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Biomedical subjects

E Melamed

Publications and source records attributed to E Melamed.

At least 163 records · Page 9Linked to original sources
PubMed1986

Diphenylhydantoin and phenobarbital suppress the dopaminergic neurotoxicity of MPTP in mice.

The combined administration of MPTP with the anticonvulsant drugs diphenylhydantoin or phenobarbital suppressed the MPTP-induced striatal DA depletions in mice. Co-treatment with diazepam, sodium valproate or carbamazepine was ineffective. The mechanism responsible for the protective effect of diphenylhydantoin and phenobarbital against DA neurotoxicity of MPTP is unknown but some previously available findings suggest that they may act, in part, via inhibition of MAO-B and/or DA reuptake in the striatum.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Systemic administration of antioxidants does not protect mice against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP).

We examined whether DA neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) can be prevented by combined systemic administration of antioxidants. C57 black mice were injected s.c. with MPTP (30 mg/kg), once daily for two days, alone, or with ascorbic acid (1 g/kg), alpha-tocopherol (100 mg/kg), or dimethylsulfoxide (50 microliters) i.p. for two days before, two days with and two days after MPTP, and decapitated 30 days later. MPTP once (30 mg/kg), alone, or with ascorbic acid (200 mg/kg) or cysteamine (75 mg/kg), two days before, one day with and 4 days after, and decapitated 10 days post-MPTP. MPTP once (15 mg/kg), alone, or with ascorbic acid (500 mg/kg, alpha-tocopherol (100 mg/kg), cysteamine (50 mg/kg) or sodium selenite (2.5 mg/kg), 90 min before and again 90 min after MPTP, and decapitated 7 days later. In all experiments, the marked striatal DA depletions produced by MPTP alone (by 40-70% from controls) were unchanged by cotreatments with the various antioxidants. Findings do not favor intraneuronal generation of superoxides and related cytotoxic free radicals as a major factor in the DA neurotoxicity of MPTP. They suggest that if natural Parkinson's disease is caused by an MPTP-like neurotoxin, early treatment with antioxidants is unlikely to protect nigrostriatal neurons and prevent disease progression.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Norepinephrine depletion in the paraventricular nucleus inhibits the adrenocortical responses to neural stimuli.

In view of the importance of teh paraventricular nuclei of the hypothalamus (PVN) in the regulation of adrenocortical secretion and the possible role of norepinephrine (NE) in this mechanism, we have studied the effects of injecting the catecholamine neurotoxin 6-hydroxydopamine into the PVN on basal corticosterone (CS) secretion and following ether stress and neural stimuli. PVN NE depletion did not affect the basal and the ether stress-induced rise in CS levels. However, it inhibited significantly the adrenal response to photic, acoustic and sciatic nerve stimulation, suggesting that the PVN NE plays a role in the activation of adrenocortical responses following afferent neural stimuli.

Acoustic Stimulation↗
PubMed1986

Hemispheric brain damage in unilateral status epilepticus.

A 20-year-old woman with psychomotor seizures developed prolonged unilateral status epilepticus followed by coma, right hemiparesis, fever, liver failure, and eventually death. Neuropathological findings included severe neuronal ischemic cell change and massive brain edema, essentially restricted to the left cerebral hemisphere. Massive destruction of the hemisphere involved in epileptic activity with sparing of the contralateral hemisphere provides supportive evidence that in humans prolonged seizure activity can cause permanent brain damage.

Adult↗
PubMed1986

Levels of some organochlorine residues in blood of patients with arteriosclerotic disease.

This study aims to elucidate if any association exists between the development of arteriosclerotic disease and contamination of the internal human environment with certain organochlorine compounds (OCCs). For this purpose the levels of DDT isomers and their metabolites, and of lindane, dieldrin, heptachlor epoxide, and polychlorinated biphenyls (PCBs) were determined in blood serum of 11 patients suffering from slight to moderate (group A), and 24 patients with moderate to severe (group B), arteriosclerotic lesions. The control group consisted of 27 patients with no obvious manifestations of arteriosclerosis. The main findings of the study in comparison with the control group were: Mean OCC residue levels in blood were slightly higher in group A and markedly so in group B; The variability and the extent of departure from normality of distributions of organochlorine insecticides (OCIs) decreased, whereas those of PCBs increased, in arteriosclerotic patients (more markedly in group B); The degree of correlation between blood serum levels of various OCCs was elevated in group A and low in group B. It remains to be ascertained whether changes in the body burden of OCCs are primary, resulting from increased exposure to and absorption of these compounds which thus contribute to the development of arteriosclerosis, or are of secondary origin, due to inhibition of xenobiotic metabolism caused by interference of the arteriosclerotic process with the functions of drug metabolizing enzymes of liver microsomes.

Arteriosclerosis↗
PubMed1986

Effect of postnatal light deprivation on the ontogenesis of dopamine neurons in rat retina.

In rats raised from birth under a regular dark-light cycle, retinal dopamine (DA) levels were low at 12 days, increased progressively and steeply at 16, 20, 30 and 60 days and peaked at about 75 days postnatally. Dark-rearing from birth suppressed the magnitude of the normal developmental pattern of DA concentrations in retina and at 20, 30 and 60 days of age they were markedly smaller compared with those in age-matched controls grown under regular cyclic illumination. In adult rats reared up to the age of 60 days in regular cyclic lighting and then transferred to complete darkness for additional periods of 7-60 days, there were marked reductions in retinal DA levels. In rats reared in total darkness for 16, 20 or 30 days after birth and then transferred to regular dark-light conditions for additional periods of up to 30 or 60 days, retinal DA levels were always higher than those in animals with continuous light deprivation. They were similar to or even higher than those in rats grown under regular dark-light cycle. Findings suggest that light stimulation is essential for the postnatal ontogenetic increases of synthesis and storage of DA within retinal DAergic neurons. Suppressed DA accumulation in retina induced by dark-rearing from birth is not irreversible and can be completely corrected by re-exposure to regular lighting conditions regardless of the durations of postnatal light deprivation.

Animals↗
PubMed1986

Dissociation of the effects of castration and testosterone replacement on sexual behavior and neural metabolism of dopamine in the male rat.

Sexually experienced, adult male rats were either castrated, castrated and implanted SC with a Silastic capsule containing testosterone (T), or sham operated. Coital performance of castrates gradually declined such that 4 weeks after surgery no males in this group ejaculated whereas 89% and 100%, respectively, of the rats in the castrated, T-treated and the sham-operated groups displayed ejaculation. Males in all three groups were decapitated 33-34 days post-operatively after 10 min exposure either to the behavioral test chamber, with an estrous female restrained in one corner behind a wire mesh screen, or to a home cage. Brains were quickly removed and the caudate-putamen, nucleus accumbens, septum, and preoptic area/anterior hypothalamus were frozen and saved for later estimation of dopamine (DA) and two neural metabolites of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The concentrations of DA, DOPAC, and HVA, as well as the ratio of DOPAC/DA, did not differ significantly in any of the 4 brain regions assayed among males in the three endocrine groups, regardless of whether they were killed after exposure to an estrous female or a home cage. The results fail to support the hypothesis that T-induced alterations in neurotransmission in nigro-striatal, mesolimbic, or incertohypothalamic DA pathways mediate the activational effect of this steroid on masculine sexual behavior.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Delayed onset of responses to single doses of L-dopa in parkinsonian fluctuators on long-term L-dopa therapy.

Dose-related fluctuations in response to L-Dopa such as the "wearing-off" phenomenon are a common side effect of long-term L-Dopa therapy. In a retrospective clinical analysis, 18 of 32 chronically treated parkinsonian fluctuators developed a delay in onset of a beneficial effect induced by single doses of L-Dopa. In these patients, there was a threefold increase in latency from ingestion of the first morning dose to "start-up" of a response (from 0.4 +/- 0.2 to 1.1 +/- 0.3 h) in parallel to a twofold decrease in its duration (from 4.2 +/- 1.1 to 1.7 +/- 0.8 h). Longer durations of illness and of L-Dopa therapy, occurrence of totally ineffective doses, poorer responsiveness to afternoon and evening doses, and early-morning dystonia were more prevalent in this group. In 14 of the 32 parkinsonian fluctuators, monitored "start up" of clinical effect occurred at about an hour after the first morning oral dose of L-Dopa. The dose-induced elevations in plasma L-Dopa levels started after a mean of about 0.5 h and were maximal at 1.25 h. The study suggests that prolongation of "start-up" latencies in response to single doses of L-Dopa is a rather common complication of chronic treatment and may increase patients' disability by further decreasing the duration of daily "on" periods. Causes for this phenomenon are unknown but retarded absorption of orally administered L-Dopa may be important.

Aged↗
PubMed1986

Regional cerebral blood flow in patients with Parkinson's disease under chronic levodopa therapy: measurements during "on" and "off" response fluctuations.

In ten Parkinsonians who developed dose-related response fluctuations under long-term levodopa therapy, regional cerebral blood flow (rCBF) and plasma levodopa levels were measured simultaneously, once during an "off" phase and again at an "on" stage of clinical benefit induced by a single oral dose of levodopa. Although plasma levodopa increased threefold during the "on" period, rCBF and the degree of its reduction from normal age-matched control values remained unchanged and similar to those in the "off" phase. Study suggests that the rCBF decreases in Parkinson's disease are unaffected by levodopa and are not due to deficient dopaminergic neurotransmission in the brain.

Adult↗
PubMed1986

Episodic unresponsiveness to single doses of L-dopa in parkinsonian fluctuators.

Episodic total unresponsiveness to single doses of L-dopa developed in 14 of 32 parkinsonians with declining efficacy and response fluctuations after chronic L-dopa therapy. Complete lack of clinical benefit after occasional doses was unpredictable, occurred at least once daily mostly in the afternoon, and differed from other response failures related to food intake. In two patients, total unresponsiveness after dose ingestion coincided with lack of increases in plasma L-dopa levels suggesting that phenomenon was due, in part, to failure of L-dopa absorption from the gut.

Aged↗
PubMed1985

In vivo effect of MPTP on monoamine oxidase activity in mouse striatum.

Striatal monoamine oxidase (MAO)-B, but not MAO-A, activity decreased in mice at 2 and 10 days and was back to control values at 20 and 30 days after systemic administration of N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Striatal dopaminergic (DA) depletions were maximal at 2 days and were only partially reversed at 30 days post-treatment. In rats, unilateral kainic acid lesions increased MAO-B but not MAO-A activity probably due to reactive gliosis, but MPTP did not affect DA levels in control and kainic acid-lesioned striata. Findings support the importance of MAO-B in the toxicity of MPTP and suggest that resistance of rat DA neurons to the neurotoxin is probably not due to species differences in MAO-B activity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Dopamine but not norepinephrine or serotonin uptake inhibitors protect mice against neurotoxicity of MPTP.

Combined administration of nomifensine, a DA reuptake inhibitor, and MPTP completely prevented the long-term (30 days post-treatment) striatal DA depletions induced by MPTP in mice. Cotreatment with desipramine and clomipramine or fluoxetine, inhibitors of NE and 5-HT, respectively had no effect on DA neurotoxicity of MPTP. The findings indicate that MPTP (or MPP+) is a substrate for the specific DA reuptake system and may explain, in part, its selective toxic effects on DA neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Suppression of MPTP-induced dopaminergic neurotoxicity in mice by nomifensine and L-DOPA.

To examine effects of various pharmacological manipulations of dopamine (DA) metabolism on DA neurotoxicity of N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), C57 black mice were injected with MPTP (30 mg/kg s.c., once daily for two days) alone or in combination with apomorphine, bromocriptine, haloperidol, L-DOPA or nomifensine. MPTP markedly decreased neostriatal DA concentrations at 2, 10, 20 and 30 days post-treatment indicating persistent degeneration of nigrostriatal DA neurons. Suppression or acceleration of DA turnover rates by the DA agonists apomorphine and bromocriptine or by the DA antagonist haloperidol, respectively, did not affect MPTP toxicity. MPTP-induced neostriatal DA depletions were markedly suppressed by nomifensine, a DA reuptake inhibitor, and attenuated by exogenous L-DOPA. MPTP may be a substrate for the DA reuptake system and its specific transport into nigrostriatal terminals may be an important factor for its selective neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Mesolimbic dopaminergic neurons are not spared by MPTP neurotoxicity in mice.

In C57 black mice, MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) (30 mg/kg X 2, 20 mg/kg X 15, 30 mg/kg X 15, or 35 mg/kg X 1) depleted DA in both striatum and accumbens but not in frontal cortex, hypothalamus and retina. DA decreases were more pronounced in striatum than in accumbens, were maximal at 2 days, partially reversed later but persisted up to 30 days after treatment. DA depletions in nigra were smaller earlier and maximal later. The study suggests that, in mice, MPTP damages nigrostriatal and mesolimbic projections but spares other DA neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Effect of L-DOPA on glucose oxidation and incorporation into glycogen in discrete brain regions of the rat.

Previous reports in which the [14C]deoxyglucose mapping technique was used, have demonstrated that systemic administration of L-DOPA can either increase or decrease glucose utilization in various brain regions. However, in the striatum, which contains a high concentration of dopamine, no conclusive results were found using this technique. In the present study we attempted, by implicating a different technique, to evaluate the effect of L-DOPA on glucose metabolism in the striatum. This approach is based on in vitro measuring of glucose oxidation to CO2 and its incorporation to glycogen. Rats were injected with carbidopa (100 mg/kg) and 1 h later with L-DOPA (50 mg/kg). The rats were sacrificed by decapitation 1 h after L-DOPA injection and the following brain regions were assayed for glucose oxidation to CO2 and its incorporation to glycogen: striatum, hypothalamus, hippocampus and prefrontal cortex. A significant increase of glucose oxidation of 50% was found in the striatum and hippocampus, while no change was demonstrated in the hypothalamus and cortex. The incorporation of glucose to glycogen was markedly reduced in the striatum and hippocampus while no change was found in the hypothalamus or cortex. The present results demonstrate that L-DOPA treatment increases glucose metabolism in specific brain areas. The mechanism involved might be an increase in cellular uptake of glucose and/or activation of enzymes participating in glucose metabolic pathways.

Animals↗