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 mechanism by which deep brain stimulation (DBS) of the subthalamic nucleus (STN) achieves its effects in Parkinson's disease (PD) is not known. In animal models of PD, stimulation and lesioning of the STN have some effects which are the same, but others which differ, in reversing cellular and behavioral changes induced by dopamine depletion. We compared the effects of short-term STN stimulation and lesions upon extracellular levels of dopamine and metabolites using in vivo microdialysis of the dorsal striatum of awake, intact and unilateral 6-hydroxydopamine (6OHDA)-lesioned rats. STN stimulation in control rats decreased striatal dopamine levels and caused a relative increase in dopamine metabolism, as expressed by HVA/dopamine and DOPAC/dopamine ratios. This suggests an increase in both vesicular dopamine release (metabolized to HVA), and release from the cytoplasmic dopamine pool (metabolized to DOPAC). STN lesions in control rats increased the HVA/dopamine ratio, also suggesting a relative increase in vesicular dopamine release. These results indicate that STN stimulation and lesioning can affect striatal dopamine metabolism in the intact system. In 6OHDA-lesioned rats at baseline, metabolic ratios were markedly decreased as compared with controls. STN lesions of 6OHDA-lesioned rats did not affect relative metabolic ratios as compared with baseline levels. In 6-OHDA-lesioned rats, STN stimulation decreased extracellular levels of dopamine, and, to a greater extent, metabolites, resulting in a decrease in metabolic ratios. This further decrease in dopamine turnover with STN stimulation would serve to maintain dopamine levels in the dopamine-depleted striatum, and may account for the therapeutic benefit of DBS in Parkinson's disease.
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PMID:Subthalamic nucleus stimulation and lesioning have distinct state-dependent effects upon striatal dopamine metabolism. 1902 Dec 15

Evidence for involvement of cytochrome P450 2E1 in the MPTP-induced mouse model of PD has been reported [Vaglini, F., Pardini, C., Viaggi, C., Bartoli, C., Dinucci, D., Corsini, G.U., 2004. Involvement of cytochrome P450 2E1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease. J. Neurochem. 91, 285-298]. We studied the sensitivity of Cyp2e1(-/-) mice to the acute administration of MPTP in comparison with their wild-type counterparts. In Cyp2e1(-/-) mice, the reduction of striatal DA content was less pronounced 7 days after MPTP treatment compared to treated wild-type mice. Similarly, TH immunoreactivity analysis of the substantia nigra of Cyp2e1(-/-) mice did not show any neuronal lesions after MPTP treatment. In contrast to this, wild-type animals showed a minimal but significant lesioning by the toxin as evaluated also by means of non-stereologic computerized assisted analysis of this brain area. Striatal levels of DA metabolites after 7 days were variably affected by the toxin, but consistent differences between the two animal strains were not observed. We evaluated short-term changes in the levels of striatal DA and its metabolites, and we monitored striatal MPP(+) levels. Striatal MPP(+) was cleared more rapidly in Cyp2e1(-/-) mice than in wild-type animals and, consistently, striatal DA content decreased faster in Cyp2e1(-/-) mice than in wild-type animals, and 3-methoxytyramine and HVA levels showed an early and sharp rise. Our findings suggest that Cyp2e1(-/-) mice are weakly sensitive to MPTP-induced brain lesions, markedly in contrast with a protective role of the enzyme as suggested previously. The differences observed between the knockout mice and their wild-type counterparts are modest and may be due to an efficient compensatory mechanism or genetic drift in the colonies.
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PMID:MPTP-induced model of Parkinson's disease in cytochrome P450 2E1 knockout mice. 1929 32

Dysfunction of the proteasome has been suggested to contribute in the degeneration of nigrostriatal dopaminergic neurons. Here, we investigated to determine whether systematic administration of proteasome inhibitor, carbobenzoxy-L: -gamma-t-butyl-L: -glutamyl-L: -alanyl-L: -leucinal (PSI) protects against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice. Three administrations of MPTP at 1-h intervals to mice reduced significantly the concentration of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) in the striatum after 5 days. In contrast, PSI (0.3 and 1.0 mg/kg) prevented a significant decrease in dopamine, DOPAC and HVA contents of the striatum 5 days after MPTP treatment. In our Western blot analysis study, PSI at a dose of 1.0 mg/kg prevented a significant decrease in TH (tyrosine hydroxylase) protein and a significant increase in glial fibrillary acidic protein 5 days after MPTP treatment. Furthermore, our immunohistochemical study showed that PSI at a dose of 1.0 mg/kg prevented a significant loss in TH immunopositive neurons in the striatum and substantia nigra 5 days after MPTP treatment. In contrast, PSI caused a significant increase in the number of intense ubiquitin immunopositive cells in the striatum and substantia nigra 5 days after MPTP treatment. These results indicate that proteasome inhibitors can protect against MPTP neurotoxicity in mice. The neuroprotective effect of PSI against dopaminergic cell damage may be mediated by the elevation of ubiquitination. Thus, our findings provide further valuable information for the pathogenesis of Parkinson's disease.
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PMID:Systemic administration of proteasome inhibitor protects against MPTP neurotoxicity in mice. 1937 Apr 11

1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, is known to cause a parkinsonism-like syndrome in rodents and primates. In this study we evaluated the effects of single and multiple 1BnTIQ (50 mg/kg i.p.) administration on the concentrations of dopamine, serotonin, and respective metabolites (homovanillic acid, HVA; 3,4-dihydroxyphenylacetic acid, DOPAC; 3-methoxytyramine, 3-MT; and 5-hydroxyindolacetic acid, 5-HIAA), in substantia nigra, striatum (STR), and nucleus accumbens of Wistar rats. In addition, the effect of 1BnTIQ on locomotor activity and dopamine release in vivo was also estimated in rat STR. In a behavioral study, acute administration of 1BnTIQ (50 mg/kg i.p.) produced a significant decrease in exploratory locomotor activity. A high-performance liquid chromatography with electrochemical detection ex vivo study showed that a single injection of 1BnTIQ produced a dramatic fall in the dopamine concentration in the noted brain regions (approximately 65%; P < 0.01), but not in striatal serotonin. Moreover, 1BnTIQ reduced the content of the extraneuronal dopamine metabolite 3-MT by 70% (P < 0.01). Conversely, levels of DOPAC, HVA, and 5-HIAA were elevated by 220, 320, and 185%, respectively (P < 0.01). Interestingly, multiple 1BnTIQ treatments (50 mg/kg/day i.p. x 10 days) resulted in development of tolerance to its dopamine depressing effect, while the impairment of dopamine synthesis was persisted. An in vivo microdialysis study demonstrated that 1BnTIQ (50 mg/kg i.p.) produced a profound and long-lasting decrease in extraneuronal striatal dopamine. Concurrently, however, DOPAC and HVA were elevated. This comparison between ex vivo and in vivo effects of 1BnTIQ provides greater insight into the neurotoxic actions of 1BnTIQ specific to dopamine neurons. 1BnTIQ neurotoxicity may be related to an impairment of dopamine storage, leading to a fall in intraneuronal dopamine and enhanced dopamine catabolism through a monoamine oxidize-dependent oxidative pathway that results in free radical production and ultimate cell death. Because 1BnTIQ is an endogenous compound, it may be one of the factors responsible for idiopathic Parkinson's disease.
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PMID:1-Benzyl-1,2,3,4-tetrahydroisoquinoline, an endogenous parkinsonism-inducing toxin, strongly potentiates MAO-dependent dopamine oxidation and impairs dopamine release: ex vivo and in vivo neurochemical studies. 1938 84

The aim of this study was to investigate the impact of gender difference in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated animal model of Parkinson's disease (PD). In the present study, we investigated the time-dependent alterations of dopamine and its metabolites, striatal tyrosine hydroxylase (TH) protein, dopamine transporter (DAT) protein, glial fibrillary acidic protein (GFAP) protein and midbrain TH protein and motor function in male and female mice 5h and 1, 3 and 7 days after four administrations of MPTP (20mg/kg) at 2-h intervals. The present study showed that the decrease of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) content in female mice was more pronounced than that in male animals 1, 3 and 7 days after MPTP treatment. Our Western blot analysis study also demonstrated that the decrease of both striatal and midbrain TH protein levels in female mice was more pronounced than that in male animals from 1 to 7 days after MPTP treatment. As compared to male mice, in contrast, the increase of striatal GFAP protein levels in female mice was observed from 5h to 7 days after MPTP treatment. Furthermore, the present study showed that motor deficits were found in both male and female mice 1 and 7 days after MPTP treatment. In the present study, moreover, the decrease of striatal DAT protein levels in female mice was more pronounced than that in male animals 1, 3 and 7 days after MPTP treatment. These results demonstrate that our administrations of MPTP at 2-h intervals can cause more severe damage in female mice as compared with male animals. The gender difference may be due to the decrease of DAT expression caused by MPTP. Thus our findings provide further valuable information for the pathogenesis of PD.
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PMID:Gender differences on MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in C57BL/6 mice. 1963 14

The biochemical basis of major depression (MD) in Parkinson's disease (PD) is largely unknown. To increase our understanding of MD in PD patients, the levels of monoamine metabolites (HVA, 5-HIAA and MHPG), BDNF, orexin-A, IL-6 and corticosterone were examined in cerebrospinal fluid. The analyses were performed in MD patients with (n = 11) and without (n = 12) PD at baseline and after 12 weeks' of treatment with the antidepressant citalopram, and in patients with solely PD (n = 14) at baseline and after 12 weeks. The major findings were that PD patients with MD had significantly lower baseline levels of MHPG, corticosterone and IL-6 when compared to patients with solely MD. In response to citalopram treatment, patients with solely MD exhibited an expected decrease in 5-HIAA and MHPG levels which was not found in PD patients with MD. Moreover, the levels of BDNF and IL-6 were lower in PD patients with MD compared with patients with solely MD after treatment with citalopram. Thus, the biochemical basis and the response to citalopram differ between PD patients with MD and patients with solely MD.
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PMID:Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson's disease and major depression. 1984 54

Early phases of Parkinson's disease (PD) are characterized by a mild reduction of dopamine (DA) in striatum and by emergence of psychiatric disturbances that precede overt motor symptoms. In order to characterize the neurochemical re-arrangements induced by such striatal impairment, we used a mouse model in which a low dose of 6-hydroxydopamine (6-OHDA) was bilaterally injected into the dorsal striatum. These mice showed a DA reduction of about 40% that remained stable up to 12 weeks after injection. This reduction was accompanied by changes in DA metabolite levels, such as HVA, transiently reduced at 4 weeks, and DOPAC, decreased at 12 weeks. No change in the 5-hydroxytryptamine (5-HT) levels was found but the 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio was increased at 4 weeks. In addition, at the same time-point, the levels of 15-F(2t)-IsoP, an index of oxidative stress, and of PGE(2), a major product of cyclooxygenase-2, were decreased in different brain areas while BDNF levels were increased. These neurochemical changes were accompanied by altered behavioral responses concerning the emotional reactivity. Overall, the present findings suggest that a change of 5-HT metabolism and a modification of oxidative stress levels may play a role in the early PD degeneration phases.
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PMID:Striatal 6-OHDA lesion in mice: Investigating early neurochemical changes underlying Parkinson's disease. 1991 95

Exercise has been shown to be potently neuroprotective in several neurodegenerative models, including 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). In order to determine the critical duration of exercise necessary for DA neuroprotection, mice were allowed to run for either 1, 2 or 3months prior to treatment with saline or MPTP. Quantification of DA neurons in the SNpc show that mice allowed to run unrestricted for 1 or 2months lost significant numbers of neurons following MPTP administration as compared to saline treated mice; however, 3months of exercise provided complete protection against MPTP-induced neurotoxicity. To determine the critical intensity of exercise for DA neuroprotection, mice were restricted in their running to either 1/3 or 2/3 that of the full running group for 3months prior to treatment with saline or MPTP. Quantification of DA neurons in the SNpc show that mice whose running was restricted lost significant numbers of DA neurons due to MPTP toxicity; however, the 2/3 running group demonstrated partial protection. Neurochemical analyses of DA and its metabolites DOPAC and HVA show that exercise also functionally protects neurons from MPTP-induced neurotoxicity. Proteomic analysis of SN and STR tissues indicates that 3months of exercise induces changes in proteins related to energy regulation, cellular metabolism, the cytoskeleton, and intracellular signaling events. Taken together, these data indicate that exercise potently protects DA neurons from acute MPTP toxicity, suggesting that this simple lifestyle element may also confer significant protection against developing PD in humans.
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PMID:Exercise protects against MPTP-induced neurotoxicity in mice. 2011 69

This is the first autopsy case of SCA2 with parkinsonian phenotype. At the age of 46, the patient got symptoms of parkinsonism to which anti-parkinsonian drugs were effective. He had mosaic 38, 40 CAG repeat expansions on chromosome 12q23-24, being diagnosed as SCA2, and his mother and his son also had CAG expansions on the same locus. In addition to parkinsonism, he also exhibited autonomic disturbance, dementia, and mild cerebellar ataxia Brain images revealed severe atrophy of pons and medulla oblongata, resembling MSA-C. HVA and 5-HIAA were reduced in the cerebrospinal fluid, and the heart-mediastinum (H/M) ratio in myocardial 123I-MIBG cintigram was decreased, which suggested Lewy body pathology. He died at the age of 75 and the autopsy revealed atrophy of the olivo-ponto-cerebellar (OPC) system and substantia nigra which was compatible to SCA2, although the OPC system atrophy was less severe than formerly reported SCA2 cases. The degrees of atrophy of the OPC system and substantia nigra might explain the predominancy of clinical symptoms. Anti-1C2 positive inclusions in the pontine nuclei, inferior olive nuclei, cerebellum and substantia nigra confirmed a polyglutamine disease. In addition, there were the anti-phosphorylated alpha-synuclein positive, Lewy body related pathological changes in the substantia nigra, the locus ceruleus, the dorsal motor nuclei of vagus, and the sympathetic nerve in the myocardium. Major genetic abnormalities related to Parkinson disease were not detected. As another case of SCA2 with Lewy body pathology was reported in Japan, the coexistence of SCA2 and Lewy body pathology may not be accidental. Since myocardial MIBG scincigram can predict Lewy body pathology, we should seek more clinical cases of SCA2 with Lewy body pathology.
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PMID:[Autopsy case of SCA2 with Parkinsonian phenotype]. 2023 84

Temporal variation in the motor function of Parkinson's disease (PD) patients suggests the potential importance of a chronobiological and chronopharmacological approach in its clinical management. We previously documented the effects of striatal injection of 6-OHDA (as an animal model of PD) on the circadian rhythms of temperature (T), heart rate (HR), and locomotor activity (A). The present work assessed the possible influence of L-Dopa on these same rhythms in the 6-OHDA animal model of PD. The study began after a four-week recovery period following surgical implantation of telemetric devices to monitor the study variables and/or anaesthesia. The study was divided into an initial one-week control period (W1) for baseline measurement of T, HR, and A rhythms. Thereafter, stereotaxic 6-OHDA lesioning was done. and a second monitoring for two weeks followed (W2, W3). Rats were then randomly divided into two groups: eight control rats received, via a mini-osmotic pump implanted subcutaneously, the excipient saline; the other eight rats received L-Dopa (100 mg/kg SC/day). After a seven-day period (W4), the pumps were removed and the T, HR, and A rhythms were monitored for two weeks (W5 and W6). To control for 6-OHDA striatal dopamine-induced depletion, 12 other rats were injected by identical methods (eight rats with 6-OHDA and four controls with saline) and sacrificed at W1, W3, and W5 for dopamine striatal content determination. To verify the delivery of levodopa from the osmotic pumps, plasma levels of levodopa and its main metabolites 3-OMD, DOPAC, and HVA were determined on separate group of rats receiving the drug under the same experimental conditions (osmotic pumps delivering continuously 10 microl/h for seven days, 100 mg/kg/subcutaneously). Our results agree with previously reported rhythmic changes induced by 6-OHDA--loss of circadian rhythmicity or changes in the main parameters of the registered rhythms. When circadian rhythmicity was abolished, L-Dopa treatment improved or accelerated recovery of the circadian rhythms, the effect being more pronounced for the HR rhythm. When circadian rhythms were not abolished but perturbed, L-Dopa treatment did not improve the 6-OHDA-induced changes in the T and A mesor (24 h mean level), while a significant effect was observed for HR. It appears that constant-rate L-Dopa infusion is unable to totally balance dopamine depletion; taking into account the circadian pattern of many structures implicated in drug effect, a sinusoidal delivery of L-Dopa must be evaluated in future experiments.
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PMID:Effects of L-Dopa on circadian rhythms of 6-OHDA striatal lesioned rats: a radiotelemetric study. 2037 Apr 68


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