding. The marked increase in binding seen after haloperidol withdrawal was no longer apparent in animals treated with both haloperidol and EST, indicating that EST acts to attenuate the increase in binding seen after withdrawal of chronic haloperidol. It is suggested that chronic haloperidol may influence presynaptic recognition sites that regulate serotonin uptake and that EST may interact with haloperidol to "stabilize" these presynaptic sites.

Animals↗
PubMed1985

DL-threo-DOPS as a precursor of noradrenaline.

DL-threo-Dihydroxyphenylserine (DL-threo-DOPS) is a non-physiological precursor of noradrenaline (NA). The formation of NA from DL-threo-DOPS has been reported to occur in various mammalian tissue. Since NA deficiency is thought to be underlying mechanism in several neurological disorders, we studied the role of the DL-threo-DOPS as a precursor of NA. In rats treated with DL-threo-DOPS, heart NA levels increased in a dose-dependent manner with maximal effect obtained 1 h after intraperitoneal injection of the drug. However, no effect of DL-threo-DOPS on brain NA levels or DA metabolism was detected. The effect of DL-threo-DOPS on heart NA levels was completely inhibited in the presence of carbidopa and significantly enhanced in the presence of pargyline. Under these conditions, DL-threo-DOPS had no effect on brain catecholamines. Depletion of catecholamines was obtained by pretreatment with either alpha-methyl-p-tyrosine (AMPT), reserpine or FLA-63. DL-threo-DOPS increased NA levels in the heart but not in the brain. Finally, coadministration of DL-threo-DOPS with levodopa potentiated the effect of levodopa on brain DA metabolism. This effect was independent of peripheral dopa decarboxylase activity and was also shown in circling behaviour in rats with unilateral destruction of the nigrostriatal pathway. In rats, DL-threo-DOPS is an effective peripheral precursor of NA but the drug itself has no effect on brain catecholamines. DL-threo-DOPS may, however, enhance levodopa effects in the brain.

Animals↗
PubMed1985

Clonazepam-induced up-regulation of serotonin1 binding sites in frontal cortex of rat.

Chronic administration of the benzodiazepine, clonazepam, increased the number of [3H]5-hydroxytryptamine (5-HT1) binding sites in the frontal cortex of the rat. The increase reflected a change in the maximum density of binding sites (Bmax) with no change in ligand affinity (Kd). Increased binding occurred after continued exposure (10 days) to large (5.0 mg/kg) doses of clonazepam. The changes in [3H]5-HT binding were regional in that they occurred in membranes from the frontal cortex but not the brainstem. The effects were also at least partially selective for 5-HT receptors since the binding of the beta-adrenergic radioligand, [3H]dihydroalprenolol, was not affected by clonazepam. A second benzodiazepine, diazepam, did not affect the binding of [3H]5-HT at doses of 30 mg/kg per day. The latter data suggest that the effects of benzodiazepines on serotonin 5-HT1 receptors are unique to clonazepam.

Animals↗