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)

Over the last decade, adenosine receptors in the central nervous system have been implicated in the modulation of cognitive functions. Despite the general view that endogenous adenosine modulates cognition through the activation of adenosine A1 receptors, evidence is now emerging on a possible role of A2A receptors in learning and memory. The present review attempts to examine results reported in different studies using diverse animal models, to provide a comprehensive picture of the recent evidence of a relationship between adenosinergic function and memory deficits. The present data suggest that caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A2A receptor antagonists can improve memory performance in rodents evaluated through different tasks. They might also afford protection against memory dysfunction elicited in experimental models of aging, Alzheimer's disease, Parkinson's disease and, in spontaneously hypertensive rats (SHR), a putative genetic model of attention deficit hyperactivity disorder (ADHD).
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PMID:Adenosine receptor antagonists for cognitive dysfunction: a review of animal studies. 1798 38

Data from Asian populations on dietary and lifestyle factors associated with Parkinson's disease are sparse. In 1993-2005, the authors examined these factors in relation to Parkinson's disease in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women. Baseline data were collected through in-person interviews using structured questionnaires. All 157 incident Parkinson's disease cases were identified either through follow-up interviews or via linkage with hospital discharge databases and Parkinson's disease outpatient registries and were confirmed by review of medical records. Current versus never smokers exhibited a reduced risk of Parkinson's disease (relative risk = 0.29, 95% confidence interval: 0.16, 0.52). Total caffeine intake was inversely related to Parkinson's disease risk (p for trend = 0.002); the relative risk for the highest versus lowest quartile was 0.55 (95% confidence interval: 0.35, 0.88). Black tea, a caffeine-containing beverage, showed an inverse association with Parkinson's disease risk that was not confounded by total caffeine intake or tobacco smoking (p for trend = 0.0006; adjusted relative risk for the highest vs. lowest tertile of intake = 0.29, 95% confidence interval: 0.13, 0.67). Green tea drinking was unrelated to Parkinson's disease risk. Diet had no strong influence on risk. Ingredients of black tea other than caffeine appear to be responsible for the beverage's inverse association with Parkinson's disease.
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PMID:Differential effects of black versus green tea on risk of Parkinson's disease in the Singapore Chinese Health Study. 1815 41

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Recent epidemiological studies suggest that caffeine, one of the major components of coffee, has a protective effect against developing PD. However, the detailed mechanisms of how caffeine suppresses neuronal death have not been fully elucidated. We investigated the cytoprotective mechanisms of caffeine using human dopaminergic neuroblastoma SH-SY5Y cells as a PD model. Caffeine prevented the apoptotic cell death induced by serum/retinoic acid (RA) deprivation, MPP+, rotenone, and 6-OHDA in SH-SY5Y cells in a dose dependent manner. Caffeine lowered caspase-3 activity induced by serum/RA deprivation and 6-OHDA administration, and also decreased the number of apoptotic condensed and/or fragmented nuclei. Akt was phosphorylated 60 min after caffeine administration in a dose dependent manner; PI3K inhibitors, wortmannin and LY294002 canceled this cytoprotective effect of caffeine. On the other hand, MAPKs such as Erk1/2, p38, or JNK were not activated by caffeine. These results suggest that caffeine has a cytoprotective effect due to the activation of the PI3K/Akt pathways in SH-SY5Y cells.
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PMID:Caffeine activates the PI3K/Akt pathway and prevents apoptotic cell death in a Parkinson's disease model of SH-SY5Y cells. 1820 23

Caffeine, the most consumed psychoactive drug and non-specific adenosine receptor antagonist, has recently been shown to exert a neuroprotective effect against brain injury in animal models of Parkinson's disease (PD) and stroke. However, the effects of caffeine on traumatic brain injury (TBI) are not known. In this study, we investigated the effects of acute and chronic caffeine treatment on brain injury in a cortical-impact model of TBI in mice. Following TBI, neurological deficits, cerebral edema, as well as inflammatory cell infiltration were all significantly attenuated in mice pretreated chronically (for 3 weeks) with caffeine in drinking water compared with the mice pretreated with saline. Furthermore, we found that chronic caffeine treatment attenuated glutamate release and inflammatory cytokine production, effects that were correlated with an upregulation of brain A1 receptor mRNA. By contrast, acute treatment with caffeine (i.p. injection, 30 min before TBI) was not effective in protecting against TBI-induced brain injury. These results suggest that chronic (but not acute) caffeine treatment attenuates brain injury, possibly by A1 receptor-mediated suppression of glutamate release and inhibition of excessive inflammatory cytokine production. These results highlight the potential benefit of chronic caffeine intake for preventing TBI and provide a rationale for the epidemiological investigation of the potential association between TBI and human caffeine intake.
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PMID:Chronic but not acute treatment with caffeine attenuates traumatic brain injury in the mouse cortical impact model. 1820 47

This review will examine how dopamine, a monoamine neurotransmitter, and adenosine, a neuromodulator, regulate behavioral activation, primarily as reflected by locomotor activity, in rodents. Complex interactions among 2 major types of adenosine receptors (A1AR and A2AAR) and 2 dopamine receptors (D1R and D2R) occur due to physical interactions that alter their ligand-binding properties and subsequent effects on common postreceptor signaling molecules. The output from these interactions in striatum modulates neurotransmission and subsequently influences spontaneous locomotor activity. Caffeine is a nonselective adenosine receptor antagonist that blocks 2 major types of adenosine receptors, A1AR and A2AAR, in the brain. Pharmacologic manipulation of these receptors with drugs such as caffeine offers potential therapeutic benefit for treatment of Parkinson disease.
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PMID:Adenosine and dopamine receptor interactions in striatum and caffeine-induced behavioral activation. 1824 65

The authors examined whether a diet that increases plasma urate level is also related to reduced risk of Parkinson's disease (PD). The study population comprised 47,406 men in the Health Professionals Follow-up Study. The potential effect of diet on plasma urate level was estimated by regressing plasma urate on intakes of selected foods and nutrients in a subsample of 1,387 men. Coefficients of this regression model were then used to calculate a dietary urate index for all cohort participants. Multivariate relative risks of PD were estimated by means of Cox proportional hazards models. After 14 years of follow-up (1986-2000), the authors documented 248 incident cases of PD. A higher dietary urate index was associated with a lower risk of PD (top quintile vs. bottom: relative risk = 0.47, p-trend = 0.0008), after adjustment for age, smoking, caffeine intake, and other potential confounders. This association remained strong and significant after further adjustment for each component of the index individually (p-trend < 0.02 for each). These data support urate as a potentially protective factor in PD and suggest that dietary changes expected to increase plasma urate level may contribute to lower risk of PD. These potential benefits, however, should be weighed against expected adverse effects on risk of gout and other chronic diseases.
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PMID:Diet, urate, and Parkinson's disease risk in men. 1832 73

Epidemiological evidence revealed that cigarette smokers and coffee drinkers have lower risk of Parkinson's disease (PD). Nicotine inhibits monoamine oxidase activity, and induces expression of neurotrophic factors and nicotinic acetylcholinergic receptors. However, caffeine is capable of antagonizing adenosine A(2A) receptor. Toxicant responsive enzymes and vesicular monoamine transporter-2 (VMAT-2) play critical roles in chemically induced PD. Despite some known functions, the effects of nicotine and caffeine on the expression and activity of toxicant responsive genes and on VMAT-2 are still not known. The study was therefore undertaken to investigate the effect of nicotine and caffeine on the expression and activity of toxicant responsive genes, i.e., CYP1A1, CYP2E1, GST-ya, GST-yc, GSTA4-4 and VMAT-2 in the striatum of control and MPTP-induced PD phenotype in mouse. The animals were treated intraperitoneally daily with nicotine (1 mg/kg) or caffeine (20 mg/kg) for 8 weeks, followed by 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 20 mg/kg)+nicotine or caffeine for 4 weeks. MPTP significantly attenuated CYP1A1 and VMAT-2, and augmented CYP2E1, GST-ya, GST-yc and GSTA4-4 expression/activity. Nicotine or caffeine-treated animals showed significant restoration against most of the MPTP-induced alterations. The results obtained thus suggest that nicotine and caffeine modulate MPTP-induced alterations in CYP1A1, CYP2E1, GST-ya, GST-yc, GSTA4-4 and VMAT-2 expression/activity.
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PMID:Nicotine and caffeine-mediated modulation in the expression of toxicant responsive genes and vesicular monoamine transporter-2 in 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease phenotype in mouse. 1837 8

Epidemiological studies indicate that caffeine consumption reduces the risk of Parkinson's disease (PD) in men, and antagonists of the adenosine 2A receptor ameliorate the motor symptoms of PD. These findings motivated us to identify proteins whose expression is regulated by caffeine in a sexually dimorphic manner. Using mass spectroscopy, we found that Cox7c, a nuclear-encoded subunit of the mitochondrial enzyme cytochrome oxidase, is up-regulated in the striatum of male but not female mice after receiving a single dose of caffeine. The expression of two other Cox subunits, Cox1 and Cox4, was also stimulated by caffeine in a male-specific fashion. This up-regulation of Cox subunits by caffeine was accompanied by an increase in Cox enzyme activity in the male striatum. Caffeine-induced stimulation of Cox expression and activity were reproduced using the adenosine 2A receptor (A2AR)-specific antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-epsilon]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261), and coadministration of the A2AR-specific agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680) counteracted the elevation of Cox expression and activity by caffeine. Caffeine also increased Cox activity in PC-12 cells. In contrast, small interfering RNA (siRNA) knockdown of Cox7c expression in PC-12 cells blunted Cox activity, and this was counteracted by caffeine treatment. Caffeine was also found to increase Cox7c mRNA expression in the striatum and in PC-12 cells. This occurred at the level of transcription and was mediated by a segment of the Cox7c promoter. Overall, these findings indicate that cytochrome oxidase is a metabolic target of caffeine and that stimulation of Cox activity by caffeine via blockade of A2AR signaling may be an important mechanism underlying the therapeutic benefits of caffeine in PD.
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PMID:Caffeine stimulates cytochrome oxidase expression and activity in the striatum in a sexually dimorphic manner. 1858 56

Epidemiological evidence suggests that caffeine or its metabolites reduce the risk of developing Parkinson's disease, possibly by protecting dopaminergic neurons, but the underlying mechanism is not clearly understood. Here, we show that the primary metabolite of caffeine, paraxanthine (PX; 1, 7-dimethylxanthine), was strongly protective against neurodegeneration and loss of synaptic function in a culture system of selective dopaminergic cell death. In contrast, caffeine itself afforded only marginal protection. The survival effect of PX was highly specific to dopaminergic neurons and independent of glial cell line-derived neurotrophic factor (GDNF). Nevertheless, PX had the potential to rescue dopaminergic neurons that had matured initially with and were then deprived of GDNF. The protective effect of PX was not mediated by blockade of adenosine receptors or by elevation of intracellular cAMP levels, two pharmacological effects typical of methylxanthine derivatives. Instead, it was attributable to a moderate increase in free cytosolic calcium via the activation of reticulum endoplasmic ryanodine receptor (RyR) channels. Consistent with these observations, PX and also ryanodine, the preferential agonist of RyRs, were protective in an unrelated paradigm of mitochondrial toxin-induced dopaminergic cell death. In conclusion, our data suggest that PX has a neuroprotective potential for diseased dopaminergic neurons.
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PMID:Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels. 1862 27

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with selective loss of dopaminergic neurons in substantia nigra pars compacta. Among the proposed mechanisms of dopaminergic degeneration, oxidative stress is believed to play an important role. On the other hand, L-DOPA used as the main medication in PD and overproduction of dopamine (DA) in striatal neurons could elicit toxic effects due to formation of free radicals (FRs). Adenosine, an endogenous neuromodulator was shown in various experimental models to have neuroprotective properties. In our study, we investigated the role of adenosine A(1) and A(2A) receptor ligands in hydroxyl radical generation by L-DOPA in the rat striatum. The hydroxyl radical was assayed by HPLC-ED as a product of its reaction with p-hydroxybenzoic acid (PBA). Intrastriatal infusion of L-DOPA(50 microM) markedly increased dialysate level of DA and 3,4-dihydroxybenzoic acid (3,4-DHBA). An adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA, 25-50 microM), nonselectiveA(1)/A(2A) receptor agonist 2-chloroadenosine (2-CADO, 50-100 microM), and selective A(2A) receptor agonist CGS 21680 (25-50 microM) decreased the level of 3,4-DHBA. A non-selective A(1)/A(2A) adenosine receptor antagonist caffeine (100 microM) produced similar effect on 3,4-DHBA level. At the same time, CPA and 2-CADO, but not CGS 21680 or caffeine, decreased L-DOPA-induced DA release. The adenosine receptor ligands alone only weakly changed extracellular DA level and did not influence hydroxyl radical production. However, they showed scavenging activity in Fenton reaction in vitro. The primary caffeine metabolite in rodents, 1,3,7-trimethyl uric acid (1,3,7-mUA) decreased both, DA synthesis and 3,4-DHBA level. Thus, paradoxically, both agonists of A(1) receptor and agonist of A(2A) receptor as well as antagonist of A(1) and A(2A) receptors (caffeine), all decreased generation of FRs. Our study suggests that a decrease in hydroxyl radical generation caused by adenosine receptor ligands results from attenuation of L-DOPA-induced DA release or from their scavenging activity.
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PMID:Paradoxical effects of adenosine receptor ligands on hydroxyl radical generation by L-DOPA in the rat striatum. 1862 56


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