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)

A(2A) adenosine receptor antagonists have been proposed as a new therapy for Parkinson's disease (PD). Since oxidative stress plays an important role in the pathogenesis of PD, we studied the effect of the selective A(2A) adenosine receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on L: -3,4-dihydroxyphenylalanine (L: -DOPA)-induced hydroxyl radical generation using in vivo microdialysis in the striatum of freely moving rats. L: -DOPA (100 mg/kg; in the presence of benserazide, 50 mg/kg) given acutely or repeatedly for 14 days generated a high level of hydroxyl radicals, measured by HPLC with electrochemical detection, as the product of their reaction with p-hydroxybenzoic acid (PBA). CSC (1 mg/kg) and ZM 241385 (3 mg/kg) decreased haloperidol (0.5 mg/kg)-induced catalepsy, while at low doses of 0.1 and 0.3 mg/kg, respectively, they did not display an effect. CSC (1 and 5 mg/kg) and ZM 241385 (3 and 9 mg/kg) given acutely, or CSC (1 mg/kg) and ZM 241385 (3 mg/kg) given repeatedly, increased the production of hydroxyl radicals in dialysates from rat striatum. Both acute and repeated administration of CSC (0.1 and 1 mg/kg) and ZM 241385 (3 mg/kg) decreased L: -DOPA-induced generation of hydroxyl radicals. However, a high single dose of either CSC (5 mg/kg) and ZM 241385 (9 mg/kg) markedly potentiated the effect of L: -DOPA on hydroxyl radical production. The increase in hydroxyl radical production by acute and chronic injection of CSC and ZM 241385 may be related to the increased release of dopamine (DA) and its metabolism in striatal dialysates. Similarly, increased DA release following a single high dose of CSC or ZM 241385 appears to be responsible for augmentation of L: -DOPA-induced hydroxyl radical formation. Conversely, the inhibition of L: -DOPA-induced production of hydroxyl radical by single and repeated low doses of CSC or repeated low doses of ZM 241385 may be related to reduced DA metabolism. Summing up, A(2A) antagonists, used as a supplement of L: -DOPA therapy, depending on the dose used, may have a beneficial or adverse effect on ongoing neurodegenerative processes and accompanying oxidative stress.
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PMID:Effect of adenosine A(2A) receptor antagonists on L-DOPA-induced hydroxyl radical formation in rat striatum. 1938 78

8-(3-chlorostryryl) caffeine (CSC), a selective adenosine A(2A) receptor antagonist, has been reported to inhibit the levodopa-induced motor fluctuation in Parkinson's disease. However, the underlying mechanism of its action remains largely unknown. In our study, we investigated the signaling pathway by which CSC inhibited levodopa-induced motor fluctuation in rats with a 6-hydroxydopamine (6-OHDA)-induced lesion. We treated 6-OHDA-lesioned rats with levodopa (50 mg/kg/day, twice daily) for 22 days, followed by levodopa+CSC (5 mg/kg/day, twice daily) or levodopa+vehicle for 7 days. The sham-lesioned and 6-OHDA-lesioned rats treated with saline for 29 days served as sham and lesion control groups. We found that the treatment of CSC reversed the shortening of the rotational motor response duration induced by levodopa administration and the effect was maintained until the end of the treatment. The chronic levodopa treatment upregulated the adenosine A(2A) receptor expression and modified downstream signaling pathway including decreasing the phosphorylation of DARPP-32 at Thr75 site and increasing the phosphorylation of ERK1/2 in the lesioned striatum. However, the following CSC treatment attenuated the levodopa-induced adenosine A(2A) receptor upregulation and abolished the aberrant phosphorylation of DARPP-32 at Thr75 site and that of ERK1/2. Our results indicate that the inhibitory effect of CSC on levodopa-induced motor fluctuation may be associated with the inhibition of Adenosine A(2A) Receptor and downstream DARPP-32 and ERK1/2 signaling pathway.
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PMID:Inhibitory effect of 8-(3-chlorostryryl) caffeine on levodopa-induced motor fluctuation is associated with intracellular signaling pathway in 6-OHDA-lesioned rats. 1939 28

The previous study showed that chronic treatment with Withania somnifera extract (WS) inhibited haloperidol-induced catalepsy. It is suggested that caffeine and WS may be useful adjuvants in pharmacotherapy of Parkinson's disease. There are no studies on the effect of haloperidol on mice withdrawn from caffeine or W. somnifera. We therefore studied the effect of a single administration of standardised WS containing 5.1% total withanolides (WS, 30 or 100 mg kg(-1) i.p.) and/or caffeine (3 mg kg(-1) i.p.) and withdrawal from 6 days treatment with WS and/or caffeine, on haloperidol-induced catalepsy in albino mice. Single administration of both WS and caffeine, used either alone or in combination, significantly inhibited catalepsy. Mice withdrawn from caffeine significantly inhibited haloperidol-induced catalepsy, but mice withdrawn from WS showed increased catalepsy. The study indicated that withdrawal from WS does not retain anticataleptic activity, and caffeine but not WS may be a good adjuvant in pharmacotherapy of Parkinson's disease.
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PMID:Caffeine withdrawal retains anticataleptic activity but Withania somnifera withdrawal potentiates haloperidol-induced catalepsy in mice. 1941 55

To determine if reproductive factors or exogenous estrogen are associated with risk of Parkinson's disease (PD), we conducted a prospective study with 22 years of follow-up among postmenopausal participants in the Nurses' Health Study. Relative risks (RRs) and 95% confidence intervals (CIs) of PD were estimated from a Cox proportional hazards model adjusting for potential confounders. Risk of PD was not significantly associated with any of the reproductive factors measured or exogenous estrogen use. Use of postmenopausal hormones, however, may modify the associations of smoking and caffeine intake with PD risk. The inverse relation between smoking and PD risk was attenuated among ever users of postmenopausal hormones (P for interaction = 0.05). Similar results were obtained for caffeine (P for interaction = 0.09). In exploratory analyses, women using progestin-only hormones were found to have an increased PD risk, but this result was based on a very small number of cases (n = 4). In this large longitudinal study, we found no evidence of a beneficial effect of exogenous or endogenous estrogens on risk of PD. The use of postmenopausal hormone use may interact with other risk factors, but findings are preliminary and need confirmation in other populations.
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PMID:Reproductive factors, exogenous estrogen use, and risk of Parkinson's disease. 1942 86

While dopamine replacement remains the standard pharmacotherapy for Parkinson's disease, chronic L-dopa treatment is associated with development of debilitating motor fluctuations such as L-dopa-induced dyskinesia (LID). In this study we evaluated the effects of the partial dopamine D(2) agonist terguride on the development of LID in hemiparkinsonian mice (unilaterally lesioned with 6-hydroxydopamine). First, consistent with the partial agonist property, terguride had 1000-fold higher potency than dopamine, yet producing one-third level of maximal activation of dopamine, as assayed by [(35)S]GTPgammaS binding. Furthermore, in the absence and presence of dopamine in vitro, terguride increased and decreased striatal [(35)S]GTPgammaS binding, respectively. Next, we found that co-administration of terguride (at 0.1 and 0.5mg/kg, i.p.) with L-dopa (1.8 mg/kg) daily for 14 days, significantly attenuated the development and expression of L-dopa-induced rotational sensitization. Furthermore, the cross-challenge paradigm revealed that chronic L-dopa treatment (but not terguride) sensitized locomotor response to the dopamine D(1) agonist SKF 81297 while chronic treatment with terguride (but not L-dopa) produced sensitized locomotor responses to the adenosine A(2A) antagonist 8-(3-chlorostyryl)caffeine (CSC). Importantly, the co-administration of terguride with L-dopa did not show locomotor sensitization to either SFK 81297 or CSC upon challenge. Together, these results suggest that co-administration of partial dopamine D(2) agonists with L-dopa may prophylactically attenuate L-dopa-induced abnormal behavioral responses such as LID.
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PMID:Co-administration of the partial dopamine D2 agonist terguride with L-dopa attenuates L-dopa-induced locomotor sensitization in hemiparkinsonian mice. 1946 6

Parkinson's disease (PD) is a progressive neurodegenerative disorder, characterized by the selective loss of dopaminergic neurons of the nigrostriatal pathway. Epidemiological studies have shown an inverse relationship between coffee consumption and susceptibility to PD. Cytochrome P450 1A2 (CYP1A2) is involved in caffeine metabolism and its clearance. Caffeine, on the other hand, antagonizes adenosine A(2A) receptor and regulates dopamine signaling through dopamine transporter (DAT). The present study was undertaken to investigate the expression of CYP1A2, adenosine A(2A) receptor and DAT in mouse striatum and to assess their levels in 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropryridine (MPTP) treated mouse striatum with and without caffeine treatment. The animals were treated intraperitoneally daily with caffeine (20 mg/kg) for 8 weeks, followed by MPTP (20 mg/kg)+caffeine (20 mg/kg) for 4 weeks or vice versa, along with respective controls. Tyrosine hydroxylase immunoreactivity, levels of dopamine and 1-methyl 4-phenylpyridinium ion (MPP(+)), expressions of CYP1A2, adenosine A(2A) receptor and DAT and CYP1A2 catalytic activity were measured in control and treated mouse brain. Caffeine partially protected MPTP-induced neurodegenerative changes and modulated MPTP-mediated alterations in the expression and catalytic activity of CYP1A2, expression of adenosine A(2A) receptor and DAT. The results demonstrate that caffeine alters the striatal CYP1A2, adenosine A(2A) receptor and DAT expressions in mice exposed to MPTP.
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PMID:Effect of caffeine on the expression of cytochrome P450 1A2, adenosine A2A receptor and dopamine transporter in control and 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine treated mouse striatum. 1952 64

Chronic caffeine consumption has been inversely associated with the risk of developing Parkinson's disease. Here we assessed whether chronic caffeine treatment increases the resistance of male Wistar rats to haloperidol (1mg/kg, s.c.)-induced catalepsy, measured in the bar test at 15 min intervals during 3h. Caffeine (5mg/kg/day) was delivered for 6 months via drinking water. Control rats received only tap water. Treatments began when animals were 3-4 months old. In order to unveil long-lasting catalepsy refractoriness not attributable to the presence of caffeine in the brains of rats, they were evaluated from day 18 to day 27 after caffeine withdrawal, a time that is far in excess for the full excretion of a caffeine dose in this species. The average cataleptic immobility measured in caffeine-treated rats (n=23) was 1148+/-140 s, a value 34+/-8% lower than that recorded in control animals (n=20), whose mean immobility was 1736+/-137 s (P=0.0026, t-test). The percentage of catalepsy reduction measured in caffeine-treated rats evaluated on days 18-20 after caffeine discontinuation (-32+/-13%, n=12, P<0.05) was comparable to the catalepsy decrease recorded in those animals tested on days 21-27 (-36+/-10%, n=11, P<0.02), a finding compatible with the notion that the effect was indeed mediated by enduring changes of brain functioning and not by the physical presence of caffeine or its metabolites. Caffeine-treated rats also had higher catalepsy latency scores compared with control rats (P<0.01, U-test). The present findings show that chronic consumption of caffeine produces perdurable resistance to catalepsy induced by dopamine receptor blockade, possibly through enhancement of dopamine transmission, giving further support to the epidemiological results indicating that prolonged caffeine consumption affords neuroprotection against Parkinson's disease.
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PMID:Long-lasting resistance to haloperidol-induced catalepsy in male rats chronically treated with caffeine. 1965 37

Nearly two-thirds of patients with Parkinson's disease (PD) use vitamins or nutritional supplements, and many more may use other complementary therapies, yet <50% of patients have discussed the use of these complementary therapies with a healthcare professional. Physicians should be aware of the complementary therapies their patients with PD are using, and the possible effects of these therapies on motor and non-motor symptoms. Complementary therapies, such as altered diet, dietary supplements, vitamin therapy, herbal supplements, caffeine, nicotine, exercise, physical therapy, massage therapy, melatonin, bright-light therapy and acupuncture, may all influence the symptoms of PD and/or the effectiveness of dopaminergic therapy. Preliminary evidence suggests complementary therapy also may influence non-motor symptoms of PD, such as respiratory disorders, gastrointestinal disorders, mood disorders, sleep and orthostatic hypotension. Whenever possible, clinicians should ensure that complementary therapy is used appropriately in PD patients without reducing the benefits of dopaminergic therapy.
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PMID:Potential influences of complementary therapy on motor and non-motor complications in Parkinson's disease. 1973 93

Caffeine causes most of its biological effects via antagonizing all types of adenosine receptors (ARs): A1, A2A, A3, and A2B and, as does adenosine, exerts effects on neurons and glial cells of all brain areas. In consequence, caffeine, when acting as an AR antagonist, is doing the opposite of activation of adenosine receptors due to removal of endogenous adenosinergic tonus. Besides AR antagonism, xanthines, including caffeine, have other biological actions: they inhibit phosphodiesterases (PDEs) (e.g., PDE1, PDE4, PDE5), promote calcium release from intracellular stores, and interfere with GABA-A receptors. Caffeine, through antagonism of ARs, affects brain functions such as sleep, cognition, learning, and memory, and modifies brain dysfunctions and diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, Epilepsy, Pain/Migraine, Depression, Schizophrenia. In conclusion, targeting approaches that involve ARs will enhance the possibilities to correct brain dysfunctions, via the universally consumed substance that is caffeine.
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PMID:Caffeine and adenosine. 2016 66

Sporadic Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases and as such they represent major public health problems. Finding effective treatments for AD and PD represents an unmet and elusive goal largely because these diseases are chronic and progressive, and have a complicated and ill-understood pathogenesis. Although the underlying mechanisms are not fully understood, caffeine, the most commonly ingested psychoactive drug in the world, has been shown in human and animal studies to be protective against AD and PD. One mechanism implicated in the pathogenesis of AD and PD is blood-brain barrier (BBB) dysfunction and we reported recently that caffeine exerts protective effects against AD and PD at least in part by keeping the BBB intact. The present review focuses on the role of BBB dysfunction in the pathogenesis of AD and PD, caffeine's protective effects against AD and PD, and potential mechanisms whereby caffeine protects against BBB leakage.
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PMID:Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer's and Parkinson's diseases. 2016 68


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