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)

Oxidative stress is an important mechanism of cell death in Parkinson's disease (PD) and brain ischemia. Vitamins C, E and A are important antioxidants and deficiency of these agents has been implicated in the mechanisms of atherosclerosis. We measured the levels of the above antioxidant vitamins in 44 patients with PD, 12 patients with vascular parkinsonism (VP), 11 patients with other parkinsonism syndromes of various causes and 39 controls. Vitamin A levels did not differ between groups. Vitamins C and E were found decreased in VP, while they were normal in PD indicating low levels of antioxidant vitamins in VP and stressing the necessity of maintaining sufficient dietary intake of these agents in the elderly.
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PMID:Plasma levels of antioxidant vitamins C and E are decreased in vascular parkinsonism. 1554 5

Neural stem cells, which exist in various regions of the CNS throughout the mammalian lifespan, can be expanded and induced to differentiate into neurons and glia in vitro and in vivo. Because of these characteristics, there has been increasing interest in the identification and characterization of neural stem cells and neural progenitor cells both for basic developmental biology studies and for therapeutic applications to the damaged brain. Transplantation of neural stem cells or their derivatives into a host brain and the proliferation and differentiation of endogenous stem cells by pharmacological manipulations are potential treatments for many neurodegenerative diseases and brain injuries, such as Parkinson's disease, brain ischemia and spinal cord injury. Continued progress in neural stem cell research is providing a new future for brain repair.
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PMID:Biology and clinical application of neural stem cells. 1467 88

Various regions of the brain have been successfully transduced by recombinant adeno-associated virus (rAAV) vectors with no detected toxicity. When using the cytomegalovirus immediate early (CMV) promoter, a gradual decline in the number of transduced cells has been described. In contrast, the use of cellular promoters such as the neuron-specific enolase promoter or hybrid promoters such as the chicken beta-actin/CMV promoter resulted in sustained transgene expression. The cellular tropism of rAAV-mediated gene transfer in the central nervous system (CNS) varies depending on the serotype used. Serotype 2 vectors preferentially transduce neurons whereas rAAV5 and rAAV1 transduce both neurons and glial cells. Recombinant AAV4-mediated gene transfer was inefficient in neurons and glial cells of the striatum (the only structure tested so far) but efficient in ependymal cells. No inflammatory response has been described following rAAV2 administration to the brain. In contrast, antibodies to AAV2 capsid and transgene product were elicited but no reduction of transgene expression was observed and readministration of vector without loss of efficiency was possible from 3 months after the first injection. Based on the success of pioneer work performed with marker genes, various strategies for therapeutic gene delivery were designed. These include enzyme replacement in lysosomal storage diseases, Canavan disease and Parkinson's disease; delivery of neuroprotective factors in Parkinson's disease, Huntington disease, Alzheimer's disease, amyotrophic lateral sclerosis, ischemia and spinal cord injury; as well as modulation of neurotransmission in epilepsy and Parkinson's disease. Several of these strategies have demonstrated promising results in relevant animal models. However, their implementation in the clinics will probably require a tight regulation and a specific targeting of therapeutic gene expression which still demands further developments of the vectors.
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PMID:Recombinant AAV-mediated gene delivery to the central nervous system. 1497 64

1. Riluzole is used for the treatment of amyotrophic lateral sclerosis and reported to have neuroprotective effects in animal models of Parkinson's disease, Huntington's disease, and brain ischemia. The neuroprotective action of riluzole has been attributed to its ability to inhibit glutamate release (A. Doble, Neurology 47(4):233S-241S, 1996). 2. The effect of riluzole on L-[2,3-3H] glutamate uptake was investigated in rat cortical astrocyte cultures. 3. Riluzole showed a biphasic concentration-dependent effect on basal glutamate uptake. At low concentrations (1 and 10 microM) riluzole significantly increased glutamate uptake, whereas from 100 microM promoted a slight reduction. 4. Considering the large range of glutamate levels in the synaptic cleft, we studied the 1 microM riluzole effect on uptake of glutamate at different concentrations (1-1000 microM). Riluzole was more effective at low glutamate concentrations (10 microM), enhancing the basal glutamate uptake up to 42%. 5. The action of riluzole on astrocytic glutamate uptake could be an additional mechanism to its neuroprotective role, perhaps suggesting a modulatory action on glutamatergic system involving glutamate clearance from synaptic cleft.
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PMID:Riluzole enhances glutamate uptake in rat astrocyte cultures. 1504 16

Vascular endothelial growth factor (VEGF) has previously been shown to display neuroprotective effects following ischemia, suggesting that VEGF may potentially be applied as a neuroprotective agent for the treatment of other neurological diseases. In this study, we investigated the neuroprotective capacity of VEGF in a model of Parkinson's disease. VEGF was found to be neuroprotective against cell death of primary E14 murine ventral mesencephalic neurons induced by 6-hydroxydopamine (6-OHDA) treatment in vitro. Further, rats receiving a continuous infusion of VEGF into the striatum via encapsulated hVEGF-secreting cells (baby hamster kidney-VEGF) displayed a significant decrease in amphetamine-induced rotational behavior and a significant preservation of tyrosine hydroxylase-positive neurons and fibers compared with control animals. VEGF likely functions via direct mechanisms by signaling through the neuropilin receptor expressed upon dopaminergic neurons in response to 6-OHDA treatment. Further, VEGF is likely to promote neuroprotection indirectly by activating the proliferation of glia and by promoting angiogenesis. Our results support a potential neuroprotective role for VEGF in the treatment of Parkinson's disease.
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PMID:Neuroprotective effects of vascular endothelial growth factor (VEGF) upon dopaminergic neurons in a rat model of Parkinson's disease. 1506 46

Dopamine receptor agonists are protective in different models of neurodegeneration by both receptor-dependent and -independent mechanisms. We used SH-SY5Y cells, differentiated into neuron-like type, to evaluate if cabergoline, a dopamine D2 receptor agonist endowed with anti-oxidant activity, protects the cells against ischemia (oxygen-glucose deprivation model). Cabergoline protected the cells from ischemia-induced cell death in a concentration-dependent manner (EC(50)=1.2 microM), as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release, and fluorescein diacetate-propidium iodide staining. This effect, observed even when the drug was added after oxygen-glucose deprivation, was not mediated by either dopamine D2 receptor activation or anti-apoptotic Bcl-2 protein over-expression (Western blotting analysis), but was linked to a reduction in cellular free radical loading (2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining) and membrane lipid peroxidation (thiobarbituric acid-reacting test). In conclusion, cabergoline protects in vitro neurons against ischemia-induced cell death, suggesting its possible use in the therapy of other neurodegenerative diseases in addition to Parkinson's disease.
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PMID:Cabergoline protects SH-SY5Y neuronal cells in an in vitro model of ischemia. 1508 38

Neurons need iron, which is reflected in their expression of the transferrin receptor. The concurrent expression of the ferrous iron transporter, divalent metal transporter I (DMT1), in neurons suggests that the internalization of transferrin is followed by detachment of iron within recycling endosomes and transport into the cytosol via DMT1. To enable DMT1-mediated export of iron from the endosome to the cytosol, ferric iron must be reduced to its ferrous form, which could be mediated by a ferric reductase. The presence of nontransferrin-bound iron in brain extracellular fluids suggests that neurons can also take up iron in a transferrin-free form. Neurons are thought to be devoid of ferritin in many brain regions in which there is an association between iron accumulation and cellular damage, for example, neurons of the substantia nigra pars compacta. The general lack of ferritin together with the prevailing expression of the transferrin receptor indicates that iron acquired by activity of transferrin receptors is directed toward immediate use in relevant metabolic processes, is exported, or is incorporated into complexes other than ferritin. Iron has long been considered to play a significant role in exacerbating degradation processes in brain tissue subjected to acute damage and neurodegenerative disorders. In brain ischemia, the damaging role of iron may depend on the inhibition of detoxifying enzymes responsible for catalyzing the oxidation of ferrous iron. Brain ischemia may also lead to an increase in iron supply to neurons as transferrin receptor expression by brain capillary endothelial cells is increased. Pharmacological blockage of the transferrin receptor/DMT1-mediated uptake could be a target to prevent further iron uptake. In chronic neurodegenerative settings, a deleterious role of iron is suggested since cases of Alzheimer's disease, Parkinson's disease, and Huntington's disease have a significantly higher accumulation of iron in affected regions. Dopaminergic neurons are rich in neuromelanin, shown to be more redox-active in Parkinson's disease cases. Iron-containing inflammatory cells may, however, account for the main portion of iron present in neurodegenerative disorders. More knowledge about iron metabolism in normal and diseased neurons is warranted as this may identify pharmaceutical targets to improve neuronal iron management.
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PMID:The metabolism of neuronal iron and its pathogenic role in neurological disease: review. 1510 52

Melatonin is a natural occurring compound with well-known antioxidant properties. In the last decade a new effect of melatonin on mitochondrial homeostasis has been discovered and, although the exact molecular mechanism for this effect remains unknown, it may explain, at least in part, the protective properties found for the indoleamine in degenerative conditions such as aging as well as Parkinson's disease, Alzheimer's disease, epilepsy, sepsis and other injuries such as ischemia-reperfusion. A common feature in these diseases is the existence of mitochondrial damage due to oxidative stress, which may lead to a decrease in the activities of mitochondrial complexes and ATP production, and, as a consequence, a further increase in free radical generation. A vicious cycle thus results under these conditions of oxidative stress with the final consequence being cell death by necrosis or apoptosis. Melatonin is able of directly scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates antioxidative enzymes, increases the efficiency of the electron transport chain thereby limiting electron leakage and free radical generation, and promotes ATP synthesis. Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival.
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PMID:Melatonin and mitochondrial function. 1518 71

Molecular biology has recently contributed significantly to the recognition of selenium (Se)2 and Se-dependent enzymes as modulators of brain function. Increased oxidative stress has been proposed as a pathomechanism in neurodegenerative diseases including, among others, Parkinson's disease, stroke, and epilepsy. Glutathione peroxidases (GPx), thioredoxin reductases, and one methionine-sulfoxide-reductase are selenium-dependent enzymes involved in antioxidant defense and intracellular redox regulation and modulation. Selenium depletion in animals is associated with decreased activities of Se-dependent enzymes and leads to enhanced cell loss in models of neurodegenerative disease. Genetic inactivation of cellular GPx increases the sensitivity towards neurotoxins and brain ischemia. Conversely, increased GPx activity as a result of increased Se supply or overexpression ameliorates the outcome in the same models of disease. Genetic inactivation of selenoprotein P leads to a marked reduction of brain Se content, which has not been achieved by dietary Se depletion, and to a movement disorder and spontaneous seizures. Here we review the role of Se for the brain under physiological as well as pathophysiological conditions and highlight recent findings which open new vistas on an old essential trace element.
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PMID:Selenium and brain function: a poorly recognized liaison. 1521 Mar 2

Creatine mediates remarkable neuroprotection in experimental models of amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and traumatic brain injury. Because caspase-mediated pathways are shared functional mechanistic components in these diseases, as well as in ischemia, we evaluated the effect of creatine supplementation on an experimental stroke model. Oral creatine administration resulted in a remarkable reduction in ischemic brain infarction and neuroprotection after cerebral ischemia in mice. Postischemic caspase-3 activation and cytochrome c release were significantly reduced in creatine-treated mice. Creatine administration buffered ischemia-mediated cerebral ATP depletion. These data provide the first direct correlation between the preservation of bioenergetic cellular status and the inhibition of activation of caspase cell-death pathways in vivo. An alternative explanation to our findings is that creatine is neuroprotective through other mechanisms that are independent of mitochondrial cell-death pathways, and therefore postischemic ATP preservation is the result of tissue sparing. Given its safety record, creatine might be considered as a novel therapeutic agent for inhibition of ischemic brain injury in humans. Prophylactic creatine supplementation, similar to what is recommended for an agent such as aspirin, may be considered for patients in high stroke-risk categories.
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PMID:Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. 1522 38


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