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)

Epidemiological studies have consistently demonstrated an inverse association between coffee consumption and Parkinson's disease (PD). This study was designed to investigate the beneficial effect of caffeine at a dose comparable to that of human exposure in a model of PD. For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were pretreated with caffeine (20 mg/kg; i.p.) 1 h before surgery and treated twice a day (10 mg/kg) for 1 month. Apomorphine-induced rotations and number of Nissl-stained neurons of substantia nigra pars compacta (SNC) were counted. The results demonstrated that caffeine administration for 1 month could attenuate the rotational behavior in lesioned rats and protect the neurons of SNC against 6-OHDA toxicity.
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PMID:Protective effect of caffeine against neurodegeneration in a model of Parkinson's disease in rat: behavioral and histochemical evidence. 1554 5

The risk of Parkinson's disease (PD) is associated with a lower intake of caffeine, a non-selective adenosine A2A antagonist. In agreement, genetic or pharmacological inactivation of adenosine A2A receptors in animal models of PD has demonstrated both symptomatic and neuroprotective effects. These findings and the lack of disease modifying therapies have led to intense research on adenosine A2A antagonists as a novel treatment for PD. In the present study the neuroprotective effect of the A2A receptor antagonist KW-6002 was investigated using different models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, which induced dopaminergic terminal and or dopaminergic cell loss and inflammation. Treatment with KW-6002 prevented the loss of dopaminergic striatal terminals and nigral cell bodies and inhibited the nigral microglia activation. Our results confirm previous findings that pharmacological inactivation of A2A receptors inhibits MPTP-induced dopaminergic damage at the level of striatum. In addition, we demonstrate for the first time that, after MPTP treatment in mice, an A2A antagonist is neuroprotective, and has anti-inflammatory effects, at the level of the substantia nigra. Thus, our data further support the use of A2A receptor antagonists as a novel neuroprotective therapy for PD.
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PMID:KW-6002 protects from MPTP induced dopaminergic toxicity in the mouse. 1575 79

In Parkinson's disease (PD), the striatal dopamine depletion and the following overactivation of the indirect pathway of the basal ganglia leads to very early disinhibition of the subthalamic nucleus (STN) that may contribute to the progression of PD by glutamatergic overstimulation of the dopaminergic neurons in the substantia nigra. Adenosine A2A antagonism has been demonstrated to attenuate the overactivity of the striatopallidal pathway. To investigate whether neuroprotection exerted by the A2A antagonist 8-(3-chlorostyryl)caffeine (CSC) correlates with a diminution of the striatopallidal pathway activity, we have examined the changes in the mRNA encoding for enkephalin, dynorphin, and adenosine A2A receptors by in situ hybridization induced by subacute systemic pretreatment with CSC in rats with striatal 6-hydroxydopamine(6-OHDA) administration. Animals received CSC for 7 days until 30 min before 6-OHDA intrastriatal administration. Vehicle-treated group received a solution of dimethyl sulfoxide. CSC pretreatment partially attenuated the decrease in nigral tyrosine hydroxylase immunoreactivity induced by 6-OHDA, whereas no modification of the increase in preproenkephalin mRNA expression in the dorsolateral striatum was observed. The neuroprotective effect of the adenosine A2A antagonist CSC in striatal 6-OHDA-lesioned rats does not result from a normalization of the increase in striatal PPE mRNA expression in the DL striatum, suggesting that other different mechanisms may be involved.
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PMID:Neuroprotection induced by the adenosine A2A antagonist CSC in the 6-OHDA rat model of parkinsonism: effect on the activity of striatal output pathways. 1596 57

A placebo is a sham treatment, such as a pill, liquid, or injection without biological activity, used in pharmacology to control for the activity of a drug. However, in many cases this placebo induces biological or psychological effects in the human. Two theories have been proposed to explain the placebo effect: the conditioning theory, which states that the placebo effect is a conditioned response, and the mentalistic theory, which sees the patient's expectation as the primary cause of the placebo effect. The mechanisms involved in these processes are beginning to be understood through new techniques of investigation in neuroscience. Dopamine and the endorphins have been clearly shown to be mediators of placebo effects. Brain imaging has demonstrated that placebos can mimic the effect of the active drugs and activate the same brain areas. This is the case for placebo-dopamine in Parkinson's disease, for placebo-analgesics or antidepressants, and for placebo-caffeine in the healthy subject. It remains to be understood how conditioning and expectation are able to activate memory loops in the brain that reproduce the expected biological responses.
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PMID:Mechanisms of the placebo effect and of conditioning. 1599 Apr 50

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin causing symptoms that may resemble those observed in patients suffering from Parkinson's disease. Therefore, MPTP-treated laboratory animals are currently the most favored models to study therapeutic intervention strategies in this disease. It was demonstrated recently that caffeine (1,2,3-trimethylxanthine) intake decreases the risk of Parkinson's disease in various human populations and attenuates MPTP-induced neurological effects in animal models. Since the effects of caffeine on MPTP-treated animals were mimicked by several antagonists of the adenosine A(2A) receptor, it was suggested that caffeine attenuates MPTP toxicity by blocking this receptor. Here, using microcalorimetry and molecular modeling, we demonstrate that caffeine can form stacking (pi-pi) complexes with MPTP. We found that a biological activity of MPTP (induction of mutations in a microbiological mutagenicity assay), which is completely independent on the A(2A) receptor blockade, is significantly reduced by caffeine. Therefore, we suggest that caffeine may attenuate neurotoxicity of MPTP (and possibly other polycyclic aromatic toxins) and reveal its protective effects on the risk of Parkinson's disease not only by blocking the A(2A) receptor but also by sequestering neurotoxin molecules in mixed complexes, especially in stomach.
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PMID:Formation of stacking complexes between caffeine (1,2,3-trimethylxanthine) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine may attenuate biological effects of this neurotoxin. 1616 86

Adenosine A(2A) receptor (A(2A)R) antagonists, including the non-specific adenosine antagonist caffeine, have been proposed as a novel, non-dopaminergic treatment strategy for Parkinson's disease (PD). However, the long-term interaction between caffeine and L-dopa treatment in PD models has not been characterized. We examined the interaction between caffeine and L-dopa following a repeated treatment paradigm in hemiparkinsonian mice. In contrast to the progressively sensitized rotational behavior induced by daily L-dopa (2.0 mg/kg) treatment, tolerance for the rotational response to daily caffeine (2.5 or 10 mg/kg) treatment tended to develop over several weeks. However, after a subsequent two-week washout, challenge with same drug demonstrated an extinction of the sensitized L-dopa-induced rotation, but a sensitization of the caffeine-induced rotation. In a cross-challenge paradigm, daily treatment of mice with L-dopa (compared to daily saline) produced a three-fold enhancement in the rotational response to a subsequent re-challenge with caffeine. Similarly, daily treatment of mice with caffeine produced a six-fold enhancement in the rotational response to a subsequent re-challenge with L-dopa. Furthermore, daily co-administration of caffeine plus L-dopa produced enhanced rotational behavior, compared to caffeine or L-dopa alone, indicating an additive or synergistic interaction between caffeine and L-dopa during repeated treatment. Cross-sensitization between caffeine and L-dopa following repeated treatment and their positive interaction during chronic co-adminstration in hemiparkinsonian mice suggest that repeated exposure to caffeine may alter L-dopa responses in PD.
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PMID:Cross-sensitization between caffeine- and L-dopa-induced behaviors in hemiparkinsonian mice. 1623 44

Epidemiological studies have strongly linked caffeine consumption with a reduced risk of developing Parkinson's disease (PD) in men. Interestingly, in women, this inverse association is present only in those who have not taken postmenopausal estrogens, suggesting an interaction between the influences of estrogen and caffeine use on the risk of PD. To explore a possible biological basis for this interaction, we systematically investigated how the neuroprotective effect of caffeine is influenced by gender, ovariectomy (OVX), and then exogenous estrogen in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. (1) Caffeine treatment produced a dose-dependent attenuation of MPTP-induced striatal dopamine loss in both young and retired breeder (RB) male, but not female, mice. (2) In female mice (both young and RB), caffeine was less potent or altogether ineffective as a neuroprotectant after sham surgery compared to OVX or after OVX plus estrogen replacement compared to OVX plus placebo treatment. (3) Estrogen treatment also prevented the protection of caffeine against dopamine loss in young male mice. (4) Consistent with the putative protective effect of estrogen, female and OVX plus estrogen mice were relatively resistant to MPTP toxicity compared to male and OVX plus placebo mice, respectively. (5) There was no overall difference in brain levels of caffeine and its metabolites between OVX plus placebo and OVX plus estrogen mice. Together, these results suggest that estrogen can occlude and thereby prevent the neuroprotective effect of caffeine in a model of PD neurodegeneration, supporting a biological basis for the interaction between estrogen and caffeine in modifying the risk of PD.
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PMID:Estrogen prevents neuroprotection by caffeine in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. 1640 51

The adenosine A2A receptor has emerged as a possible target for the treatment of Parkinson's disease (PD). Evidence suggests that antagonism of the A2A receptor not only improves the symptoms of the disease but may also protect against the underlying degenerative processes. We have recently reported that several known adenosine A2A receptor antagonists (A2A antagonists) also are moderate to very potent inhibitors of monoamine oxidase B (MAO-B). The most potent among these was (E)-8-(3-chlorostyryl)caffeine (CSC), a compound frequently used when examining the in vivo pharmacological effects of A2A antagonists. Since MAO-B inhibitors are also thought to possess antiparkinsonian properties, dual targeting drugs that block both MAO-B and A2A receptors may have enhanced therapeutic potential in the treatment of PD. In this study, we prepared selected analogues of CSC in an attempt to examine specific structural features that may be important for potent MAO-B inhibition. The results of a SAR study established that the potency of MAO-B inhibition by (E)-8-styrylcaffeinyl analogues depends upon the van der Waals volume (V(w)), lipophilicity (pi), and the Hammett constant (sigma(m)) of the substituents attached to C-3 of the phenyl ring of the styryl moiety. Potency also varies with substituents attached to C-4 with bulkiness (V(w)) and lipophilicity (pi) being the principal substituent descriptors.
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PMID:Inhibition of monoamine oxidase B by analogues of the adenosine A2A receptor antagonist (E)-8-(3-chlorostyryl)caffeine (CSC). 1644 1

Coffee is a complex mixture of chemicals that provides significant amounts of chlorogenic acid and caffeine. Unfiltered coffee is a significant source of cafestol and kahweol, which are diterpenes that have been implicated in the cholesterol-raising effects of coffee. The results of epidemiological research suggest that coffee consumption may help prevent several chronic diseases, including type 2 diabetes mellitus, Parkinson's disease and liver disease (cirrhosis and hepatocellular carcinoma). Most prospective cohort studies have not found coffee consumption to be associated with significantly increased cardiovascular disease risk. However, coffee consumption is associated with increases in several cardiovascular disease risk factors, including blood pressure and plasma homocysteine. At present, there is little evidence that coffee consumption increases the risk of cancer. For adults consuming moderate amounts of coffee (3-4 cups/d providing 300-400 mg/d of caffeine), there is little evidence of health risks and some evidence of health benefits. However, some groups, including people with hypertension, children, adolescents, and the elderly, may be more vulnerable to the adverse effects of caffeine. In addition, currently available evidence suggests that it may be prudent for pregnant women to limit coffee consumption to 3 cups/d providing no more than 300 mg/d of caffeine to exclude any increased probability of spontaneous abortion or impaired fetal growth.
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PMID:Coffee and health: a review of recent human research. 1650 75

Mitochondrial dysfunction caused by oxidative stress and genetic defects have been implicated in the loss of dopaminergic neurons in Parkinson's disease. However, the key molecular events that provoke neurodegeneration still remain poorly understood. We recently showed that shortly after exposure to oxidative stress, only those cells showing phosphorylation of p53 at Ser-15 subsequently undergo active cell death. To investigate the role of this early p53 signaling response in cell death, 6-hydroxydopamine was used to induce oxidative stress in dopaminergic neurons generated from embryonic stem cells and PC12-D(2)R cells. Exposure to toxic concentrations of 6-hydroxydopamine induced phosphorylation of p53 at Ser-15 even before cells show mitochondrial permeabilization and apoptosis. We found that 6-hydroxydopamine induced phosphorylation of ataxia telangiectasia mutated (ATM) kinase an event integral to p53 activation and caffeine (ATM kinase inhibitor) inhibited Ser-15 phosphorylation. Phosphorylation of Ser-15 was correlated with enhanced induction and functional activation of p53 manifest as transcription of the pro-apoptotic p53 target Puma. Moreover, inhibition of the p53 abrogated the induction of Puma and promotion of apoptosis due to 6-hydroxydopamine treatments. Thus, these data suggest that activation of p53 signaling immediately after neurotoxin exposure acts as an initiating factor to mediate apoptosis in dopaminergic cells.
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PMID:Activation of p53 signaling initiates apoptotic death in a cellular model of Parkinson's disease. 1654 96


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