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)

Advances in our understanding of the cause and pathogenesis of Parkinson's disease (PD) have permitted the rational selection of putative neuroprotective agents for study in PD. However, the list of agents that might provide neuroprotective effects derived from laboratory studies is daunting, and we face the challenge of determining which agents to bring to the clinic and how to find the resources (patients and funds) to properly study so many promising therapeutic opportunities.1 Appropriate outcome variables that are not confounded by any symptomatic effect of the drug and are acceptable to clinicians and regulatory authorities also remain to be defined. The first clinical trials designed to test the capacity of putative neuroprotective agents to alter the natural history of PD have now been performed and illustrate some of these problems. The DATATOP (Deprenyl and Tocopherol Antioxidant Therapy of PD) study used the time to reach a disease milestone in untreated PD patients (ie, need for levodopa) as the primary end point. However, interpretation of results was confounded by the drug's symptomatic effect. The SINDEPAR (Sinemet-Deprenyl-Parlodel) study used the change in motor score between initial visit and final visit after washout of all study medications as the primary end point. However, here too there were concerns about confounding symptomatic effects, because antiparkinsonian medications have now been shown to have a long duration response that can persist for weeks and perhaps even months after withdrawal. More recent studies have used surrogate markers of the integrity of nigrostriatal function such as striatal uptake of fluorodopa on positron emission tomography (PET) or beta-CIT-on single-photon emission computerized tomography (SPECT) as primary outcome measures. However, it has not yet been confirmed that striatal uptake of these isotopes does in fact correlate with the remaining number of dopamine neurons or terminals, and the possibility of a confounding pharmacological effect has not yet been completely excluded. To date, no drug has been established to have a neuroprotective effect in PD, and none has been approved for a neuroprotective indication. Furthermore, regulatory agencies have not yet agreed that any of the outcome measures currently used will be acceptable for approval of a new drug. Resolution of these issues is of critical importance to convince pharmaceutical companies to expend the hundreds of millions of dollars necessary to bring a new drug to market. Drugs that already have been approved in PD for their symptomatic effects, such as dopamine agonists or propargylamines (eg, selegiline), offer the best opportunity for establishing that a drug is neuroprotective in PD in the immediate future, but herein also lies the difficulty of establishing that any benefits observed are not solely because of the drug's symptomatic properties. Currently, this will most likely entail demonstrating that the drug provides benefit for PD patients for both imaging and clinical markers of disease progression.
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PMID:Neuroprotection in Parkinson's disease: clinical trials. 1266 1

The Parkinson Study Group who conducted the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial designed their study in the belief that the MAO inhibitor (-)-deprenyl (selegiline), the antioxidant alpha-tocopherol, and the combination of the two compounds will slow the clinical progression of the disease to the extent that MAO activity and the formation of oxygen radicals contribute to the pathogenesis of nigral degeneration. In fact, (-)-deprenyl only delayed the onset of disability associated with early, otherwise untreated Parkinson's disease, however, in contrast to the expectation of the authors, alpha-tocopherol proved to be ineffective in the DATATOP study. Enhancer substances, (-)-deprenyl, (-)-1-phenyl-2-propylaminopentane [(-)-PPAP] the (-)-deprenyl analogue free of MAO inhibitory potency, and R-(-)1-(benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP] the presently known most potent enhancer substance, are peculiar stimulants. They enhance the impulse propagation mediated release of the catecholamines in the brain. Due to their enhancer effect, the amount of catecholamines released from selected discrete brain areas (striatum, substantia nigra, tuberculum olfactorium, locus coeruleus) is significantly higher in rats treated with an enhancer substance than in saline treated rats. We compared the effect of (-)-deprenyl 0.025 and 0.25 mg/kg, (-)-PPAP 0.1 mg/kg, (-)-BPAP 0.0001 mg/kg, and alpha-tocopherol 25 and 50 mg/kg, in this test. The doses of (-)-deprenyl and alpha-tocopherol were selected to be in compliance with the dose given in the DATATOP study. Compared to saline treated rats, the enhancer substances significantly increased the amount of dopamine released from the striatum, substantia nigra and tuberculum olfactorium and the amount of norepinephrine released from the locus coeruleus; alpha-tocopherol was ineffective. The results indicate that alpha-tocopherol was ineffective, because, unlike (-)-deprenyl it dose not enhance the activity of the nigrostriatal dopaminergic neurons.
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PMID:A pharmacological analysis elucidating why, in contrast to (-)-deprenyl (selegiline), alpha-tocopherol was ineffective in the DATATOP study. 1267 9

Aging is a major risk factor for neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to oxidative stress which can induce neuronal damage, ultimately leading to neuronal death by apoptosis or necrosis. A large body of evidence indicates that oxidative stress is involved in the pathogenesis of AD, PD, and ALS. Several studies have shown that nutritional antioxidants (especially vitamin E and polyphenols) can block neuronal death in vitro, and may have therapeutic properties in animal models of neurodegenerative diseases including AD, PD, and ALS. Moreover, clinical data suggest that nutritional antioxidants might exert some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed. Particular emphasis will be given to the role played by the nuclear transcription factor -kB (NF-kB) in apoptosis, and in the pathogenesis of neurodegenerative disorders, such as AD, PD, and ALS. The effects of ROS and antioxidants on NF-kB function and their relevance in the pathophysiology of neurodegenerative diseases will also be examined.
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PMID:Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. 1276 2

Though the etiology is not well understood, late-onset Parkinson's disease (PD) appears to result from several key factors including exposure to unknown environmental toxicants, toxic endogenous compounds and genetic alterations. A plethora of scientific evidence suggest that these environmental and endogenous factors cause PD by producing mitochondrial (mito) oxidative stress and damage in the substantia nigra, leading to cell death. Thus assuming a critical role for mito oxidative stress in PD, therapies to treat or prevent PD must target these mito and protect them against oxidative damage. The focus of this article is to briefly review the experimental and clinical evidence for the role of environmental toxicants and mito oxidative stress/damage in PD as well as discuss the potential protective role of mito d-alpha-tocopherol (T) enrichment and vitamin E therapy in PD. New experimental data are presented that supports the enrichment of mito with T as a critical event in cytoprotection against toxic mito-derived oxidative stress. We propose that chronic, high dose vitamin E dietary supplementation or parenteral vitamin E administration (e.g. vitamin E succinate) may serve as a successful therapeutic strategy for the prevention or treatment of PD (by enriching substantia nigra mito with protective levels of T).
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PMID:Vitamin E therapy in Parkinson's disease. 1282 Dec 88

Erythrocyte lipid peroxidation, oxidative hemolysis, erythrocyte antioxidant enzymes, viz. superoxide dismutase, glutathione reductase, glutathione peroxidase, catalase and plasma antioxidants, viz. vitamin A, vitamin E, vitamin C and ceruloplasmin have been determined by spectrophotometric methods in 15 patients with Parkinson's disease (PD) and in 50 controls. Lipid peroxidation, oxidative hemolysis and plasma ceruloplasmin were significantly higher in PD patients as compared to normals. Erythrocyte antioxidants in PD patients were not significantly different from the controls. However, plasma vitamin C in PD patients was significantly lower than the controls. It is concluded that these patients are under oxidative stress which points to a possible involvement of free radicals in PD.
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PMID:Free radical toxicity and antioxidants in Parkinson's disease. 1286 18

In spite of the extensive studies performed on postmortem substantia nigra from Parkinson's disease patients, the aetiology of the disease has not yet been established. Nevertheless, these studies have demonstrated that, at the time of death, a cascade of events had been initiated that may contribute to the demise of the melanin-containing nigro-striatal dopamine neurons. These events include increased levels of iron and monoamine oxidase (MAO)-B activity, oxidative stress, inflammatory processes, glutamatergic excitotoxicity, nitric oxide synthesis, abnormal protein folding and aggregation, reduced expression of trophic factors, depletion of endogenous antioxidants such as reduced glutathione, and altered calcium homeostasis. To a large extent, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease confirm these findings. Furthermore, neuroprotection can be afforded in these models with iron chelators, radical scavenger antioxidants, MAO-B inhibitors, glutamate antagonists, nitric oxide synthase inhibitors, calcium channel antagonists and trophic factors. Despite the success obtained with animal models, clinical neuroprotection is much more difficult to accomplish. Although the negative studies obtained with the MAO-B inhibitor selegiline (deprenyl) and the antioxidant tocopherol (vitamin E) may have resulted from an inappropriate choice of drug (selegiline) or an inadequate dose (tocopherol), the niggling problem that still remains is why these drugs, and others, do work in animals while they fail in the clinic. One reason for this may be related to the fact that in normal human brains the number of dopaminergic neurons falls by around 3-5% every decade, while in Parkinson's disease this decline is greater. Brain autopsy studies have shown that by the time the disease is identified, some 70-75% of the dopamine-containing neurons have been lost. More sensitive reliable methods and clinical correlative markers are required to discern between confoundable symptomatic effects versus a possible neuroprotective action of drugs, namely, the ability to delay or forestall disease progression by protecting or rescuing the remaining dopamine neurons or even restoring those that have been lost.A number of other possibilities for the clinical failure of potential neuroprotectants also exist. First, the animal models of Parkinson's disease may not be totally reflective of the disease and, therefore, the chemical pathologies established in the animal models may not cause, or contribute to, the progression of the disease clinically. Second, because of the series of events occurring in neurodegeneration and our ignorance about which of these factors constitutes the primary event in the pathogenic process, a single drug may not be adequate to induce neuroprotection and, as a consequence, use of a cocktail of drugs may be more appropriate. The latter concept receives support from recent complementary DNA (cDNA) microarray gene expression studies, which show the existence of a gene cascade of events occurring in the nigrostriatal pathway of MPTP, 6-OHDA and methamphetamine animal models of Parkinson's disease. Even with the advent of powerful new tools such as genomics, proteomics, brain imaging, gene replacement therapy and knockout animal models, the desired end result of neuroprotection is still beyond our current capability.
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PMID:Neuroprotective strategies in Parkinson's disease : an update on progress. 1287 56

Fluctuating cognition is evidenced in different forms of dementia and is accompanied by electroencephalographic (EEG) abnormalities. The authors hypothesize that cholinesterase inhibitors are effective mostly in patients with fluctuating cognition. Twenty-three patients affected by mild dementia with similar scores on Mini-Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog), and Unified Parkinson's Disease Rating Scale evaluation were classified in a group with fluctuating cognition (n = 11) and a group of nonfluctuators (n = 12). All patients were assigned randomly to the branches of a double-blind crossover study of donepezil (DPZ), a 5 to 10-mg dose, versus vitamin E, a 2000 IU dose, for 30 days. MMSE, ADAS-cog, University of California at Los Angeles Neuropsychiatric Inventory (NPI), quantitative EEG, P3 event-related potentials, choice reaction time variability (CRTV) were assessed at baseline and at the end of treatments. At the end of the crossover study all patients received DPZ for 6 months. The dominant EEG frequency variability, low EEG frequencies amplitude, the P3 latency and jitter, CRTV, and NPI was significantly different in the fluctuating cognition group than the nonfluctuating group at baseline (P < 0.001). Short-term DPZ administration induced a significant increase in MMSE scores, reduction of ADAS-cog and of NPI scores (P < 0.003-0.001), increase of EEG alpha activity and reductions of P3 latency and jitter, dominant frequency variability and CRTV (P < 0.009-0.001) in the fluctuating cognition group, and significant increases of MMSE scores (P = 0.03) and a decrease of P3 jitter and dominant frequency variability (P < 0.034-0.041) in the nonfluctuating group. Short-term DPZ effects differed significantly between fluctuating cognition and nonfluctuating patients (0.001). Significant effects of the 6-month observation were observed only in fluctuating cognition patients. Logistic analysis showed that P3 latency predicts the effect of DPZ (P = 0.04, P < 0.01) in the crossover study, and CRTV predicts the effect at the 6-month follow-up.
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PMID:The effects of a cholinesterase inhibitor are prominent in patients with fluctuating cognition: a part 3 study of the main mechanism of cholinesterase inhibitors in dementia. 1452 Jan 64

Few, if any, studies have examined the effect of vitamin E deficiency on brain mitochondrial oxidative phosphorylation. The latter was studied using brain mitochondria isolated from control and vitamin E-deficient rats (13 months of deficiency) after exposure to iron, an inducer of oxidative stress. Mitochondria were treated with iron (2 to 50 microM) added as ferrous ammonium sulfate. Rates of state 3 and state 4 respiration, respiratory control ratios, and ADP/O ratios were not affected by vitamin E deficiency alone. However, iron uncoupled oxidative phosphorylation in vitamin E-deficient mitochondria, but not in controls. In vitamin E-deficient mitochondria, iron decreased ADP/O ratios and markedly stimulated state 4 respiration; iron had only a modest effect on these parameters in control mitochondria. Thus, vitamin E may have an important role in sustaining oxidative phosphorylation. Low concentrations of iron (2 to 5 microM) oxidized mitochondrial tocopherol that exists in two pools. The release of iron in brain may impair oxidative phosphorylation, which would be exacerbated by vitamin E deficiency. The results are important for understanding the pathogenesis of human brain disorders known to be associated with abnormalities in mitochondrial function as well as iron homeostasis (e.g., Parkinson's disease).
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PMID:Iron uncouples oxidative phosphorylation in brain mitochondria isolated from vitamin E-deficient rats. 1506 78

We examined the toxicity of paraquat, a possible environmental risk factor for neurodegenerative disorders like Parkinson's disease (PD). Paraquat is structurally similar to the neurotoxin MPP+ that can induce Parkinsonian-like features in rodents, non-human primates and human. Exposure of cerebellar granule cells to relatively low concentrations of paraquat (5 microM) produces apoptotic cell death with a reduction in mitochondrial cytochrome c content, proteolytic activation and caspase-3 activity increase and DNA fragmentation. Paraquat-induced apoptosis was significantly attenuated by co-treatment of cerebellar granule cells with the radical scavenger vitamin E, suggesting that paraquat-induced free radicals serve as important signal in initiation of cell death. As a decrease in mitochondrial cytochrome c content is also prevented by allopurinol, we suggest that xanthine oxidase plays an important role in the free radical production that precedes the apoptotic cascade and cell death after paraquat exposition.
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PMID:Paraquat-induced apoptotic cell death in cerebellar granule cells. 1515 3

The safety and tolerability of high dosages of coenzyme Q10 were studied in 17 patients with Parkinson's disease (PD) in an open label study. The subjects received an escalating dosage of coenzyme Q10--1200, 1800, 2400, and 3000 mg/day with a stable dosage of vitamin E (alpha-tocopherol) 1200 IU/day. The plasma level of coenzyme Q10 was measured at each dosage. Thirteen of the subjects achieved the maximal dosage, and adverse events were typically considered to be unrelated to coenzyme Q10. The plasma level reached a plateau at the 2400 mg/day dosage and did not increase further at the 3000 mg/day dosage. Our data suggest that in future studies of coenzyme Q10 in PD, a dosage of 2400 mg/day (with vitamin E/alpha-tocopherol 1200 IU/day) is an appropriate highest dosage to be studied.
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PMID:Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson's disease. 1524 48


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