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 neuroleptic malignant syndrome (NMS) is an uncommon disorder characterised by muscular stiffness and hyperthermia. It is caused by the administration of neuroleptics or by the acute withdrawal of levodopa therapy in idiopathic Parkinson's disease. An identical syndrome may be seen rarely in untreated catatonic schizophrenia. Shock, respiratory failure and myoglobinuria occur sometimes with serious consequences. Treatment should include active cooling measures and the administration of dopamine agonists. Dantrolene may also be of benefit in severe cases.
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PMID:The neuroleptic malignant syndrome--a review. 286 16

From a personal case and a review of the literature, it is recalled that bromocriptine may induce pleuropulmonary fibrosis. The various presentations of this condition are described. The index patient is a 56-year-old man, with Parkinson disease and a negative history for respiratory disease, who was taking bromocriptine in a high dose (60 mg/d). Under this treatment, he exhibited weight loss and an inflammatory syndrome and developed interstitial pneumopathy with secondary pleuropulmonary fibrosis, which resolved in part once therapy was discontinued. Bromocriptine, which is an ergot alcaloid with dopaminergic properties, has been used since 1965 in therapy. Its indications, which at the outset were restricted to endocrinology, were extended in 1972 to Parkinson disease, with a significant increase in dosages from 1979. Its responsibility in pleuropulmonary fibroses was suspected in 1981 by Rinne on data from 5 patients. As of now, 8 cases have been reported. All are Parkinson patients who, after a variable time interval (15 days to 3 years), developed a uniform picture of pleuropulmonary disease with rapidly increasing dyspnea upon exertion and deterioration of general health. These features mirror inflammation then fibrosis of the pleura and lung tissue, which results in a variable degree of chronic restrictive respiratory failure. The course is equally uniform, with partial resolution under corticosteroid therapy and more or less significant residual fibrosis at discontinuation of treatment. Immunoallergic rather than toxic or vasomotor mechanisms seem involved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Pleuropulmonary fibrosis and bromocriptine]. 632 51

We discuss the etiology and pathogenesis of Parkinson's disease (PD). Our group and others have found a decrease in complex I of the mitochondrial electron transfer complex in the substantia nigra of patients with PD; in addition, we reported loss of the alpha-ketoglutarate dehydrogenase complex (KGDHC) in the substantia nigra. Dual loss of complex I and the KGDHC will deleteriously affect the electron transport and ATP synthesis; we believe that energy crisis is the most important mechanism of nigral cell death in PD. Oxidative stress has also been implicated as an important contributor to nigral cell death in PD, but we believe that oxidative stress is a secondary phenomenon to respiratory failure, because respiratory failure will increase oxygen free-radical formation and consume glutathione. The primary cause of mitochondrial respiratory failure has not been elucidated yet, but additive effect of environmental neurotoxins in genetically predisposed persons appears to be the most likely possibility.
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PMID:Role of mitochondria in the etiology and pathogenesis of Parkinson's disease. 759 19

There is growing evidence that oxidative stress and mitochondrial respiratory failure with attendant decrease in energy output are implicated in nigral neuronal death in Parkinson disease (PD). It is not known, however, which cellular elements (neurons or glial cells) are major targets of oxygen-mediated damage. 4-Hydroxy-2-nonenal (HNE) was shown earlier to react with proteins to form stable adducts that can be used as markers of oxidative stress-induced cellular damage. We report here results of immunochemical studies using polyclonal antibodies directed against HNE-protein conjugates to label the site of oxidative damage in control subjects (ages 18-99 years) and seven patients that died of PD (ages 57-78 years). All the nigral melanized neurons in one of the midbrain sections were counted and classified into three groups according to the intensity of immunostaining for HNE-modified proteins--i.e., no staining, weak staining, and intensely positive staining. On average, 58% of nigral neurons were positively stained for HNE-modified proteins in PD; in contrast only 9% of nigral neurons were positive in the control subjects; the difference was statistically significant (Mann-Whitney U test; P < 0.01). In contrast to the substantia nigra, the oculomotor neurons in the same midbrain sections showed no or only weak staining for HNE-modified proteins in both PD and control subjects; young control subjects did not show any immunostaining; however, aged control subjects showed weak staining in the oculomotor nucleus, suggesting age-related accumulation of HNE-modified proteins in the neuron. Our results indicate the presence of oxidative stress within nigral neurons in PD, and this oxidative stress may contribute to nigral cell death.
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PMID:Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. 861 Jan 3

Mitochondrial respiratory failure secondary to complex I inhibition may contribute to the neurodegenerative process underlying nigral cell death in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be inhibitors of complex I, and have been implicated in the cause of PD as endogenous neurotoxins. To determine the potency and structural requirements of isoquinoline derivatives to inhibit mitochondrial function, we examined the effects of 22 neutral and quaternary compounds from three classes of isoquinoline derivatives (11 isoquinolines, 2 dihydroisoquinolines, and 9 1,2,3,4-tetrahydroisoquinolines) and MPP+ on the enzymes of the respiratory chain in mitochondrial fragments from rat forebrain. With the exception of norsalsolinol and N,n-propylisoquinolinium, all compounds inhibited complex I in a time-independent, but concentration-dependent manner, with IC50s ranging from 0.36-22 mM. Several isoquinoline derivatives were more potent inhibitors of complex I than 1-methyl-4-phenylpyridinium ion (MPP+) (IC50 = 4.1 mM), the most active being N-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.36 mM) and 6-methoxy-1,2,3,4-tetrahydroisoquinoline (IC50 = 0.38 mM). 1,2,3,4-Tetrahydroisoquinoline was the least potent complex I inhibitor (IC50 approximately 22 mM). At 10 mM, only isoquinoline (23.1%), 6,7-dimethoxyisoquinoline (89.6%), and N-methylsalsolinol (34.8%) inhibited (P < 0.05) complex II-III, but none of the isoquinoline derivatives inhibited complex IV. There were no clear structure-activity relationships among the three classes of isoquinoline derivatives studied, but lipophilicity appears to be important for complex I inhibition. The effects of isoquinoline derivatives on mitochondrial function are similar to those of MPTP/MPP+, so respiratory inhibition may underlie their reported neurotoxicity.
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PMID:Inhibition of complex I by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 861 71

We review the recent progress in the research of the etiology, pathogenesis and treatment of Parkinson's disease. It has been postulated that mitochondrial respiratory failure and oxidative stress are two major contributors to nigral cell death in Parkinson's disease. Loss of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase complex in the substantia nigra has been reported. Evidence to indicate oxidative stress includes a high dopamine content, increase in superoxide dismutase activities, increase in iron, and decrease in glutathione in the substantia nigra. The question posed is which one occurs first. We believe mitochondrial respiratory failure occurs first, because slowing down of the electron transport induces an increase in the formation of activated oxygen species. The primary cause of Parkinson's disease is still unknown, but we believe the interaction of environmental toxins and genetic predispositions is important. In this respect, molecular genetic studies on familial Parkinson's disease are very important.
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PMID:Parkinson's disease: from etiology to treatment. 877 62

1-Methyl-4-phenylpyridinium ion (MPP+), an oxidative metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is considered to be directly responsible for MPTP-induced Parkinson's disease-like symptoms by inhibiting NADH-ubiquinone oxidoreductase (complex I) in the mitochondrial respiratory chain. Here we demonstrate that 25 microM MPP+ decreases the content of mitochondrial DNA to about one-third in HeLa S3 cells. On the contrary, 0.1 microM rotenone, which inhibits complex I to the same extent as 25 microM MPP+ in the cells, increases the content of mitochondrial DNA about 2-fold. Hence, the effect of MPP+ on mitochondrial DNA is not mediated by the inhibition of complex I. To examine the replication state of mitochondrial DNA, we measured the amount of nascent strands of mitochondrial DNA. The amount is decreased by MPP+ but increased by rotenone, suggesting that the replication of mitochondrial DNA is inhibited by MPP+. Because the proper amount of mitochondrial DNA is essential to maintain components of the respiratory chain, the decrease of mitochondrial DNA may play a role in the progression of MPTP-induced Parkinson's disease-like symptoms caused by the mitochondrial respiratory failure.
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PMID:The content of intracellular mitochondrial DNA is decreased by 1-methyl-4-phenylpyridinium ion (MPP+). 909 84

Lewy body disease (LBD) is a progressive neurological disorder with parkinsonism, having many Lewy bodies (LBs) and degenerative changes. LBD is classified into the three types according to the distribution of LBs: "brain-stem type", "transitional type" and "diffuse type". The brain-stem type is identical to classical Parkinson's disease (PD). The diffuse type is nominated as "diffuse Lewy body disease" (DLBD). DLBD is a neuropathological entity, characterized by abundant LBs not only in the basal ganglia and brain-stem but in the cerebral cortex, combined with senile changes. Juvenile onset DLBD is called "pure form" of DLBD because of no or few senile changes. The LBs are present in the amygdala, nucleus basalis of Meynert, hypothalamic nuclei, substantia nigra, nucleus paranigralis, locus caeruleus, dorsal vagal nucleus and reticular nuclei. The cerebral LBs are numerous in the parahippocampal gyrus, cingular gyrus, and insular, frontal and temporal cortices. The LBs show immunoreactivity to ubiquitin and the ubiquitin-immunoreactive neurites in the CA2-3 region appear to be specific for DLBD. The clinical features of DLBD in the senium are progressive dementia, psychotic state, parkinsonism and autonomic signs. In general, progressive dementia is an initial symptom, followed by parkinsonism in the later stage. Some show progressive autonomic failure. A few present respiratory failure or vocal cord palsy resulting in sudden death in DLBD. DLBD is characterized neurochemically by severe affection of multiple neurotransmitters networks. In DLBD an impairment of the innominato-cortical cholinergic and mesocortical dopaminergic system, differentiating from Alzheimer's disease and PD, may play an important role in developing disease process.
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PMID:[Diffuse Lewy body disease]. 957 69

We discuss neurochemical and neurogenetic correlates of Parkinson's disease (PD) based on the recent progress in the study of its etiology and pathogenesis. Nigral degeneration with the presence of Lewy bodies in the remaining neurons is the pathologic hallmark of PD, and the resultant loss of striatal dopamine is responsible for most of the clinical manifestations. Although the primary cause is still unknown, mitochondrial respiratory failure and oxidative stress appear to be two major contributors to the nigral cell death. Many endogenous and exogenous compounds with structural similarity to MPTP have been postulated as potential neurotoxins inducing nigral cell death in PD, but there is little evidence of accumulation of such compounds in the nigra. Genetic influence has increasingly been recognized as an important risk factor for PD. In this respect, genetic linkage analysis and molecular cloning of the disease genes in familial parkinsonism are of utmost importance today. Recently, the disease gene for one of the autosomal dominant forms of familial PD was identified, and we cloned the gene for an autosomal recessive type of familial parkinsonism that had been mapped to the long arm of chromosome 6 by our group. Information obtained on familial parkinsonism will contribute to the studies on sporadic PD as well.
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PMID:Neurochemical and neurogenetic correlates of Parkinson's disease. 972 14

This review discusses the etiology and pathogenesis of Parkinson's disease (PD). Mitochondrial respiratory failure and oxidative stress appear to be two major contributors to nigral neuronal death in PD. Complex I deficiency has been reported by several groups and appears to be one of the basic abnormalities responsible for mitochondrial failure. The principal question is whether or not complex I deficiency is primary or secondary. The second question is whether or not complex I deficiency is localized in the nigrostriatal system or is systemically present. It is our impression that complex I deficiency is not the primary cause but that its deficiency appears to be systemic. The primary cause may be the combination of genetic background and potential nigral neurotoxins. Exposure of nigral neurons to a high risk for oxidative damage because of its high dopamine content may be the reason for more pronounced nigral complex I deficiency compared to systemic organs. Oxidative stress and mitochondrial failure produce a vicious cycle in nigral neurons. To explore the genetic risk factors of sporadic PD, studies on familial PD and parkinsonism are important. Recently, an autosomal dominant form of familial PD was found to be caused by point mutations of the alpha-synuclein gene, and an autosomal recessive familial parkinsonism was mapped to the long arm of chromosome 6 near the Mn-SOD gene locus. Information obtained in these familial cases will contribute to the research on sporadic PD.
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PMID:Mitochondrial dysfunction in Parkinson's disease. 974 80


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