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)

When a patient presents a neurological disorder, it is important to consider drugs is a possible cause. The risk to suffer neurological complications by drugs is unknown. It is difficult to calculate the number of drug addicts or the number of occasional drug users. It is important take into account that some patients are using more than one drug. The acute use of cannabis induces important changes in cognition and psychomotor performance. No signs of neurotoxicity were found in chronic marihuana users. Some "designer drugs" can induce neurotoxicity. MDMA, that have hallucinogenic activity, is a neurotoxin in animals. MPTP kill dopaminergic neurons in the substantia nigra, inducing Parkinson's disease. Volatile substances containing toluene or n-hexane are usually abused by young people. They can produce neurological damage when are used chronically (p. ex. cerebral atrophy or peripheral neuropathies).
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PMID:[Neurologic complications of drug addiction. General aspects. Complications caused by cannabis, designer drugs and volatile substances]. 270 Feb 91

n-Hexane, similar hydrocarbons, and derivatives are common environmental pollutants and by-products of lipid peroxidation, and they may have a nigrotoxic effect like that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. This report describes our second case of parkinsonism in a subject exposed to n-hexane. Positron emission tomography studies demonstrated regional striatal abnormalities of the nigrostriatal dopaminergic system and of glucose metabolism that were different from those found in idiopathic Parkinson's disease.
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PMID:n-Hexane-induced parkinsonism: pathogenetic hypotheses. 765 43

Oxidative stress may contribute to nigral cell death in Parkinson's disease based on postmortem investigations showing increased iron levels, decreased levels of reduced glutathione (GSH), and impaired mitochondrial function. This leads to oxidative damage because lipid peroxidation is increased in substantia nigra and there is a widespread increase in protein and DNA oxidation in the brain in Parkinson's disease. Nitric oxide (NO) may be one of the free radical species involved in nigral degeneration. NO is involved in the production of hydroxyl radicals resulting from MPP+-induced dopamine efflux in striatum. Mice treated with the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole show reduced toxicity to MPTP and knock-out mice lacking neuronal NOS show decreased MPTP susceptibility. In primates, 7-nitroindazole inhibits MPTP toxicity but this remains controversial because no protection is afforded by the nonspecific NOS inhibitor, L-NAME. Indeed, in Parkinson's disease itself, there is little evidence for nitric oxide's involvement in nigral pathology. A susceptibility factor for the development of Parkinson's disease may involve isoforms of cytochrome P450, some of which are found in the brain. CYP2EI, which is associated with free radical production and the formation of endogenous toxins, is selectively localized in nigral dopamine-containing cells. CYP2E1 metabolizes n-hexane leading to the formation of its neurotoxic metabolite 2,5-hexanedione which may explain cases of solvent-induced parkinsonism. Oxidative processes clearly contribute to the pathology of Parkinson's disease but are probably secondary to some other primary unidentified cause, presumably genetic or environmental. Nevertheless, their involvement may allow therapeutic intervention in the cascade of events associated with the progression of Parkinson's disease.
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PMID:Oxidative mechanisms in nigral cell death in Parkinson's disease. 961 15

It has been shown that the primary striatal dopaminergic hypofunction which is at the origin of Parkinson's disease, results in a secondary hyperactivity of glutamatergic neurotransmission. In the search for a therapy of Parkinson's disease, ionotropic, mainly NMDA, receptor antagonists were found to have moderately beneficial, yet also some undesirable side-effects. Therefore the present study was aimed at determining whether some metabotropic glutamate receptor (mGluR) ligands may have antiparkinsonian effects in the haloperidol-induced muscle rigidity. To this end three mGluR ligands were used: the potent and selective mGluR I antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), the mixed group II agonist/ group I antagonist (S)-4-carboxy-3-hydroxyphenyl-glycine ((S)-4-C3HPG), and the potent group II agonist (+)-2-aminobicyclo[3.1.0.]hexane-2,6,-dicarboxylic acid (LY354740). Only LY354740 penetrated the brain from the periphery; for this reason other drugs were injected bilaterally into the rostral striatum or nucleus accumbens. The muscle tone was recorded by a mechanomyographic/electromyographic (MMG/EMG) method which measured the resistance of a rat's hind foot and the EMG reflex response of its muscles to passive movements. (S)-4C3HPG (5 and 15 microg/0.5 microl) and LY354740 (5 and 10mg/kg i.p.) diminished the muscle rigidity induced by haloperidol (1 mg/kg i.p.). AIDA (0.5-15 microg/0.5 microl) injected into the striatum was only slightly effective in the highest dose used. However, when injected into the nucleus accumbens AIDA (15microg/0.5microl) significantly and strongly counteracted the haloperidol-induced muscle rigidity. Our results suggest that stimulation of group II striatal mGluRs seems to play a major role in diminution of parkinsonian-like muscle rigidity. However, it seems that the antagonism of group I mGluRs located in the nucleus accumbens may also be of importance to the antiparkinsonian effect.
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PMID:The role of metabotropic glutamate receptor (mGluR) ligands in parkinsonian muscle rigidity. 1102 78

The aim of the present studies was to examine the ability of a potent, systemically active, selective Group II mGlu receptor (mGluR2/3) agonist, 1R,4R,5S,6R-2-oxa-4-minobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) to provide both functional relief and neuroprotection in rodent models of Parkinson's disease (PD). In functional studies, intracerebroventricular administration of LY379268 (1, 5, 10, 20 nmol/2 microl) produced a dose-dependent increase in locomotor activity in the reserpine (5 mg/kg ip)-treated rat. In contrast, systemic administration of LY379268 (0.1, 1, 10 mg/kg ip) did not reverse reserpine-induced akinesia and failed to effect rotational behaviour 1 month after unilateral lesioning of the nigrostriatal tract by 6-hydroxydopamine (6-OHDA; 4 microg infused into the substantia nigra (SN)). In neuroprotective studies, animals were treated with LY379268 (10 mg/kg/day ip) either for 7 days following 6-OHDA injection into the SN (4 microg) or for 21 days following 6-OHDA injection into the striatum (10 microg) before measurement of tyrosine hydroxylase immunoreactivity in the striatum and/or SN as an index of neuroprotection. LY379268 provided some protection against nigral infusion of 6-OHDA and also some functional improvement and correction of dopamine turnover was observed. The compound also provided significant protection in the striatum and some protection in the SN against striatal infusion of 6-OHDA. These data suggest that activation of Group II mGlu receptors can provide some protection in models of PD, while their role in providing functional improvement is less clear.
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PMID:Evaluation of the mGluR2/3 agonist LY379268 in rodent models of Parkinson's disease. 1211 1

Recent findings have shown that dendritically released dopamine (DA) plays an important modulatory role in the substantia nigra pars reticulata (SNr). It is therefore possible that the loss of DA observed in Parkinson's disease (PD) could hold important consequences for nigral function. Previously, we have shown that activation of presynaptically localized group II metabotropic glutamate receptors (mGluRs) inhibits excitatory transmission at the subthalamic nucleus (STN)-SNr synapse and that activation of presynaptically localized group III mGluRs decreases excitatory and inhibitory transmission in the SNr. To test the hypothesis that nigral DA can modulate mGluR function in the SNr, we performed whole-cell patch-clamp recordings from gamma-aminobutyric acidergic SNr neurons in slices obtained from rats that were acutely reserpinized. In slices obtained from reserpinized animals, the effect of group II mGluR activation by the selective agonist (+)-2-aminobicyclo[3.1.0]-hexane-2,6-dicarboxylate monohydrate (LY354740) (100 nM), but not group III mGluR activation [L-(+)-2-amino-4-phosphonobutyric acid, L-AP4, 500 microM], at STN-SNr synapses is significantly decreased. This effect could be mimicked in control slices by prior bath application of haloperidol (20 microM) and R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390) (20 microM) but not sulpiride (50 microM). Furthermore, application of dopamine (100 microM) and (+/-)-6-chloro-7,8-dyhydroxy-3allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-benzazepine (SKF82958) (1 microM) but not quinpirole (10 microM) could rescue the group II mGluR effect in reserpinized slices. The effect of group III mGluR activation (L-AP4, 100 microM) on inhibitory synaptic transmission was also significantly reduced in slices from reserpine-treated animals. This effect was mimicked by haloperidol (20 microM), SCH23390 (20 microM), and sulpiride (50 microM) in control slices. Thus, in a Parkinsonian state, the loss of nigral DA may add to the overall pathophysiological changes in basal ganglia output.
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PMID:Dopamine modulates the function of group II and group III metabotropic glutamate receptors in the substantia nigra pars reticulata. 1213 Jul

Although genomic screening studies have identified several genes associated with Parkinson's disease (PD), there is evidence that environmental factors are also involved in the pathogenesis of the disease and that hydrocarbon-solvents may be one of them. The genetic component is less evident in late-onset PD. To assess whether age and PD may affect the catabolism of the hydrocarbon n-hexane, a two-part study was performed. In the first part the urinary levels of its main metabolites, 2,5-hexanedione and 2,5-dimethylpyrroles, were measured in 108 patients and 108 healthy controls, matched by age and sex. Metabolite urinary excretion was significantly reduced in PD patients as compared with controls and was inversely related to age in both groups. In the second part the same comparison was made between 24 non-smoking and 10 smoking patients, matched to controls, after smoking of a hydrocarbon-rich cigarette. In these subjects also n-hexane and 2,5-hexanedione blood levels were measured. There was no appreciable difference in n-hexane blood levels between patients and controls in non-smokers, whereas there was a significant increase in patients over controls in smokers (p < 0.01). 2,5-hexanedione blood levels were significantly lower in patients than in healthy controls, both in non-smokers and in smokers, but the reduction was more pronounced in smokers (-46.3 % versus -10.7 %). The same was true for 2,5-hexanedione and 2,5-dimethylpyrrole urinary levels. This study suggests that aging and PD may be associated with a reduction in the capacity to eliminate the hydrocarbon n-hexane. This metabolic alteration may play a role in the pathogenesis of PD.
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PMID:Poor metabolization of n-hexane in Parkinson's disease. 1273 34

Studies have demonstrated that smokers have lower levels of brain monoamine oxidase (MAO) A and B activity and lower MAO-B platelet activity than non-smokers. Recent speculations suggest that in addition to nicotine, tobacco components which are MAO inhibitors, may contribute to some tobacco related psychopharmacological effects. Furthermore, epidemiological evidence indicates a lower incidence of Parkinson's disease in smokers than in non-smokers. This relationship also might be linked to MAO inhibition. These intriguing observations prompted studies on the effects of tobacco leaf and tobacco smoke constituents on MAO activity. Studies reported here demonstrate that crude hexane tobacco leaf and hexane and aqueous leaf extracts have MAO inhibitory properties. Rat brain mitochondrial MAO-A and MAO-B activity are not altered following continuous 28 day exposure to (osmotic minipump) to two tobacco alkaloids, (S)-nicotine or (R,S)-N-methylanatabine. However, earlier studies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated parkinsonian C57BL/6 mouse model have provided indirect evidence that the tobacco derived 2,3,6-trimethyl-1,4-naphthoquinone (an MAO-A and B inhibitor) is effective in inhibiting MAO-B in vivo and is neuroprotective. Results reported here from more extensive tobacco leaf extractions provide evidence for three additional compounds with MAO-B inhibitory properties. One contains a chromone system, another a polyunsaturated macro-cycle and the third we have identified as farnesylacetone. These findings provide support to the thesis that components of tobacco smoke may be responsible for the inhibition of brain MAO-A and brain and platelet MAO-B in human smokers.
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PMID:Studies on the interactions of tobacco leaf and tobacco smoke constituents and monoamine oxidase. 1282 16

Essential tremor (ET) is a common neurological disorder. Its etiology and pathogenesis are not well understood and several environmental factors (i.e., toxicants) have been studied. Organochlorine pesticides (OCPs) are potent tremor-producing chemicals. These pervasive environmental contaminants have been linked with other tremor disorders (e.g., Parkinson's disease) but they have not been assessed in ET cases. Our objective was to test the hypothesis that ET is associated with OCP exposure. Serum OCP concentrations and lifetime occupational histories were assessed in ET cases and control subjects. Six serum OCP concentrations (p,p'-DDE, p,p'-DDT, beta-hexachlorocyclo-hexane, oxychlordane, trans-nonachlor, and dieldrin) were assessed. Data from a lifetime occupational history were reviewed by a blinded industrial hygienist. The six serum OCP concentrations were similar in 136 ET cases and 144 control subjects. There was no association in ET cases between the six serum OCP concentrations and total tremor score. Three (2.2%) ET cases versus 9 (6.3%) controls had past occupational exposure to OCPs (OR=0.34, 95% CI=0.09-1.28, p=0.10). Although OCPs have been associated with other tremor disorders, we were not able to find an association between the six most tremorogenic OCPs and ET. Our data suggest that these tremor-producing chemicals are not of major etiological importance in our patients with ET.
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PMID:Organochlorine pesticide exposure in essential tremor: a case-control study using biological and occupational exposure assessments. 1662 Sep 96

Amyloid fibrils found in various neurodegenerative disorders are also recognized as high-performance protein nanomaterials with a formidable rigidity. Elucidation of an underlying molecular mechanism of the amyloid fibril formation is crucial not only to develop controlling strategy toward the diseases, but also to apply the protein fibrils for future nanobiotechnology. alpha-Synuclein is an amyloidogenic protein responsible for the radiating filament formation within Lewy bodies of Parkinson's disease. The amyloid fibril formation of alpha-synuclein has been shown to be induced from the oligomeric granular species of the protein acting as a growing unit by experiencing structural rearrangement within the preformed oligomeric structures in the presence of an organic solvent of hexane. This granule-based concerted amyloid fibril formation model would parallel the prevalent notion of nucleation-dependent fibrillation mechanism in the area of amyloidosis.
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PMID:Instantaneous amyloid fibril formation of alpha-synuclein from the oligomeric granular structures in the presence of hexane. 1846 76


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