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Biomedical subjects

E Melamed

Publications and source records attributed to E Melamed.

At least 55 records · Page 3Linked to original sources
PubMed2000

Developmental changes in antioxidant enzymes and oxidative damage in kidneys, liver and brain of bcl-2 knockout mice.

While programmed cell death is induced by a variety of internal and external stimuli, including reactive oxygen species, the anti-apoptotic protein Bcl-2 is involved in opposing cell death and affects the antioxidant status of cells. Since the exact mechanism of its action is uncertain, in this study we examined the role of Bcl-2 using a loss of function model, Bcl-2 knockout mice. The consequence of Bcl-2 knockout was assessed in kidneys, liver and brain, using protein carbonyls and cellular levels of antioxidant enzymes as markers of oxidative stress. Kidney extracts from 8 days-old Bcl-2-knockout mice had 59% higher content of protein carbonyls relative to the wild type, but similar levels of oxidized proteins at the age of 30 days. By marked contrast, in liver and brain, levels of protein carbonyls were similar at 8 days but by 30 days the liver of knockout animals (and brains, as we have shown previously) show 36% higher protein carbonyls. Measures of glutathione reductase (GRX), glutathione transferase (GST) and catalase revealed significantly higher levels in kidneys of 8 days old Bcl-2-knockout mice compared to wild type. By 30 days activities of glutathione-related enzymes and catalase increased and abolished the differences between the knockout and wild type. At 8 days, in liver there were no significant differences in activities of all enzymes between the mice, however by 30 days, the specific activity of GRX was significantly higher in Bcl-2-knockout mice, relative to controls. From day 8 to day 30 there was an increase in liver catalase activity that resulted in significantly higher levels in Bcl-2-knockout animals. Catalase activity in brains of Bcl-2-knockout, 8 days old mice was significantly higher compared to the wild type, and significantly lowers at 30 days. Taken together our findings indicate that Bcl-2 knockout results in significant perturbations of oxidative metabolism and antioxidant status of in kidney, liver and brain. Such changes are tissue specific with respect to age, magnitude and type of enzyme affected.

Animals↗
PubMed1999

[Apomorphine for treatment of "off-periods" in Parkinson's disease].

After 3-5 years of continuous use of 1-dopa preparations for Parkinson's disease, 25%-50% of patients develop side-effects such as the "on-off" phenomenon and involuntary movements that markedly impair function. One cause of these manifestations is evidently a disturbance in the absorption of 1-dopa. We attempted to avoid this problem by using subcutaneous injections. Apomorphine is a rapid-acting dopamine agonist which causes a return from "off" to "on" within minutes. We present the results of a trial of subcutaneous injections of apomorphine in 22 Parkinsonian patients (12 males, 10 females) with severe motor fluctuations. During 5 days prior to the apomorphine all received Motilium (domperidone, 60 mg/d) to prevent nausea and vomiting. All were hospitalized initially to determine optimal dosage and to teach them the technique of self-injection. 2 to 4 mg of apomorphine were injected 1 to 3 times daily for 2 to 12 months. In 17 patients (80%) "off" periods were reduced without significant side-effects. Apomorphine seems to be effective, tolerable treatment for shortening 1-dopa induced "off" periods.

Aged↗
PubMed1999

Dopamine-melanin is actively phagocytized by PC12 cells and cerebellar granular cells: possible implications for the etiology of Parkinson's disease.

Neuromelanin in the substantia nigra may be associated with the pathogenesis of nigral cell death in Parkinson's disease. We used synthetic dopamine-melanin (DA-M) as a model compound for neuromelanin and examined its toxic effects on mice cerebellar granule cells and a rat pheochromocytoma cell line (PC12). The DA-M and dopamine-treated cells showed an accumulation of black deposits when examined by light microscopy. Electron microscopy revealed different stages of DA-M phagocytosis, starting with DA-M binding, engulfment of the particles and the formation of phagosomes located in the cytoplasm. Using absorption assays, we found that NaN3 and low temperature inhibit the internalization of DA-M, pointing to an energy-dependent phagocytosis mechanism. These results suggest that neuromelanin can be phagocytised by neuronal cells which may thus be subjected to its toxic effects. These findings may contribute to our understanding of the formation and disposition of neuromelanin and its possible role in the etiology of Parkinson's disease.

Animals↗
PubMed1999

Camptocormia (bent spine) in patients with Parkinson's disease--characterization and possible pathogenesis of an unusual phenomenon.

Camptocormia is characterized by severe forward flexion of the thoracolumbar spine which increases while walking and disappears in the recumbent position. We describe for the first time eight patients with presumed idiopathic Parkinson's disease (mean age 66+/-5 yrs; mean symptom duration 13.1+/-5.1 yrs) who developed camptocormia. This impressive abnormal posture emerged 4-14 years from disease onset, and in some patients stooped posture was the prominent symptom at diagnosis. There was no clear correlation between camptocormia and levodopa treatment. In some patients the camptocormic posture improved, and in others it was unchanged or even aggravated following levodopa administration. Three patients reported worsening of this symptom during "off" periods and also with fatigue. The pathogenesis of this phenomenon is unknown but might represent either a rare type of dystonia or an extreme form of rigidity.

Aged↗
PubMed1999

Current management of motor fluctuations in patients with advanced Parkinson's disease treated chronically with levodopa.

Motor fluctuations after long-term administration of levodopa may be due to central pharmacodynamic mechanisms such as reduced striatal synthesis and storage of dopamine from exogenous levodopa and subsensitization of postsynaptic dopaminergic receptors. Peripheral pharmacokinetic mechanisms may be equally important, particularly in motor fluctuations of the "delayed on" (increased time latencies from dose intake to start-up of clinical benefit) and "no-on" (complete failure of a levodopa dose to exert an "on" response) types. Levodopa itself has a very poor solubility. In addition, there is delayed gastric emptying in many advanced patients. Therefore, an oral dose of levodopa may remain in the stomach for long periods of time before it passes into the duodenum where there is immediate absorption. Consequently, in order to overcome response fluctuations caused by impaired pharmacokinetic mechanisms and to improve its absorption, we recommend that levodopa be taken in multiple small doses, on an empty stomach, preferably crushed and mixed with a lot of liquid. Protein intake should be minimized. Prokinetic drugs such as prepulsid (Cisaprid) could be used to facilitate gastric motility and levodopa transit time. Administration of crushed levodopa through nasoduodenal or gastrojejunostomy tubes may be helpful in certain circumstances. Bypassing the stomach with subcutaneous injections of apomorphine may provide dramatic rescue from difficult "off" situations. Oral and s.c. administration of novel, extremely soluble prodrugs of levodopa, e.g., levodopa ethylester, may offer a new approach to overcome difficulties in levodopa absorption. Addition of dopamine agonists, MAO-B inhibitors, COMT inhibitors and controlled release levodopa preparations may be helpful in prolonging the duration of efficacy of each single levodopa dose. Levodopa, administered orally, usually combined with peripheral dopa decarboxylase inhibitors, continues to be the most widely-used and most effective pharmacological treatment for Parkinson's disease (Melamed, 1987). Undoubtedly, the outstanding therapeutic success of levodopa represents a dramatic and revolutionary breakthrough in medicine, in general, and in neurology, in particular. Although, since the introduction of levodopa, there have been many additional pharmacological and even surgical anti-parkinsonian strategies, it still stands out as a mandatory axis of treatment in the majority of patients (Steigler and Quinn, 1992). Indeed, levodopa therapy improves, sometimes markedly, the motor signs and symptoms of the illness, the functional capacity and quality of life and perhaps also life expectancy of the afflicted patients. It is therefore unfortunate that after an initial problem-free period of successful, smooth and stable clinical benefit from levodopa that lasts about two to five years, the responsiveness of many patients worsens with the emergence of a variety of complications (Marsden et al., 1982; Hardie et al., 1984). These adverse reactions include dyskinesias and dystonias, psychotic problems and, particularly, the troublesome motor fluctuations (Marsden and Parkes, 1977; Marsden, 1994). The latter phenomenon may be particularly complex, limiting and disabling. It is believed that most patients on long-term levodopa therapy will, sooner or later, develop response fluctuations of varying types and severity (Riley and Lang, 1993). Because of the serious impact of these phenomena on the quality of life and function of the patients, many efforts are now being undertaken to identify the responsible mechanisms and to devise preventive and therapeutic measures.

Antiparkinson Agents↗
PubMed1999

The involvement of p53 in dopamine-induced apoptosis of cerebellar granule neurons and leukemic cells overexpressing p53.

1. The pathogenesis of the selective degeneration of the dopaminergic neurons in Parkinson's disease is still enigmatic. Recently we have shown that dopamine can induce apoptosis in postmitotic neuronal cells, as well as in other cellular systems, thus suggesting a role for this endogenous neurotransmitter and associated oxidative stress in the neuronal death process. 2. Dopamine has been shown to be capable of inducing DNA damage through its oxidative metabolites. p53 is a transcription factor that has a major role in determining cell fate in response to DNA damage. We therefore examined the possible correlation between dopamine-triggered apoptosis, DNA damage and levels of total phosphorylated p53 protein in cultured mouse cerebellar granule neurons. 3. Marked DNA damage and apoptotic nuclear condensation and fragmentation were detected within several hours of exposure to dopamine. An associated marked threefold increase in p53 phosphorylation was observed within this time window. Using a temperature-sensitive p53 activation system in leukemia LTR6 cells, were found that p53 inactivation dramatically attenuated dopamine toxicity. 4. We therefore conclude that DNA damage and p53 activation may have a role in mediating dopamine-induced apoptosis. Modulation of the p53 system may therefore have a protective role against the toxicity of this endogenous neurotransmitter and associated oxidative stress.

Animals↗
PubMed1999

Semaphorins as mediators of neuronal apoptosis.

Shrinkage and collapse of the neuritic network are often observed during the process of neuronal apoptosis. However, the molecular and biochemical basis for the axonal damage associated with neuronal cell death is still unclear. We present evidence for the involvement of axon guidance molecules with repulsive cues in neuronal cell death. Using the differential display approach, an up-regulation of collapsin response mediator protein was detected in sympathetic neurons undergoing dopamine-induced apoptosis. A synchronized induction of mRNA of the secreted collapsin-1 and the intracellular collapsin response mediator protein that preceded commitment of neurons to apoptosis was detected. Antibodies directed against a conserved collapsin-derived peptide provided marked and prolonged protection of several neuronal cell types from dopamine-induced apoptosis. Moreover, neuronal apoptosis was inhibited by antibodies against neuropilin-1, a putative component of the semaphorin III/collapsin-1 receptor. Induction of neuronal apoptosis was also caused by exposure of neurons to semaphorin III-alkaline phosphatase secreted from 293EBNA cells. Anti-collapsin-1 antibodies were effective in blocking the semaphorin III-induced death process. We therefore suggest that, before their death, apoptosis-destined neurons may produce and secrete destructive axon guidance molecules that can affect their neighboring cells and thus transfer a "death signal" across specific and susceptible neuronal populations.

Animals↗
PubMed1999

Early-occurrence of manual motor blocks in Parkinson's disease: a quantitative assessment.

OBJECTIVES: Quantitative analysis of internally-cued, repetitive motor performance in patients with Parkinson's disease (PD). MATERIAL AND METHODS: Computerized quantitative measurements of the frequency, duration and temporal profile of manual motor blocks (MMBs) during performance of a manual tapping task, in 39 patients with PD, as compared to 17 age-matched healthy controls. RESULTS: Performance of PD patients was markedly abnormal both quantitatively and qualitatively, as reflected by an increase (7.0% vs. 4.6%) in MMBs, and by their occurrence from onset of movement. The phenomenon was already observed in the early stages of the disease, and was also correlated with the occurrence of freezing of gait. A standard levodopa-carbidopa (125-12.5 mg) dose only partially affected this phenomenon. CONCLUSIONS: Augmented motor blocks in internally-cued performance should be recognized as a frequent, distinct and generalized feature of PD. Whereas the gait disorder is regarded as characteristic of the advanced stage of PD, our findings suggest that the basic defect in internal rhythm formation can be detected by sensitive measurement tools from the early stages of the disease. In addition, the methodology developed in this study to quantitatively measure manual motor blocks may be a useful tool for future development of therapeutic regimens for this debilitating aspect of motor dysfunction in PD.

Aged↗
PubMed1999

Psychosis: impact on the patient and family.

Psychosis represents a milestone in the progression of PD, often severely taxing caregivers and frequently warranting nursing-home placement. This step is often necessary because caregivers cannot tolerate, among other stressors, their loved ones' sexual aberrations and irrational accusations (which can be caused by paranoid ideation). Other salient features of parkinsonian psychosis comprise vivid nightmares, which often herald its onset; hallucinations, which are principally visual and stereotypical in content; agitation; aggression; delirium; and confusion that exceeds the typical erosion in mentation. Hallucinosis and paranoid ideation may in turn precipitate weight loss; food may be deemed inedible because of imagined contaminants, for instance, either worm infestations or a delusional fear of poisoning by the caregiver. Parkinsonian psychosis exhibits an age predilection; correlates with the duration of disease and levodopa therapy; and may be associated with increases in the dosage of this agent or other drugs given, either as monotherapy or with levodopa. Levodopa or dopamine agonist toxicity can lead to psychosis because of dopaminergic hypersensitivity. Unfortunately, attempts to diminish this untoward effect (eg, reducing the levodopa dosage, introducing neuroleptics) may curb the psychosis but also erode control of parkinsonian features. To avert this "dopamine dilemma," we have tested a selective serotonin antagonist (ondansetron), which essentially attenuated visual hallucinosis, improved delusional ideation and confusion, and was well tolerated. Other agents that can be tried for parkinsonian psychosis include the atypical neuroleptics olanzapine and clozapine.

Family↗