Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A modified primate model of Parkinson's disease was developed to assess the effectiveness of various agents that act via dopamine, acetylcholine, serotonin or glutamate systems. Using a MPTP dosing regimen a reversible parkinsonian-like syndrome was produced in the marmoset. An obvious advantage of such a protocol is that it allows multiple drug studies to be undertaken in animals, without the need for prolonged anti-parkinsonian therapy to maintain their health. Results show that dopamine D2 agonists (bromocriptine, quinpirole, N,N-dipropyl,A,5,6-DTN, (+)3PPP and PHNO), anti-muscarinics (atropine, scopolamine and benztropine), in addition to L-DOPA and nomifensine, all reduced the bradykinesia induced by MPTP. The D1 agonist SKF-38393 and the partial dopamine agonist (-)3PPP were both ineffective. Finally, agents with potential therapeutic use in Parkinson's disease were also tested. However, a glutamate antagonist (MK801) and three serotonin antagonists (ritanserin, ketanserin and ICI 170,809) were all unable to alter the MPTP effects, at the doses used in our study.
 ...
PMID:Effects of classical and novel agents in a MPTP-induced reversible model of Parkinson's disease. 197 76

Psychoses are a common clinical problem in patients with Parkinson's disease. Treatment with typical neuroleptics or withdrawal of antiparkinsonian drugs may improve mental symptoms but will worsen the parkinsonism. Quetiapine (Seroquel), ICI 204,636, is a novel antipsychotic medication with a low potential for producing extrapyramidal side effects. In this open-label clinical study of 2 patients with Parkinson's disease, treatment with Seroquel successfully controlled psychotic symptoms without worsening of motor disability.
 ...
PMID:Quetiapine (Seroquel) in the treatment of psychosis in patients with Parkinson's disease. 960 12

Parkinson's disease is characterized by the mesencephalic dopaminergic neuronal loss, possibly by apoptosis, and the prevalence is higher in males than in females. The estrogen receptor (ER) subtype in the mesencephalon is exclusively ER beta, a recently cloned novel subtype. Bound with estradiol, it enhances gene transcription through the estrogen response element (ERE) or inhibits it through the activator protein-1 (AP-1) site. We demonstrated that 17beta-estradiol provided protection against nigral neuronal apoptosis caused by exposure to either bleomycin sulfate (BLM) or buthionine sulfoximine (BSO). BLM and BSO-induced nigral apoptosis was blocked by inhibitors for caspase-3 or c-Jun/AP-1. The antiapoptotic effect by estradiol was blocked by ICI 182,780, an antagonist for ER, but not by a synthesized peptide that inhibits binding of the ER to the ERE. Estradiol had no effects on caspase-3 activation and c-Jun NH(2)-terminal kinase (JNK), which were activated by BLM. It also suppressed apoptosis by serum deprivation, which was independent of caspase-3 activation. Therefore, the antiapoptotic neuroprotection by estradiol is mediated by transcription through AP-1 site downstream from JNK and caspase-3 activation. Furthermore, 17alpha-estradiol, a stereoisomer without female hormone activity, also provided an antiapoptotic effect. Therefore, the antiapoptotic effect is independent of female hormone activity.
 ...
PMID:Mechanisms of antiapoptotic effects of estrogens in nigral dopaminergic neurons. 1083 42

The prevalence of Parkinson's disease is higher in males than in females. Although the reason for this gender difference is not clear, the level of female steroid hormones or their receptors may be involved in the pathogenesis. The estrogen receptor subtype expressed in the midbrain is limited to the novel beta subtype, whose role in the central nervous system has not been resolved. We demonstrated that ligand-activated estrogen receptor beta suppressed dopaminergic neuronal death in an in vitro Parkinson's disease model which uses 1-methyl-4-phenylpyridinium ions (MPP(+)). MPP(+) treatment caused the upregulation of c-Jun amino-terminal kinase (JNK) and dopaminergic neuronal death, the latter being blocked by curcumin, an inhibitor of the c-Jun/AP-1 cascade. 17alpha- and 17beta-estradiol both protected dopaminergic neurons from MPP(+)-induced neuronal death and this was blocked by a pure antagonist of the estrogen receptor, ICI 182,780, but not by an inhibitor of estrogen receptor dimerization, YP537. These data indicated that the neuroprotection provided by 17alpha-estradiol was via inhibitory transcriptional regulation at the activator protein-1 (AP-1) site mediated by estrogen receptor beta. Thus, 17alpha-estradiol is a suitable candidate for neuroprotective therapy of Parkinson's disease because it is associated with few undesirable feminizing effects.
 ...
PMID:Estradiol protects dopaminergic neurons in a MPP+Parkinson's disease model. 1212 7

Catechol-O-methyltransferase (COMT) is a crucial enzyme in dopamine and levodopa metabolism. Previously we reported that physiological concentrations of 17beta-estradiol (E2) down-regulated steady-state 1.3-kb COMT mRNA levels in MCF-7 cells. In this study, we investigated whether similar reductions occurred in a glial cell line (U138MG) and whether COMT protein and activity levels paralleled the reduction in COMT mRNA levels in MCF-7 cells. In addition, we explored the mechanism of E2 action. E2 had no effect on COMT mRNA levels in U138MG cells, but significantly reduced COMT protein and activity in MCF-7 cells (activity by 53% at 10(-7) M of E2, by 45% at 10(-8) M, and by 28% at 10(-9) M relative to non-E2-treated cells). A specific estrogen receptor antagonist (ICI 182780) blocked these estrogenic effects. Estrogen receptor in nuclear extracts of MCF-7 cells, which were pretreated with E2 (10(-9) M) for 48 h, bound to the whole proximal and distal promoter regions, as determined by electrophoretic mobility shift analysis (EMSA). We propose that E2 decreased COMT activity through down-regulation of its gene and protein expression mediated via ER interaction with response elements in the promoter region of the gene. Our findings may explain the lower of COMT activity in women compared to that in men, and, in part, the beneficial effects of E2 therapy in post-menopausal Parkinson's disease patients.
 ...
PMID:Human catechol-O-methyltransferase down-regulation by estradiol. 1457 93

Incidence of Parkinson's disease is lower in women as compared with men. Although neuroprotective effect of estrogen is recognized, the underlying molecular mechanisms are unclear. MPTP (1-methyl-4-phenyl-1, 2, 3, 6, tetrahydro-pyridine), a neurotoxin that causes Parkinson's disease-like symptoms acts through inhibition of mitochondrial complex I. Administration of MPTP to male mice results in loss of dopaminergic neurons in substantia nigra, whereas female mice are unaffected. Oxidation of critical thiol groups by MPTP disrupts mitochondrial complex I, and up-regulation of glutaredoxin (a thiol disulfide oxidoreductase) is essential for recovery of complex I. Early events following MPTP exposure, such as increased AP1 transcription, loss of glutathione, and up-regulation of glutaredoxin mRNA is seen only in male mice, indicating that early response to neurotoxic insult does not occur in females. Pretreatment of female mice with ICI 182,780, estrogen receptor (ER) antagonist sensitizes them to MPTP-mediated complex I dysfunction. Constitutive expression of glutaredoxin is significantly higher in female mice as compared with males. ICI 182,780 down-regulates glutaredoxin activity in female mouse brain regions (midbrain and striatum), indicating that glutaredoxin expression is regulated through estrogen receptor signaling. Higher constitutive expression of glutaredoxin could potentially contribute to the neuroprotection seen in female mouse following exposure to neurotoxins, such as MPTP.
 ...
PMID:Estrogen and neuroprotection: higher constitutive expression of glutaredoxin in female mice offers protection against MPTP-mediated neurodegeneration. 1513 75

A large body of research has documented neuroprotective effects of estrogen against oxidative stress. Some neurodegenerative diseases such as Parkinson's disease, in which oxidative stress has been implicated as a contributing factor, affect more males than females, suggesting a possible protective effect of estrogen. We used the clonal substantia nigra cell line SN4741 to compare the neuroprotective properties of estrogen and raloxifene against oxidative stress, and to determine whether raloxifene acted as an estrogen agonist or antagonist in this system. We pretreated SN4741 cultures with alpha-estradiol, beta-estradiol, and raloxifene, and exposed them to hydrogen peroxide. Low nanomolar levels of raloxifene, beta-estradiol, and alpha-estradiol all significantly reduced cell death caused by oxidative stress. The estrogen receptor (ER) antagonist ICI 182,780 failed to reverse the neuroprotection by beta-estradiol, suggesting that the effect is not mediated by a classical ER. Western blotting using an antibody to the C-terminus region of ER-alpha revealed two bands, one at approximately 67 kDa (corresponding to ER-alpha) and a more prominent band at approximately 55-56 kDa. These results suggest that, in this cell line, both raloxifene and estrogen may be acting via a non-classical estrogen receptor.
 ...
PMID:Estradiol and raloxifene protect cultured SN4741 neurons against oxidative stress. 1561 39

Single or paired pulse paradigms of transcranial magnetic stimulation (TMS) provide several parameters to test motor cortex excitability, such as motor threshold (MT), motor evoked potential (MEP) amplitude, electromyographic silent period to cortical stimulation (CSP) and intracortical facilitation (ICF) or inhibition (ICI). Various changes in TMS parameters, revealing motor cortex dysfunction, were found in patients with Parkinson's disease (PD). For instance, low MT and increased MEP size disclosed an enhanced corticospinal motor output at rest, while reduced ICF and failure of MEP size increase during contraction suggested defective facilitatory cortical inputs, particularly for movement execution. Inhibitory cortical pathways were also found less excitable at rest (reduced ICI) and sometimes during contraction (shortened CSP). By restoring cortical inhibition, dopaminergic drugs and deep brain stimulation probably overcome the difficulty to focus neuronal activity onto the appropriate network required for a specific motor task. The application of repetitive TMS trains over motor cortical areas also showed some effect on cortical excitability, opening perspectives to consider the motor cortex as a target for therapeutic neuromodulation in PD. However, systematic studies of cortical excitability remained to be performed in large series of patients with PD, taking into account disease stage, clinical symptoms and medication influence.
 ...
PMID:Motor cortex dysfunction revealed by cortical excitability studies in Parkinson's disease: influence of antiparkinsonian treatment and cortical stimulation. 1566 Nov

Estrogen provides neuroprotection against neurodegenerative diseases, including Parkinson's disease. Its effects may stem from interactions with neurons, astrocytes, and microglia. We demonstrate here in primary cultures of rat mesencephalic neurons that estrogen protects them from injury induced by conditioned medium obtained from lipopolysaccharide (LPS)-activated microglia. LPS-induced nitrite production and tumor necrosis factor-alpha up-regulation in microglia were blocked by estrogen pretreatment. Estrogen neuroprotection was related to microglial activation of estrogen receptors (ERs), insofar as the protective effect of the microglia-conditioned medium was overridden by pretreatment of microglia with the ER antagonist ICI 182,780. On the other hand, the specific ERalpha antagonist, MPP dihydrochloride, only partially blocked the effects of estrogen, suggesting that estrogen protection was mediated via both ERalpha and ERbeta. LPS treatment did not change ERalpha mRNA levels in microglia, astrocytes, and neurons, but it up-regulated ERbeta mRNA levels in microglia and astrocytes. Similarly, increased ERbeta protein levels were detected in LPS-activated microglia. More interesting was that immunocytochemical analysis revealed that ERbeta was localized in the cytoplasm of microglia and in the cell nucleus of astrocytes and neurons. In summary, our results support the notion that estrogen inhibits microglial activation and thus exhibits neuroprotective effects through both ERalpha and ERbeta activation. The cytoplasm location of microglial ERbeta suggests the possible involvement of nonclassical effects of estrogen on microglia. Changes in microglial ERbeta expression levels may modulate such effects of estrogen.
 ...
PMID:Estrogen provides neuroprotection against activated microglia-induced dopaminergic neuronal injury through both estrogen receptor-alpha and estrogen receptor-beta in microglia. 1601 43

Dopamine is actively and specifically eliminated from the extracellular space by astrocytes and neurones through dopamine transporters (DAT) and, afterwards, either recycled into vesicles or metabolised. The availability of dopamine reflects a critical point in the regulation of dopamine activity within the nigrostriatal circuit under normal and pathological conditions. From previous studies, we know that oestrogen regulates the efficacy of dopaminergic neurones at the synaptic level and improves dopamine function during Parkinson's disease. Accordingly, we investigated the contribution of local astroglial for extracellular dopamine elimination and the impact of oestrogen on DAT expression and activity. Using neonatal striatal and midbrain astrocyte cultures, we could demonstrate that astrocytes possess a specific dopamine uptake machinery and express DAT at considerable levels. The application of 17beta-oestradiol decreased the expression of DAT by 80% and 60% in midbrain and striatal astroglia cultures, respectively. The unspecific dopamine transporters (OCT3, VMAT2) were not detected in astroglia. Functionally, oestrogen exposure inhibited the clearance of dopamine from the extracellular space by 45% and 35% compared to controls in midbrain and striatal astroglia, respectively. The effect on DAT expression and activity was completely antagonised by the oestrogen receptor antagonist ICI 182 780. In conclusion, our data suggest that the positive reinforcement of dopamine transmission under physiological conditions and the alleviative impact of oestrogen under pathological conditions may be the result of a decline in DAT expression and therefore delayed dopamine uptake by astroglia.
 ...
PMID:Oestrogen regulates the expression and function of dopamine transporters in astrocytes of the nigrostriatal system. 1768 Aug 83


1 2 Next >>