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)

Injection of the endogenous methyl donor, S-adenosyl methionine (SAM), into rat brain induces Parkinson's disease (PD)-like symptoms possibly by stimulating deleterious protein methylation. Gel-filtration chromatography of rat brain extracts treated with [3H-methyl]-SAM revealed the presence of radioactive peaks with apparent molecular weights of about 5 kDa. Treatment with guanidine HCl altered the elution volumes of the labeled peaks. Lyophilized peak fractions released volatile 3H-methanol on incubation with NaOH, indicating the presence of carboxyl methyl esters. Because prenylated proteins are avid methyl acceptors at the terminal carboxylic acid groups, 1 micromol S-farnesylcysteine (FC) analogs blocked the SAM-induced tremors in the experimental rats. FC analogs did not only reverse the associated rigidity, abnormal posture, and hypokinesia, but stimulated hyperactivity in the animals. This amphetamine-like effect was monitored for 20 min in an animal activity monitor and movement times between 400 +/- 100 and 560 +/- 125 s covering distances between 78 +/- 29 to 125 +/- 35 m were recorded for rats treated with FC analogs with or without SAM. Control animals moved only for 60 +/- 13 s covering about 6 +/- 1 m, indicating a 7-9-fold and 13-21-fold increase in duration of movement and distance covered, respectively. N-Acetyl-S-farnesylcysteine (AFC) potentiated amphetamine-induced ipsiversive rotation of 6-hydroxydopamine-lesioned rats from 390 +/- 130 to 830 +/- 110, with AFC alone having no significant effect on net rotation compared to controls. These data indicate that intracerebroventricular injection of SAM may induce PD symptoms by interfering with the methylation/demethylation homeostasis of prenylated proteins that function in the dopaminergic and other signaling pathways, and that the FC analogs may counteract the SAM effects by acting synergistically on events subsequent to neurotransmitter release.
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PMID:Farnesyl-L-cysteine analogs block SAM-induced Parkinson's disease-like symptoms in rats. 1097 24

We developed sample preparation methods for the detection of various biogenic phenylethylamine derivatives such as 3,4-dihydroxyphenylalanine, and their cyclisation products with aldehydes, i.e., 1,2,3,4-tetrahydroisoquinoline derivatives in blood samples. 1,2,3,4-Tetrahydroisoquinolines are considered to play an essential role as neurotoxic compounds in the pathomechanism of Parkinson's disease. We used reversed-phase high-performance liquid chromatography with ultraviolet and fluorescence detection for separation and identification. Ultrafiltration, protein precipitation and solid-phase extraction were investigated for purification of blood samples and enrichment of various compounds with a wide range of hydrophilicity and hydrophobicity. Protein precipitation by methanol and perchloric acid is a fast method to separate the analytes from the plasma matrix. A higher yield of the analytes is attained with prior addition of an alkylsulfonic acid giving a fine-grained precipitate. With the addition of ion pairing compounds into the sample it is possible to enrich not only lipophilic compounds such as norharman, tryptamine and melatonin, but also hydrophilic ones such as 3,4-dihydroxyphenylalanine by reversed-phase solid-phase extraction. Ultrafiltration is not useful as a screening method.
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PMID:Development of a method for sample preparation for subsequent identification and measurement of 1,2,3,4-tetrahydroisoquinolines and other potentially neurotoxic compounds by high-performance liquid chromatography with ultraviolet and fluorescence detection in blood plasma of Parkinson's disease patients. 1107 81

alpha-Synuclein (alphaS) is a 140-residue neuronal protein that forms insoluble cytoplasmic aggregates in Parkinson's disease (PD) and several other neurodegenerative disorders. Two missense mutations (A53T and A30P) are linked to rare forms of familial PD. The normal function of alphaS is unknown, and cultured cell systems that model its modification from soluble monomers to aggregated forms have not been reported. Through a systematic centrifugal fractionation of mesencephalic neuronal cell lines and transgenic mouse brains expressing wild-type or A53T human alphaS, we observed unusual, previously unrecognized species of alphaS that migrate well above the 17-kDa monomeric form in denaturing gels. Incubation at 65 degrees C of high-speed cytosols from cells or brains revealed a modified alphaS species migrating at approximately 36 kDa and an extensive higher molecular mass alphaS-reactive smear. Extraction of the cytosols with chloroform/methanol or with a resin (Lipidex 1000) that binds fatty acids resulted in a similar pattern of higher molecular mass alphaS forms. On the basis of this effect of delipidation, we reexamined the primary structure of alphaS and detected a motif at the N and C termini that is homologous to a fatty acid-binding protein signature. In accord, we found that purified human alphaS binds oleic acid, with an apparent K(d) of 12.5 microM. We also observed an enhanced association of A53T alphaS with microsomal membranes in both mesencephalic cells and transgenic mouse brains. We conclude that alphaS has biochemical properties and a structural motif that suggest it is a novel member of the fatty acid-binding protein family and may thus transport fatty acids between the aqueous and membrane phospholipid compartments of the neuronal cytoplasm.
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PMID:alpha-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins. 1148 78

Intracellular proteinaceous inclusions (Lewy bodies and Lewy neurites) of alpha-synuclein are pathological hallmarks of neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies (DLB), and multiple systemic atrophy. The molecular mechanisms underlying the aggregation of alpha-synuclein into such filamentous inclusions remain unknown, although many factors have been implicated, including interactions with lipid membranes. To model the effects of membrane fields on alpha-synuclein, we analyzed the structural and fibrillation properties of this protein in mixtures of water with simple and fluorinated alcohols. All solvents that were studied induced folding of alpha-synuclein, with the common first stage being formation of a partially folded intermediate with an enhanced propensity to fibrillate. Protein fibrillation was completely inhibited due to formation of beta-structure-enriched oligomers with high concentrations of methanol, ethanol, and propanol and moderate concentrations of trifluoroethanol (TFE), or because of the appearance of a highly alpha-helical conformation at high TFE and hexafluoro-2-propanol concentrations. At least to some extent, these conformational effects mimic those observed in the presence of phospholipid vesicles, and can explain some of the observed effects of membranes on alpha-synuclein fibrillation.
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PMID:Conformational behavior and aggregation of alpha-synuclein in organic solvents: modeling the effects of membranes. 1261 67

Excess methylation has been suggested to play a role in the pathogenesis of Parkinson's disease (PD), since the administration of S-adenosylmethionine (SAM), a biological methyl donor, induces PD-like changes in rodents. It was proposed that SAM-induced PD-like changes might be associated with its ability to react with the dopaminergic system. In the present study the effects of SAM on dopamine receptors and transporters were investigated using rats and cloned dopamine receptor proteins. Autoradiographic examination of SAM indicated its tendency to be localized and accumulated in rat striatal region after the intracerebroventricular injection into rat brain. Moreover, results showed that SAM significantly decreased dopamine D1 and D2 receptor binding activities by decreasing the Bmax and increasing the Kd values. At concentrations of 0.1, 0.25 and 0.5 mM, SAM was able to reduce the Bmax from the control value of 848.1 for dopamine D1-specific ligand [3H] SCH 23390 to 760.1, 702.6 and 443.0 fmol/mg protein, respectively. At the same concentrations, SAM was able to increase the Kd values from 0.91 for the control to 1.06, 3.84 and 7.01 nM of [3H] SCH 23390, respectively. The effects of SAM on dopamine D2 binding were similar to those of dopamine D1 binding. SAM also decreased dopamine transporter activity. The interaction of SAM with dopamine receptor proteins produced methanol from methyl-ester formation and hydrolysis. We propose that the SAM effect might be related to its ability to react with dopamine receptor proteins through methyl-ester formation and methanol production following the hydrolysis of the carboxyl-methylated receptor proteins.
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PMID:The inhibitory role of methylation on the binding characteristics of dopamine receptors and transporter. 1515 79

Photobiomodulation by light in the red to near infrared range (630-1000 nm) using low energy lasers or light-emitting diode (LED) arrays has been shown to accelerate wound healing, improve recovery from ischemic injury in the heart and attenuate degeneration in the injured optic nerve. Recent evidence indicates that the therapeutic effects of red to near infrared light result, in part, from intracellular signaling mechanisms triggered by the interaction of NIR light with the mitochondrial photoacceptor molecule cytochrome c oxidase. We have demonstrated that NIR-LED photo-irradiation increases the production of cytochrome oxidase in cultured primary neurons and reverses the reduction of cytochrome oxidase activity produced by metabolic inhibitors. We have also shown that NIR-LED treatment prevents the development of oral mucositis in pediatric bone marrow transplant patients. Photobiomodulation improves wound healing in genetically diabetic mice by upregulating genes important in the promotion of wound healing. More recent studies have provided evidence for the therapeutic benefit of NIR-LED treatment in the survival and functional recovery of the retina and optic nerve in vivo after acute injury by the mitochondrial toxin, formic acid generated in the course of methanol intoxication. Gene discovery studies conducted using microarray technology documented a significant upregulation of gene expression in pathways involved in mitochondrial energy production and antioxidant cellular protection. These findings provide a link between the actions of red to near infrared light on mitochondrial oxidative metabolism in vitro and cell injury in vivo. Based on these findings and the strong evidence that mitochondrial dysfunction is involved in the pathogenesis of numerous diseases processes, we propose that NIR-LED photobiomodulation represents an innovative and non-invasive therapeutic approach for the treatment of tissue injury and disease processes in which mitochondrial dysfunction is postulated to play a role including diabetic retinopathy, age-related macular degeneration, Leber's hereditary optic neuropathy and Parkinson's disease.
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PMID:Mitochondrial signal transduction in accelerated wound and retinal healing by near-infrared light therapy. 1612 Apr 14

Ethylene glycol and methanol are toxic alcohols commonly found in a variety of commercial products. We report two cases, one associated with ethylene glycol and one with methanol poisoning, which both led to acute hemorrhagic necrosis of the basal ganglia and resulted in acute Parkinson's syndrome. It is unlikely that oxalate crystal deposition is the only mechanism for such basal ganglia necrosis, because similar findings were seen following methanol intoxication. We discuss other possible mechanisms that may contribute towards this unusual neurotoxicity. Both of our patients survived their toxic ingestions, but then developed acute Parkinson's syndrome within 10 days of the ingestion. However, the patient who ingested methanol developed respiratory muscle stiffness/weakness, which responded poorly to anti-Parkinsonian drug therapy. Treatment with carbidopa/levodopa improved cogwheel rigidity and bradykinesia in both patients. We conclude that acute Parkinsonism is one of the lesser-recognized devastating complications of both ethylene glycol and methanol poisoning.
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PMID:Two cases of rapid onset Parkinson's syndrome following toxic ingestion of ethylene glycol and methanol. 1718 9

An HPLC method was established and validated for the determination of compound FLZ, a synthetic novel anti-Parkinson's disease candidate drug, in rat plasma. FLZ and the internal standard bicyclol were extracted from plasma by solid-phase extraction method and analyzed on a Restek C18 column (4.6 x 250 mm, 5 microm) with a mobile phase consisting of methanol and water (60:40, v/v) at a flow rate of 1.0 mL/min. The detection wavelength was set at 320 nm. The calibration curve was linear within the concentration range from 25 to 500 ng/mL (r2 > 0.999), the limit of quantitation was 25 ng/mL and the average recovery was 92.0% with the RSD less than 5.9%. The relative standard deviation for intra- and inter-day precision was less than 3.8 and 6.9%, respectively. The established HPLC method was validated to be a simple, rapid and reliable procedure and applied to study the preclinical pharmacokinetics of FLZ in rat plasma, and it was the first time that the pharmacokinetics of FLZ had been investigated.
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PMID:Establishment of a HPLC method for preclinical pharmacokinetic study of the novel anti-Parkinson's disease candidate drug FLZ in rats. 1838 63

Parkinson's disease is a common progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Mitochondrial dysfunction has been strongly implicated in the pathogenesis of Parkinson's disease. Thus, therapeutic approaches that improve mitochondrial function may prove to be beneficial. Previously, we have documented that near-infrared light via light-emitting diode (LED) treatment was therapeutic to neurons functionally inactivated by tetrodotoxin, potassium cyanide (KCN), or methanol intoxication, and LED pretreatment rescued neurons from KCN-induced apoptotic cell death. The current study tested our hypothesis that LED treatment can protect neurons from both rotenone- and MPP(+)-induced neurotoxicity. Primary cultures of postnatal rat striatal and cortical neurons served as models, and the optimal frequency of LED treatment per day was also determined. Results indicated that LED treatments twice a day significantly increased cellular adenosine triphosphate content, decreased the number of neurons undergoing cell death, and significantly reduced the expressions of reactive oxygen species and reactive nitrogen species in rotenone- or MPP(+)-exposed neurons as compared with untreated ones. These results strongly suggest that LED treatment may be therapeutic to neurons damaged by neurotoxins linked to Parkinson's disease by energizing the cells and increasing their viability.
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PMID:Near-infrared light via light-emitting diode treatment is therapeutic against rotenone- and 1-methyl-4-phenylpyridinium ion-induced neurotoxicity. 1844 Jul 9

Neurodegenerative diseases like Alzheimer's disease and Parkinson's disease are gaining increasing relevance in our aging society. However, the complex multifactorial mechanisms of these diseases are not sufficiently understood yet. Several studies indicate that metal ions play an important role in the promotion of these diseases. Consequently, the transport pathways of metals and their species to the brain are of special interest. Following oral or inhalative uptake metals are absorbed and distributed via the blood stream in the body. Transport into the brain requires crossing of the neural barriers. Our study focuses on the investigation of the permeability of the blood-cerebrospinal fluid (CSF)-barrier for selected metals (Mn, Fe, Cu, Zn, Mg and Ca). For the first time paired human serum and CSF samples obtained from a neurological department were characterised for total metal concentrations and metal species. For CSF few data are available in the literature on total metal contents and applications of element speciation analysis in CSF samples are rare. In our study mean CSF/serum ratios (n=29) were 0.7 for Mn, 0.02 for Fe, 0.02 for Cu, 0.03 for Zn, 1.3 for Mg and 0.5 for Ca. Size exclusion chromatography (SEC) online with inductively coupled plasma mass spectrometry was further developed for the size characterisation of the metal species in CSF and serum with limits of detection of 0.4microgL(-1) for Fe, 0.01microgL(-1) for Mn, 0.2microgL(-1) for Cu, 0.2microgL(-1) for Zn, 0.6microgL(-1) for Mg and 3.8microgL(-1) for Ca in the eluate from the HPLC column. Apart from Mn the application of this technique has not been published for metal speciation in CSF, yet. In the case of some Mn species it turned out that methanol, which was contained in the mobile phase of a SEC method previously published from our group on qualitative characterisation of Mn species, was interfering with the quantification. The modified method developed in this work (with NaCl but without methanol in the mobile phase; use of internal standard) allowed reliable quantification. The results clearly indicate changes in the metal species pattern due to different permeation behaviour at the blood-CSF-barrier. As part of the method validation the relative stability of complexes of albumin, transferrin and citrate with Mn, Fe, Cu and Zn was investigated.
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PMID:Speciation analysis of selected metals and determination of their total contents in paired serum and cerebrospinal fluid samples: An approach to investigate the permeability of the human blood-cerebrospinal fluid-barrier. 1880 82


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