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)

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.
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PMID:Pharmacological actions of l-deprenyl (selegiline) and other selective monoamine oxidase B inhibitors. 799 14

A variety of degenerative diseases involving deficiencies in mitochondrial bioenergetics have been associated with mitochondrial DNA (mtDNA) mutations. Maternally inherited mtDNA nucleotide substitutions range from neutral polymorphisms to lethal mutations. Neutral polymorphisms are ancient, having accumulated along mtDNA lineages, and thus correlate with ethnic and geographic origin. Mildly deleterious base substitutions have also occurred along mtDNA lineages and have been associated with familial deafness and some cases of Alzheimer's Disease and Parkinson's Disease. Moderately deleterious nucleotide substitutions are more recent and cause maternally-inherited diseases such as Leber's Hereditary Optic Neuropathy (LHON) and Myoclonic Epilepsy and Ragged-Red Fiber Disease (MERRF). Severe nucleotide substitutions are generally new mutations that cause pediatric diseases such as Leigh's Syndrome and dystonia. MtDNA rearrangements also cause a variety of phenotypes. The milder rearrangements generally involve duplications and can cause maternally-inherited adult-onset diabetes and deafness. More severe rearrangements frequently involving detections have been associated with adult-onset Chronic Progressive External Ophthalmoplegia (CPEO) and Kearns-Sayre Syndrome (KSS) or the lethal childhood disorder, Pearson's Marrow/Pancreas Syndrome. Defects in nuclear-cytoplasmic interaction have also been observed, and include an autosomal dominant mutation causing multiple muscle mtDNA deletions and a genetically complex disease resulting in the tissue depletion of mtDNAs. MtDNA nucleotide substitution and rearrangement mutations also accumulate with age in quiescent tissues. These somatic mutations appear to degrade cellular bioenergetic capacity, exacerbate inherited mitochondrial defects and contribute to tissue senescence. Thus, bioenergetic defects resulting from mtDNA mutations may be a common cause of human degenerative disease.
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PMID:Mitochondrial DNA mutations in diseases of energy metabolism. 807 79

A case of primary autonomic failure (AF) with uncomplicated Parkinson's disease is presented with clinical and neurophysiological data. Special emphasis is placed on new methods of examining impairment of unmyelinated sympathetic and afferent C-fibres. Sympathetic vasoconstrictor responses in the skin induced by deep inspiration were examined quantitatively with laser Doppler flowmetry. The vasoconstriction was markedly depressed in primary AF compared with healthy controls and similar to secondary forms of AF. Peripheral nociceptive C-fibre function was quantitatively assessed by measurement of axon reflex vasodilatation induced by histamine iontophoresis. The axon reflex vasodilatation was completely intact in primary AF in contrast to patients with secondary peripheral small fibre neuropathy. The results indicate that sympathetic C-fibres are considerably affected by the degenerative disease, whereas the afferent C-fibres seem to be totally preserved. Modern neurophysiological methods of testing sympathetic and afferent small fibre function in combination with other neurophysiological tests, e.g. brain-stem auditory evoked potentials, might help to diagnose and differentiate primary AF in early stages and make it easier to distinguish between secondary autonomic neuropathies of unknown origin that often also involve unmyelinated afferent fibres.
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PMID:Small fibre function in primary autonomic failure. 813 30

We measured six apolipoproteins (AI, AII, B, CII, CIII, and E) in the serum of patients with several kinds of neural diseases [diabetic neuropathy and neural degenerative disorders (motor neuron degenerative disorders, spinocerebellar degeneration, Parkinson's disease)], comparing them to the age-matched healthy controls using the immunoturbidimetric method. Statistically significant decreases of serum apo-AI, apo-A-II and increases of apo-CIII, apo-E were observed in neural degenerative diseases; and, particularly, higher apo-B and apo-CII concentrations were observed in diabetic neuropathy. Most neural degenerative disease showed lower apo-AII. However, in motor neuron degenerative disorders, higher apo C-II and apo-E were seen. Lower apo-AI was seen in spinocerebellar degeneration, and lower apo-AII was seen in Parkinson's disease. Higher apo-B, CII, and E levels were observed in females with spinocerebellar degeneration and Parkinson's disease, and lower apo-AII was seen in males with spinocerebellar disease.
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PMID:Preliminary findings on the variation of serum apolipoprotein levels in neural degenerative disorders. 842 69

Striatonigral degeneration (SND) is sporadic, middle-aged on set degenerative disease of the nervous system which etiology is unknown. SND is considered one of multiple system atrophy (MSA). Clinically parkinsonian symptom is dominant and then it is difficult to distinguish from idiopathic Parkinson's disease (PD). Pathologically neuron cell loss and gliosis are recognized principally striatum (mainly putamen) and substantia nigra. Putaminal hypointensity and slit-hyper intensity in the outer margin of putamen are often seen on T2-weighted 1.5 Tesla MRI. PET with [18 F] fluorodeoxyglucose indicates a considerably decreased glucose utilisation in the striatum of SND, whereas glucose utilisation are normal in PD. Striatal dopamine D1, D2 receptors are reduced. Response to Levodopa is poor or absent.
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PMID:[Striatonigral degeneration]. 901 34

Age-related human neurodegenerative diseases are a major social and medical problem. It is therefore logical to take into consideration every theory with an overall approach to neurodegenerative diseases. This environmental proposal relies mainly on data concerning the Western Pacific amyotrophic lateral sclerosis-Parkinsonism-dementia complex (WP ALS-PD) considered as 'a prototypal human neurodegenerative disease' and on extrapolation from it to the bulk of neurodegenerative diseases (NDD). NDD would be due to an accelerated ageing process in certain populations of neurons due to the noxious synergy of (1) increased environmental slow deleterious factors (such as slow toxins) and of (2) decreased environmental protective factors (Mg deficient intake particularly). First, it was observed that three apparently dissimilar conditions occurred at extraordinary high rates in the Guam area: motoneuron disease (ALS), Parkinson's disease (P) and Alzheimer's-like dementia (D). Next, several other foci of endemic ALS-PD were found in Asia and Oceania in three Western Pacific population groups. These included the Chamorro people in Mariana Islands (Guam and Rota), the Auyu and Jakai people of West New Guinea and the Japanese residents of the Kii peninsula (Honshu island). The post-Second World War decline of the occurrence of WP ALS-PD in all three high incidence disease foci coupled with the absence of demonstrable heritable or transmissible factors had led to focus the search for the cause of this degenerative disease on nontransmissible environmental factors that are disappearing as the susceptible population groups acculturate to modern way. Epidemiologic study has shown that preference for traditional Chamorro food is the only one of 23 tested variables significantly associated with an increased risk for PD. An early suggestion incriminated the toxic seed of the false sago palm (Cycas circinalis L) which was used in traditional food and medicine. Laboratory investigation of cycad seed revealed the presence of various toxins and particularly of an 'unusual' non protein aminoacid: L-BMAA (beta-N-methylamino-L-alanine), an excitotoxic aminoacid. This slow toxin presents some structural similarity to another 'unusual' excitotoxic aminoacid: L-BOAA (beta-N-oxalyl-amino-L-alanine), an exogenous neurotoxin present in the grass pea (Lathyrus sativus) whose excessive consumption may cause lathyrism. The excitotoxicity of both L-BMAA and L-BOAA mainly concerns non-NMDA receptors. The neurotoxicity of these aminoacids varies with experimental models failing to induce an experimental model akin to WP ALS-PD or displaying many of the motor-system and behavioral changes of WP ALS-PD. It may be due to the presence of physiological levels of bicarbonate or of various toxic cofactors: bio-organic such as cycasin or inorganic such as pollutant metals e.g. aluminum or manganese, together with the lack of protective factors (e.g. calcium and magnesium deficiencies). Combined Al intoxication with Ca-Mg deficiencies is a reasonable model to investigate the pathogenesis of neurodegenerative diseases and eventually to screen their treatments. It may also be considered as a model of magnesium deficit, but it does not concern simple magnesium deficiency reversible with mere oral physiological magnesium supplementation. Magnesium deficiency cannot result in neurodegenerative disease. Combined Al intoxication with Ca-Mg deficiencies is not reversible through physiological oral magnesium supplementation. It therefore constitutes a type of experimental magnesium depletion model, instrumental in the investigation of the pathogenesis of magnesium depletion and in the screening of its still unknown possible treatments. (ABSTRACT TRUNCATED)
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PMID:Are age-related neurodegenerative diseases linked with various types of magnesium depletion? 951 30

Dementia is characterized by a decline in cognition, behavioral disturbances, and interference with daily functioning and independence. Diagnosis is sometimes delayed as patients or family members often misattribute obvious manifestations of cognitive decline to normal aging rather than to the onset of a degenerative disease. Many physicians do not perform mental status examinations or do not use them effectively to detect early symptoms. Clinical markers are available to decrease the difficulty in distinguishing dementia from depression and confusional states such as delirium. Alzheimer's disease (AD) is the most common form of dementia; others include rapidly progressive dementias, dementias associated with strokes and Parkinson's disease, and frontotemporal dementias. Often, AD coexists with other forms of dementia. Sensitivity to early warning signs, interviews with family members, and mental status examinations are essential to early detection of AD, and will prove useful to primary-care physicians who care for older patients.
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PMID:The initial recognition and diagnosis of dementia. 961 46

Adenovirus is an efficient vector for neuronal gene therapy due to its ability to infect post-mitotic cells, its high efficacy of cell transduction and its low pathogenicity. Recombinant adenoviruses encoding for therapeutical agents can be delivered in vivo after direct intracerebral injection into specific brain areas. They can be transported in a retrograde manner from the injection site to the projection cell bodies offering promising applications for the specific targeting of selected neuronal populations not easily accessible by direct injection, such as the motor neurons in the spinal cord. Adenoviral vectors are also efficient tools for the ex vivo gene therapy, that is, the genetical modification of cells prior to their transplantation into the nervous system. Recently, the efficacy of the adenovirus as a gene vector system has been demonstrated in several models of neurodegenerative diseases including Parkinson's disease (PD) and motor neuron diseases. In rat models of PD, adenoviruses encoding for either tyrosine hydroxylase, superoxide dismutase or glial-derived neurotrophic factor improved the survival and the functional efficacy of dopaminergic cells. Similarly, the intramuscular injection of an adenovirus encoding for neurotrophin-3 had substantial therapeutic effects in a mutant mouse model of motor neuron degenerative disease. However, although adenoviruses are highly attractive for neuronal gene transfer, they can trigger a strong inflammatory reaction leading in particular to the destruction of infected cells. The recent development of new generations of adenoviral vectors could shed light on the nature of the immune reaction caused by adenoviral vectors in the brain. The use of these new vectors, combined with that of neurospecific and regulatable promoters, should improve adenovirus gene transfer into the central nervous system.
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PMID:Adenovirus in the brain: recent advances of gene therapy for neurodegenerative diseases. 965 83

In recent years, the possibility that programmed cell death (PCD), which is mediated by genetic programs intrinsic to the cell, may underlie the degeneration of neurons that occurs in Parkinson's disease (PD) and allied disorders has become an important hypothesis. Although PCD was originally identified in tissues as a normal developmental phenomenon, there is no question that it can also occur in neurologic disease and models thereof. The possibility that PCD could occur in dopamine neurons in degenerative disease is made plausible by the observations that natural cell death, with the morphology of apoptosis, does occur in these neurons and that this event is regulated by developmental target interactions. In addition, it has been shown that apoptotic death can be induced in these neurons in some animal models of parkinsonism. We have shown, for example, that apoptosis can be induced during development by intrastriatal injection of the neurotoxin 6-hydroxydopamine. Other investigators have shown that apoptosis can be induced in a chronic model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyride toxicity. However, investigations in human PD brains have yielded mixed results thus far, with some investigators identifying evidence of apoptotic death but others not. Further investigation of human postmortem tissue will benefit from a more complete understanding of the molecular basis of PCD in dopamine neurons, such that its molecular features can be investigated, rather than strictly relying on the morphologic markers presently available.
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PMID:Programmed cell death: does it play a role in Parkinson's disease? 974 84

Morbus Parkinson is a progressive degenerative disease of the human central, peripheral, and enteric nervous systems. In the course of the disease, not only the substantia nigra, but also extranigral components of the motor system, as well as numerous limbic system and autonomic centers undergo serious damage. Accordingly, Parkinson's disease is a multisystem disorder. Only specific types of projection neurons fall victim to it. The first manifestation of the pathological process which causes the disease are abnormalities of the neuronal cytoskeleton. Intracytoplasmic inclusions evolving in the form of Lewy bodies in perikarya and Lewy neurites in the neuronal processes result in premature cell death of the affected neurons. On the basis of this selective neuronal vulnerability, a categorization emerges of the pathological changes within the nervous system and corresponding functional impairments.
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PMID:[Neuroanatomy of Parkinson disease. Changes in the neuronal cytoskeleton of a few disease-susceptible types of neurons lead to progressive destruction of circumscribed areas in the limbic and motor systems]. 1091 40


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