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M B Youdim

Publications and source records attributed to M B Youdim.

At least 91 records · Page 5Linked to original sources
PubMed1994

Selective MAO-A and B inhibitors, radical scavengers and nitric oxide synthase inhibitors in Parkinson's disease.

In the absence of identification of either an endogenously or an exogenously derived dopaminergic neurotoxin, the most valid hypothesis currently envisaged for etiopathology of Parkinson's disease (PD) is selective oxidative stress (OS) in substantia nigra (SN). Although OS is not proven, a significant body of evidence from studies on animal and Parkinsonian brain neurochemistry supports it. This hypothesis is based on excessive formation of reactive oxygen species (O2 and OH.) and demise of systems involved with scavenging or preventing the formation of such radicals from H2O2, generated as a consequence of dopamine oxidation (autoxidation and deamination). Since MAO (monoamine oxidase A and B are the major H2O2 generating enzymes in the SN much attention has been paid to their selective inhibitors as symptomatic and neuroprotective agents in PD. Attention should also be given to radical scavengers (e.g. iron chelators, lipid peroxidative inhibitors and Vitamin E derivatives) as therapeutic neuroprotective agents in PD. This is considered valid since a significant elevation of iron is known to occur selectively in SN zone compacta and within the remaining melanized dopamine neurons of Parkinsonian brains. Although all the mechanism of iron induced oxygen free radical formation is not fully known there is no doubt that it participates with H2O2 (Fenton chemistry) to generate cytotoxic hydroxyl radical (OH.) and induce tissue OS and neurodegeneration in 6-hydroxydopamine model of PD. The dramatic proliferation of reactive amoeboid macrophages and microglia seen in SN of PD brains together with OS is highly compatible with an inflammatory process, similar to what has been observed in Alzheimer's disease and multiple sclerosis brains. This has led us to examine the ability of reactive macrophages to produce oxygen free radicals in response to nitric oxide (NO) production. The latter radical has been implicated in the excitotoxicity of glutaminergic neurons innervating the striatum and SN. Indeed we have now observed that in reactive macrophages NO acts as a signal transducer of O2 production which can synergize with dopamine oxidation.

Amino Acid Oxidoreductases↗
PubMed1994

Oxidative stress: free radical production in neural degeneration.

It is not yet established whether oxidative stress is a major cause of cell death or simply a consequence of an unknown pathogenetic factor. Concerning chronic diseases, as Parkinson's and Alzheimer's disease are assumed to be, it is possible that a gradual impairment of cellular defense mechanisms leads to cell damage because of toxic substances being increasingly formed during normal cellular metabolism. This point of view brings into consideration the possibility that, besides exogenous factors, the pathogenetic process of neurodegeration is triggered by endogenous mechanisms, either by an endogenous toxin or by inherited metabolic disorders, which become progressively more evident with aging. In the following review, we focus on the oxidative stress theory of neurodegeneration, on excitotoxin-induced cell damage and on impairment of mitochondrial function as three major noxae being the most likely causes of cell death either independently or in connection with each other. First, having discussed clinical, pathophysiological, pathological and biochemical features of movement and cognitive disorders, we discuss the common features of these biochemical theories of neurodegeneration separately. Second, we attempt to evaluate possible biochemical links between them and third, we discuss experimental findings that confirm or rule out the involvement of any of these theories in neurodegeneration. Finally, we report some therapeutic strategies evolved from each of these theories.

Alzheimer Disease↗
PubMed1994

Pharmacological actions of l-deprenyl (selegiline) and other selective monoamine oxidase B inhibitors.

The acetylenic selective monoamine oxidase (MAO) type B suicide inhibitor, l-deprenyl (l-selegiline), has proved to be a useful adjuvant to L-dopa therapy and monotherapy of Parkinson's disease. Although not all features of its antiParkinson action are known, studies that used brains obtained at autopsy from patients who took l-deprenyl show that the selective inhibition of MAO-B with a concomitant increase of phenylethylamine and dopamine, but not of serotonin or noradrenaline, in the basal ganglia may be responsible for its mode of action. The increased life expectancy noted in patients with Parkinson's disease who received long-term therapy (9 years in an uncontrolled study) is another unexpected feature of the drug. These exciting data, if confirmed in other long-term clinical trials, may herald a neuroprotective approach to the treatment of this degenerative disease. More recent studies indicate that Parkinson's disease may eventually turn out to be a neurotoxic event resulting from oxidative stress-induced free radical species in the substantia nigra. Thus selective MAO-B inhibitors could represent a unique class of drugs, having symptomatic actions with possible neuroprotective and neurorescue actions in one.

Animals↗
PubMed1994

Biochemical actions of l-deprenyl (selegiline).

l-Deprenyl is a selective, irreversible monoamine oxidase (MAO) type B inhibitor. Dopamine is a relatively good MAO-B substrate in the human brain. Because Parkinson's disease is characterized by a decrease in dopaminergic neurotransmission in the basal ganglia, the selective inhibition of MAO-B should lead to diminished metabolism of dopamine in the nigrostriatal system and a significant increase in the concentration of the neurotransmitter. MAO-B inhibition explains the clinical efficacy of l-deprenyl in the treatment of Parkinson's disease and the prevention of the conversion of protoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is oxidized by MAO-B and can cause a parkinsonian syndrome, to their active neurotoxin. In addition, l-deprenyl appears to exhibit other biochemical actions that are independent of its MAO-B activity. These actions may be the basis of the neuroprotective effects of l-deprenyl and may include the inhibition of oxidative stress, an indirect influence on the polyamine binding site of the N-methyl-d-aspartate receptor and the stimulation of neurotrophic factors.

Animals↗
PubMed1994

Typical and atypical neuroleptics induce alteration in blood-brain barrier and brain 59FeCl3 uptake.

Long-term neuroleptic medication of schizophrenic patients induces extrapyramidal motor side effects, of which tardive dyskinesia (TD) is the most severe. The etiology of TD is still obscure. Recently, it was suggested that abnormal iron metabolism may play a crucial role in neuroleptic-induced dopamine D2 receptor super-sensitivity. The apparent relationship between neuroleptics and iron is further supported by the increase of iron in the basal ganglia of patients with TD. We now report on the ability of neuroleptic to alter the blood-brain barrier in the rat and to potentiate the normally limited iron transport into the brain. Thus, chronic treatment of rats with chlorpromazine and haloperidol facilitated 59Fe3+ uptake into brain cells. In contrast, clozapine, an atypical antipsychotic neuroleptic with little extrapyramidal motor side effects, caused iron sedimentation in brain blood vessels with no sign of detectable iron in the cells. Moreover, chronic treatment with chlorpromazine and haloperidol caused a 43% and 24% reduction, respectively, in liver nonheme iron, whereas clozapine induced an 81% increase. The apparent different potentials of chlorpromazine, haloperidol, and clozapine to increase iron transport into the brain from its peripheral stores may be linked to the severity of extrapyramidal motor side effects they induce and to the pathophysiology of TD.

Animals↗
PubMed1994

Altered brain metabolism of iron as a cause of neurodegenerative diseases?

Iron is the most abundant metal in the human body (Pollitt and Leibel, 1982; Youdim, 1988), and the brain, like the liver, contains a substantially higher concentration of iron than of any other metal (Yehuda and Youdim, 1988). Within the brain, iron shows an uneven distribution, with high levels in the basal ganglia (substantia nigra, putamen, caudate nucleus, and globus pallidus), red nucleus, and dentate nucleus (Spatz, 1922; Hallgren and Sourander, 1958; Hill and Switzer, 1984; Riederer et al., 1989). Iron deposition in the brain is mainly in organic storage forms such as ferritin but not hemosiderin (Hallgren and Sourander, 1958; Octave et al., 1983), with relatively little in a free and reactive form. Although the function of a regionally high brain iron content is unknown, the homeostasis of brain iron is thought to be necessary for normal brain function, especially in learning and memory (Youdim et al., 1989; Yehuda and Youdim, 1989; Pollit and Metallinos-Katsaras, 1990; Youdim, 1990). Thus, a high content of brain iron may be essential, particularly during development, but its presence means that injury to brain cells may release iron ions that can lead to oxidative stress via formation of oxygen free radicals. Such radicals are thought to be involved in lipid peroxidation of the cell membrane, leading to increased membrane fluidity, disturbance of calcium homeostasis, and finally cell death (Youdim et al., 1989; Halliwell, 1992). Iron is an essential participant in many metabolic processes, including (a) DNA, RNA, and protein synthesis, (b) as a cofactor of many heme and nonheme enzymes, (c) the formation of myelin, and (d) the development of the neuronal dendritic tree (Ben-Shachar et al., 1986; Youdim et al., 1991b). A deficiency of iron metabolism would therefore be expected to alter some or all of these processes (Jacobs and Worwood, 1980; Youdim, 1985, 1988). Studies of iron distribution in the human brain have demonstrated that the degree of iron deposition, primarily in the basal ganglia (a predominantly dopamine structure), increases with age (Hallgren and Sourander, 1958) and in certain disorders, most notably the basal ganglia disorders (Seitelberger, 1964). This review will present some of the experimental evidence indicating a role of disturbed iron metabolism as a cause of the neurodegenerative disorder Parkinson's disease and possibly other neurodegenerative disorders such as Alzheimer's disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Oxidoreductases↗
PubMed1994

The enigma of neuromelanin in Parkinson's disease substantia nigra.

The function of neuromelanin accumulation in the nigrostriatal dopamine neurons remains uncertain. Nevertheless, it is recognized that neuromelanin disappearance parallels the loss of dopamine neurons in Parkinson's disease, suggesting its participation in nigral cell death. It has been well known for some years that in systemic tissues melanin is a double-edged sword. On the one hand it can act as an antioxidant, but in the presence of transitional metals (primarily, iron) and drugs it promotes the formation of reactive oxygen free radicals. It is now apparent that synthetic dopamine-melanin and neuromelanin exhibit similar properties in vitro and nigrostriatal dopamine neuron co-culture studies. Thus, the identification of ionic iron in dopamine neurons of Parkinson's disease zona compacta and its association with neuromelanin has conferred a cytotoxic property to neuromelanin. This may explain the reported vulnerability of substantia nigra dopamine neurons in Parkinson's disease.

Antioxidants↗
PubMed1994

A mathematical model for appraisal of the impact of GH binding protein on GH receptor binding.

Discrepancies between GH measurements and growth rate of children have complicated diagnosis in a variety of clinical conditions. The competition of GH-BP with the GH-receptor towards GH-receptor binding can have a role in these discrepancies. A mathematical model was developed for appraising the availability of GH for receptor binding from measurements of serum GH by RIA and serum GH binding protein (BP) by a binding assay. Eighteen patients with high GH-BP (obesity), normal GH-BP (normal control) or low GH-BP (children, anorexia nervosa or cirrhosis of the liver) were the subjects of this study. Sera of patients with high, normal or low GH-BP levels were analyzed for their competition with [125I]hGH binding to rabbit liver membranes. Serum GH was measured by a commercial polyclonal RIA. Serum GH-BP was measured by a binding assay with dextran-coated charcoal separation. Receptor availability for GH was assessed by displacing of [125I]hGH from rabbit liver membranes. The decline in receptor availability for each hGH value, caused by GH-BP competition with the receptor, was calculated by subtraction of the percent displacement in the absence of GH-BP from the percent displacement in the presence of a given GH-BP value. The results were analyzed statistically to give a series of polynomes. These enabled the calculation of an activity factor for serum RIA GH levels, that should predict the receptor availability of each GH level, according to the concomitant GH-BP level.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

L-deprenyl confers specific protection against MPTP-induced Parkinson's disease-like movement disorder in the goldfish.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the goldfish causes a reversible, Parkinson's disease-like syndrome which includes loss of noradrenaline and dopamine from the brain, accumulation of the toxic metabolite 1-methyl-4-phenylpyridinium species (MPP+), and substantial reduction in movement. L-Deprenyl, a selective monoamine oxidase-B inhibitor, protects the goldfish from loss of movement, but clorgyline, a selective monoamine oxidase-A inhibitor, has no such protective action. L-Deprenyl and clorgyline primarily inhibit goldfish brain monoamine oxidase-B and monoamine oxidase-A, respectively. The mechanism by which MPTP causes reduced movement in goldfish is to cause an increase in resting time. Otherwise normal average velocity occurred during periods of movement. L-Deprenyl protection results in entirely 'normal' levels of resting time and average velocity during times of movement. Equivalent observations regarding l-deprenyl and clorgyline have been made in primate models of MPTP toxicity, and l-deprenyl is used for treatment of Parkinson's disease in humans. Therefore it is suggested that the evolutionarily equivalent subcortical circuitry and neural density of the goldfish brain may provide a useful model upon which to search for drugs relevant to human Parkinson's disease.

Animals↗
PubMed1993

The possible role of iron in the etiopathology of Parkinson's disease.

The identification of 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as dopaminergic neurotoxins that can induce parkinsonism in humans and animals has contributed to a better understanding of Parkinson's disease (PD). Although the involvement of similar neurotoxins has been implicated in PD, the etiology of the disease remains obscure. However, the recently described pathology of PD supports the view for a state of oxidative stress in the substantia nigra (SN), resulting as a consequence of the selective accumulation of iron in SN zona compacta and within the melanized dopamine neurons. Whether iron is directly involved cannot be ascertained. Nevertheless, the biochemical changes due to oxidative stress resulting from tissue iron overload (siderosis) are similar to those now being identified in parkinsonian SN. These include the reduction of mitochondrial electron transport, complex I and III activities, glutathione peroxidase activity, glutathione (GSH) ascorbate, calcium-binding protein, and superoxide dismutase and increase of basal lipid peroxidation and deposition of iron. The participation of iron-induced oxygen free radicals in the process of nigrostriatal dopamine neuron degeneration is strengthened by recent studies in which the neurotoxicity of 6-OHDA has been linked to the release of iron from its binding sites in ferritin. This is further supported by experiments with the prototype iron chelator, desferrioxamine (Desferal), a free-radical inhibitor, which protects against 6-OHDA-induced lesions in the rat. Indeed, intranigral iron injection in rats produces a selective lesioning of dopamine neurons, resulting in a behavioral and biochemical parkinsonism.

Animals↗
PubMed1993

The relevance of glial monoamine oxidase-B and polyamines to the action of selegiline in Parkinson's disease.

Dopamine and 2-phenylethylamine levels in striatal tissue are known to be increased after administration of selegiline (L-deprenyl), but it is still difficult to explain why this treatment induces longevity or dopaminergic neuroprotection in Parkinson's disease. In the absence of significant polyamine or diamine oxidase activities in human brain, polyamines and histamine are detoxified by N-acetylation and methylation, respectively. Methylhistamine as well as N-acetylated polyamine derivatives are selective substrates for monoamine oxidase type B (MAO-B). Theoretically at least, MAO-B inhibition by selegiline could result in the increase in the levels of polyamines and their N-acetyl derivatives. This could have significance for the action of selegiline in Parkinson's disease, as overactive corticostriatal glutaminergic function has been implicated in the degeneration of nigrostriatal dopamine neurons, and polyamines are potent modulators of the excitotoxic NMDA (N-methyl-D-aspartate)-glutamate subtype receptor.

Corpus Striatum↗
PubMed1993

Autoradiographic localization of strychnine-sensitive glycine receptor in bovine adrenal medulla.

The presence of an uptake system and a functional glycine receptor in adrenal medulla chromaffin cells was investigated using an autoradiographic technique in adrenal gland slices. Specific 3[H]glycine binding was observed in both adrenal cortex and medulla slices, while only specific binding of [3H]strychnine was seen only in chromaffin cells and was not associated with cortical cells. [3H]Glycine binding sites in the cortex are apparently different from those of [3H]strychnine binding sites in the medulla since excess strychnine does not displace [3H]glycine from adrenal cortex but does so from medulla. This difference supports biochemical evidence for glycine transport into medulla cells and glycine receptor sites on the chromaffin cell membrane.

Adrenal Cortex↗
PubMed1993

Dopamine metabolism and neurotransmission in primate brain in relationship to monoamine oxidase A and B inhibition.

The "cheese effect", potentiation of sympathomimetic action of indirectly acting amines such as tyramine, the main side effect of irreversible non-selective and selective monoamine oxidase (MAO) A inhibitors, has largely been eliminated in the new generation of reversible selective MAO-A and B and irreversible MAO-B inhibitors. These selective inhibitors are demonstrating unique pharmacology and initial controlled clinical studies are providing evidence to support their action as anti-depressants and anti-Parkinson's disease drugs and possibly as neuroprotectors. Thirty years of experience with non-selective MAO inhibitors has resulted in a better understanding and management of the new generation of MAO inhibitors. Because of their selective action on the specific forms of MAO, which results in selective elevation of brain noradrenaline and serotonin on the one hand and dopamine and phenylethylamine on the other, it is hoped that these drugs will be able to elucidate the functional roles of MAO-A and B subtypes with regards to dopamine metabolism in the human brain.

Animals↗
PubMed1993

Regulation of the growth hormone (GH) receptor and GH-binding protein by GH pulsatility.

Growth hormone (GH) secretion is pulsatile in man and every other mammalian species that has been studied. The magnitude of pulses, their frequency, and their regularity vary. The receptor, on its part, undergoes cycles of internalization and recycling that are in synchrony with the frequency of GH pulses. This sequence of events has been shown to be advantageous to growth. It is suggested that changes in GH secretion dynamics secondarily lead to most of the changes in GH receptor abundance and GH-binding protein (GH-BP) abundance. Across a wide scope of comparative studies, ontogenesis data, experimental systems, physiologic conditions, nutritional states, and disease situations, the pulsatility of serum GH is negatively correlated with cell membrane GH receptors and serum levels of GH-BP. It is suggested that these conditions regulate primarily the pattern of GH pulsatility, which in turn regulates the GH receptor/GH-BP, and thereby exert the specific effects on target cells to promote or suppress growth or to express distinct metabolic actions.

Adult↗
PubMed1993

Iron, melanin and dopamine interaction: relevance to Parkinson's disease.

1. Interaction between iron and melanin may provide a reasonable explanation for the vulnerability of the melanin containing dopaminergic neurons in the substantia nigra (SN) to neurodegeneration in Parkinson's disease (PD). 2. Scatchard analysis of the binding of iron to synthetic dopamine melanin revealed a high-affinity (KD = 13 nM) and a lower affinity (KD = 200 nM) binding sites. 3. The binding of iron to melanin is dependent on the concentration of melanin and on pH. 4. Iron chelators, U74500A, desferrioxamine and to a lesser extent 1,10-phenanthroline and chlorpromazine could displace iron from melanin. In contrast, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenyl-pyridinium (MPP+), which cause Parkinsonism, were unable to displace iron. 5. Melanin alone reduced lipid peroxidation in rat cortical membrane preparations. However, iron induced lipid peroxidation, which could be inhibited by desferrioxamine, was potentiated by melanin. 6. Iron bound to neuromelanin in melanized dopamine neurons was detected only in parkinsonian brains and not in controls. The interaction of iron with neuromelanin as identified by x-ray defraction technique was identical to iron interaction with synthetic dopamine melanin. 7. In the absence of an identified exogenous or endogenous neurotoxin in idiopathic Parkinson's disease, iron-melanin interaction in the SN may serve as a candidate for the oxygen-radical induced neurodegeneration of the melanin containing dopaminergic neurons.

Animals↗