Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although Parkinson's disease is characterized by a loss of dopaminergic neurons in the substantia nigra not all dopaminergic neurons degenerate in this disease. This suggests that some specific factors make subpopulations of dopaminergic neurons more susceptible to the disease. Here, we show that the most vulnerable neurons are particularly sensitive to oxidative stress and rise in intracellular calcium concentrations. Because both events seem to occur in Parkinson's disease this may explain why some dopaminergic neurons degenerate and other do not.
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PMID:Neuronal vulnerability in Parkinson's disease. 912 Apr 27

The concept of neuroprotection relates to the fact that intervention may be able to interfere with the pathogenesis of neuronal cell death. Neuroprotective therapy may make it possible to delay disease progression or prevent the disease altogether. The pathophysiological mechanism of cell death in Parkinson's disease is unknown; however, hypotheses have been developed. The discovery that the toxin MPTP can cause Parkinson's disease both in humans and in animals strengthened the hypothesis that either exogenous or endogenous toxins may be involved in the mechanism of cell death in Parkinson's disease. The mechanism of MPTP toxicity has been elucidated, lending several possible mechanisms for therapeutic intervention in Parkinson's disease. Current data suggest that oxidative stress may play a prominent role in the pathogenesis of Parkinson's disease. It is possible that the generation of free radicals leads to neuronal cell death. There is also evidence that mitochondrial damage may play a role in the pathogenesis of Parkinson's disease. Other theories of possible pathogenesis include excitotoxicity, disturbances of calcium homeostasis, immunological mechanisms, and infectious etiologies. The first agent to be tested as a candidate for neuroprotection was the MAO-B inhibitor deprenyl. Evidence is reviewed for and against the theory that this drug is neuroprotective.
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PMID:Neuroprotective therapy for Parkinson's disease. 912 47

The effects of two physiological low molecular weight iron complexes, ferric lactate and ferric adenosine triphosphate (ATP) on brain Ca2+ homeostasis modification, have been studied in vitro and in vivo. In vitro ferric ATP complex shows a higher efficiency as modifier of Ca2+ homeostasis. This higher reactivity and the in vivo observed effect of increased brain uptake of iron from ferric lactate provoked by the presence of ATP, corroborate in vitro results showing an iron transfer from ferric lactate to ATP, as well as the mediator role of ATP in the iron-induced cellular Ca2+ homeostasis modification process. The possible role of this process in Parkinson's disease is discussed.
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PMID:Effects of iron complexes on brain calcium homeostasis. 914 73

Since the discovery that the loss of the dopaminergic innervation of the striatum resulted in Parkinson's disease, physiologists have attempted to understand the role of dopamine on striatal activity. Hypotheses relying upon concepts derived from studies of fast synaptic transmission have consistently failed to explain the actions of dopamine or other receptors coupled to G-proteins which modulate the properties of voltage-dependent ionic conductances responsible for synaptic integration and spike activity. Recently, patch clamp studies have revealed that in medium spiny striatal neurons dopamine D1-class receptors modulate voltage-dependent Na+, K+ and Ca2+ channels. From a consideration of the biophysical properties of these channels and the state transitions that medium spiny neurons undergo while responding to cortical input, a novel picture of dopamine's actions is beginning to emerge. Our results and those of others suggest that D2-class receptors serve to make the transition to the depolarized 'upstate' from the hyperpolarized 'downstate' more probable in response to cortical input. But, once the transition has occurred, the alteration in excitability should be short-lived unless the neuron has recently been active. This state-dependent modulation provides a mechanism by which dopamine could shape global striatal activity governing the execution of motor behaviors.
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PMID:State-dependent regulation of neuronal excitability by dopamine. 920 32

Levodopa, which is used in the treatment of Parkinson's disease, has known cytotoxic effects on dopaminergic neurons grown in culture. Calretinin (CR) is a cytosolic calcium-binding protein found in specific subpopulations of neurons as well as in some nonneuronal tissue. CR is expressed in 10% of rat embryo dopaminergic neurons grown in vitro. Since it has been postulated that CR provides neuroprotection due to its calcium-binding properties, we investigated whether CR-containing dopaminergic neurons were spared from levodopa toxicity. Incubation of mesencephalic cells with 10(-5) to 10(-7) M levodopa on Days 1-6 in vitro produced no significant effects on the number of dopaminergic neurons containing CR, but resulted in the loss of approximately 65% of the dopaminergic cells which did not contain CR. The remaining CR-negative dopaminergic neurons exhibited dose-dependent reductions in neurite length. The neuronal processes in CR-containing dopaminergic cells retained a smooth bipolar appearance. CR-immunoreactive cells which did not contain dopamine showed slight neurite length decreases at the highest drug concentrations but no changes in neuron number. These results indicate that CR may protect dopaminergic neurons from levodopa-induced toxicity.
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PMID:Calretinin-immunoreactive dopaminergic neurons from embryonic rat mesencephalon are resistant to levodopa-induced neurotoxicity. 922 35

Apoptotic, rather than necrotic, nerve cell death now appears as likely to underlie a number of common neurological conditions including stroke, Alzheimer's disease, Parkinson's disease, hereditary retinal dystrophies and Amyotrophic Lateral Sclerosis. Apoptotic neuronal death is a delayed, multistep process and therefore offers a therapeutic opportunity if one or more of these steps can be interrupted or reversed. Research is beginning to show how specific macromolecules play a role in determining the apoptotic death process. We are particularly interested in the critical nature of gradual mitochondrial failure in the apoptotic process and propose that a maintenance of mitochondrial function through the pharmacological modulation of gene expression offers an opportunity for the effective treatment of some types of neurological dysfunction. Our research into the development of small diffusible molecules that reduce apoptosis has grown from studies of the irreversible MAO-B inhibitor (-)-deprenyl. (-)-Deprenyl can reduce neuronal death independently of MAO-B inhibition even after neurons have sustained seemingly lethal damage. (-)-Deprenyl can also influence the process outgrowth of some glial and neuronal populations and can reduce the concentrations of oxidative radicals in damaged cells at concentrations too small to inhibit MAO. In accord with earlier work of others, we showed that (-)-deprenyl alters the expression of a number of mRNAs or of proteins in nerve and glial cells and that the alterations in gene expression/protein synthesis are the result of a selective action on transcription. The alterations in gene expression/protein synthesis are accompanied by a decrease in DNA fragmentation characteristic of apoptosis and the death of responsive cells. The onco-proteins Bcl-2 and Bax and the scavenger proteins Cu/Zn superoxide dismutase (SOD1) and Mn superoxide dismutase (SOD-2) are among the 40-50 proteins whose synthesis is altered by (-)-deprenyl. Since mitochondrial membrane potential correlates with mitochondrial ATP production, we have used confocal laser imaging techniques in living cells to show that the transcriptional changes induced by (-)-deprenyl result in a maintenance of mitochondrial membrane potential, a decrease in intramitochondrial calcium and a decrease in cytoplasmic oxidative radical levels. We therefore propose that (-)-deprenyl acts on gene expression to maintain mitochondrial function and decrease cytoplasmic oxidative radical levels and thereby reduces apoptosis. An understanding of the molecular steps by which (-)-deprenyl selectively alters transcription may lead to the development of new therapies for neurodegenerative diseases.
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PMID:Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription. 926 33

An early and highly specific decrease in glutathione (GSH) in the substantia nigra is associated with Parkinson's disease, and low levels of GSH lead to the degeneration of cultured dopaminergic neurons. Using immature cortical neurons and a clonal nerve cell line, it is shown that a decrease in GSH triggers the activation of neuronal 12-lipoxygenase (12-LOX), which leads to the production of peroxides, the influx of Ca2+, and ultimately to cell death. The supporting evidence includes: 1) inhibitors of arachidonate metabolism and 12-LOX block cell death induced by GSH depletion; 2) there is an increase in 12-LOX activity and a membrane translocation in HT22 cells, and an induction of the enzyme in primary cortical neurons following the reduction of GSH; 3) 12-LOX is directly inhibited by GSH; and 4) exogenous arachidonic acid potentiates cell death. These data show that the LOX pathway is a critical intermediate in at least some forms of neuronal degeneration.
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PMID:A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. 929 33

Excitotoxicity, mitochondrial dysfunction and free radical induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease. Much of the interest in the association of neurodegeneration with mitochondrial dysfunction and oxidative damage emerged from animal studies using mitochondrial toxins. Within mitochondria 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), acts to inhibit NADH-coenzyme Q reductase (complex I) of the electron transport chain. MPTP produces Parkinsonism in humans, primates, and mice. Similarly, lesions produced by the reversible inhibitor of succinate dehydrogenase (complex II), malonate, and the irreversible inhibitor, 3-nitropropionic acid (3-NP), closely resemble the histologic, neurochemical and clinical features of HD in both rats and non-human primates. The interruption of oxidative phosphorylation results in decreased levels of ATP. A consequence is partial neuronal depolarization and secondary activation of voltage-dependent NMDA receptors, which may result in excitotoxic neuronal cell death (secondary excitotoxicity). The increase in intracellular Ca2+ concentration leads to an activation of Ca2+ dependent enzymes, including the constitutive neuronal nitric oxide synthase (cnNOS) which produces NO.. NO. may react with the superoxide anion to from peroxynitrite. We show that systemic administration of 7-nitroindazole (7-NI), a relatively specific inhibitor of cnNOS in vivo. attenuates lesions produced by striatal malonate injections or systemic treatment with 3-NP or MPTP. Furthermore 7-NI attenuated increases in lactate production and hydroxyl radical and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. Our results suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.
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PMID:The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. 930 87

We consider whether chemical pollutants in drinking water (including aromatic hydrocarbons, alkanes, halogenated aliphatic hydrocarbons, and phthalic acid) or used occupationally in agriculture that have shown no parkinsonism-inducing effect may be responsible for excess cases of Parkinson's disease (PD) in three adjacent kibbutzim in southern Israel (Negev). Literature data on PD pathogenesis have been compared with common pathogenetic pathways to xenobiotics effects; the following neurotoxic mechanisms, besides individual sensitivity, have been suggested: (1) impairment of the protective role of the substantia nigra against toxicants by binding of chemicals to melanin; (2) oxidative stress induction, including glutathione reduction, impaired calcium metabolism, and alteration of cytochrome P-450 activity; (3) blockade of iron chelators because of structural similarities to them or their precursors; (4) mediation of the production of endogenous dopaminergic neurotoxins, such as trichloroharmanes or isoquinolines; (5) blockade of dopamine receptors because of their resemblance to chemicals with affinity to these receptors; (6) stimulation of prostaglandin-H synthase and monooxygenase activity; and (7) stimulation of autoimmune processes and creation of autoimmunity to structures of the dopaminergic system caused by chemical similarity.
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PMID:Chemical exposures and Parkinson's disease in residents of three Negev kibbutzim. 931 42

Neuronal damage in certain cellular populations in the brain has been linked to oxidative stress accompanied by an elevation in intracellular calcium. Many questions remain about how such oxidative stress occurs and how it affects calcium homeostasis. Glutathione (GSH) is a major regulator of cellular redox status in the brain, and lowered GSH levels have been associated with dopaminergic cell loss in Parkinson's disease (PD). We found that transfection of antisense oligomers directed against glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis, into PC12 cells resulted in decreased GSH and increased levels of ROS. Decreased GSH levels also correlated with an increase in intracellular calcium levels. Data from this study suggest that dopaminergic neurons are very sensitive to decreases in the internal oxidant buffering capacity of the cell caused by reductions in GSH levels, and that alterations in this parameter can result in disruption of calcium homeostasis and cell death. These results may be of particular significance for therapeutic treatment of PD, as those dopaminergic neurons that are spared in this disorder appear to contain the calcium binding protein, calbindin.
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PMID:Decreased glutathione results in calcium-mediated cell death in PC12. 935 49


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