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Medicine » Mental and Behavioural Disorders and Diseases of the Nervous System » "Towards New Therapies for Parkinson's Disease", book edited by David I. Finkelstein, ISBN 978-953-307-463-4, Published: November 2, 2011 under CC BY 3.0 license. © The Author(s).

Chapter 14

Epigenetic Modulation of Adenosine A2A Receptor: A Putative Therapeutical Tool for the Treatment of Parkinson’s Disease

By Marta Barrachina, Mairena Martín, Francisco Ciruela and Isidre Ferrer
DOI: 10.5772/16697

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SAM biosynthesis cycle
Figure 1. SAM biosynthesis cycle
A, Scaled representation of 5’ UTR region of human ADORA2A gene, containing 6 isoforms of non-coding exon 1 (1A-1F). Two CGIs surrounding exon 1E were recently described (Buira et al., 2010b). The translational start site (ATG) is indicated with an arrow. B, DNA methylation percentage (mean ± SD) of a locus located in the CGIs of exon 1E of 8 human post-mortem putamens of PD (black bars) and in two cell lines (black line, SH-SY5Y, n=3; dotted lines, U87-MG, n=3).
Figure 2. A, Scaled representation of 5’ UTR region of human ADORA2A gene, containing 6 isoforms of non-coding exon 1 (1A-1F). Two CGIs surrounding exon 1E were recently described (Buira et al., 2010b). The translational start site (ATG) is indicated with an arrow. B, DNA methylation percentage (mean ± SD) of a locus located in the CGIs of exon 1E of 8 human post-mortem putamens of PD (black bars) and in two cell lines (black line, SH-SY5Y, n=3; dotted lines, U87-MG, n=3).

Epigenetic Modulation of Adenosine A2A Receptor: A Putative Therapeutical Tool for the Treatment of Parkinson’s Disease

Marta Barrachina1, 2, Mairena Martín1, Francisco Ciruela1 and Isidre Ferrer2, 2, 2

1. Introduction

Adenosine is a nucleoside distributed throughout the entire organism as an intermediary metabolite. At the extracellular level, adenosine plays multiple physiologic roles, interacting with specific receptors: A1, A2A, A2B and A3 (Fredholm et al., 2001). While the A1Rs and A3Rs are coupled in an inhibitory way to adenylate cyclase through the Gαi/o protein, the A2Rs are coupled in a stimulatory way to this enzymatic activity through Gαs protein (Ralevic & Burnstock, 1998).

Adenosine levels are increased after ischemia, hypoxia, excitotoxicity, inflammation and cerebral lesions. In these situations, it is considered that high adenosine levels play a neuroprotective role (Ribeiro et al., 2002). Interestingly, adenosine regulates the release of glutamate, the main excitatory neurotransmitter of the nervous system (Sebastiao & Ribeiro, 1996). A1Rs are widely expressed in the brain and have been shown to modulate neuronal excitability by decreasing pre-synaptic release of various neurotransmitters (Fredholm & Dunwiddie, 1988). The most dramatic inhibitory actions are on the glutamatergic system (Masino et al., 2002). In the central nervous system (CNS), A1Rs are associated with neuroprotective processes (Angulo et al., 2003; Dunwiddie and Masino, 2001). Moreover, they are upregulated in human neurodegenerative diseases with abnormal protein aggregates and it is related to compensatory mechanisms (Albasanz et al., 2007, 2008; Angulo et al., 2003; Perez-Buira et al., 2007; Rodríguez et al., 2006). Regarding A2ARs, these receptors are concentrated in the striatum, modulating dopaminergic activity, but they are also present in the hippocampus and cerebral cortex, modulating the glutamate release in the brain. Adenosine activity through A2 receptors (A2ARs) can eventually give rise to neurotoxicity, neuronal damage and cellular death (de Mendoça et al., 2000). In fact, A2ARs activity is associated with the outcome of cerebral injury as well as the development of Aβ-induced synaptotoxicity (Canas et al., 2009; Cunha, 2005; Stone et al., 2009).

2. Human brain A2AR localization and implications in PD pathophysiology

As mentioned in the previous section, A2ARs are G protein-coupled receptors that stimulate adenylyl cyclase through Gαs proteins, promoting accumulation of intracellular cAMP (Van Calker et al., 1979). The activation of these receptors mediates multiple physiological effects of adenosine, both in the CNS and in peripheral tissues (Fredholm et al., 2001). Pharmacological activation of A2ARs promotes vasodilatation, immunosuppression, tissue protection, sleep promotion and depression (Cerqueira, 2004; El Yacoubi et al., 2003; Linden, 2001; Satoh et al., 1998).

A2ARs are widely expressed, but they are highly concentrated in spleen, thymus, leukocytes and blood platelets. A2ARs levels in immune cells play a critical role in the protection of normal tissues by attenuating inflammation and tissue damage in vivo (Ohta and Sitkovsky, 2001). In the CNS, A2ARs are highly expressed in the striatum (Peterfreund et al., 1996; Schiffmann et al., 1991). Most striatal neurons (95%) are GABAergic medium spiny neurons (MSNs) which can be divided into two subtypes. One subpopulation projects to the globus pallidus and contains enkephalin. The other subpopulation projects to the substantia nigra and contains substance P and dynorphin. These neurons receive inputs from glutamatergic afferents from cortical, thalamic and limbic areas and dopaminergic afferents from the substantia nigra pars compacta and the ventral tegmental area. MSNs promote two striatal efferent pathways, the “direct” and “indirect”, affecting motor activation and inhibition, respectively. The MSNs of the direct pathway correspond to the subpopulation containing dynorphin and they also express dopamine D1 receptors, whereas indirect MSNs express enkephalin, dopamine D2 receptors (D2Rs) and A2ARs (Schiffmann et al., 2007). In these cells, A2ARs physically interact (oligomerize) with D2R, and this receptor-receptor interaction results in a tidy adenosine/dopamine functional interaction controlled by the A2AR/D2R oligomer. Consequently, two reciprocal antagonistic A2AR/D2R interactions have been described, namely an intermembrane interaction in which A2AR mediates the inhibition of D2R, thus modulating neuronal excitability and neurotransmitter release, and an interaction at the level of adenylyl-cyclase in which D2R inhibits A2AR-mediated protein phosphorylation and gene expression (for review see Ciruela et al., 2011). As a result of this interaction, antagonists of A2ARs have recently emerged as a leading candidate class of non-dopaminergic anti-parkinsonian agents, based in part on the unique CNS distribution of A2ARs and A2AR/D2R oligomers (Fuxe et al., 2003). Moreover, the metabotropic glutamate receptors 5 (mGluR5s) are co-localized in the same GABAergic striatal output neurons and in glutamatergic nerve terminals in the striatum, and they form heteromeric complexes with A2ARs (Ferré et al., 2002; Rodrigues et al., 2005). This co-localization provides a morphological framework for the existence of multiple mGlu5/A2A/D2 receptor interactions (Cabello et al., 2009). Thus, it is proposed that the increase in glutamate and adenosine extracellular levels activates A2AR and mGluR5, both synergizing and promoting the inhibition of D2Rs (Ferré et al., 2007).

Of note is the characterization of A1R-A2AR heteromers with antagonistic activities between the two receptors, preferentially at presynaptically level in glutamatergic terminals of cortico-striatal afferents to the MSNs (Ciruela et al., 2006; Quiroz et al., 2009). Under baseline conditions, reduced levels of extracellular adenosine stimulate the activity of A1Rs while glutamatergic neurotransmission is inhibited. Under conditions of neuronal excitability, the extracellular adenosine levels are increased, showing A2ARs affinity and inhibiting A1R activity, and promoting the release of glutamate, which in turn also increases activation of mGluR5 synergizing with A2ARs and thereby facilitating more glutamate release (Rodrigues et al., 2005).

Interestingly, striatal A2ARs expression levels have been found to be increased in PD patients with dyskinesias; this upregulation is attributed to the effect of levodopa (L-dopa) treatment (Calon et al., 2004). Recently, it has been proven that high A2ARs levels in the striatum and in lymphocytes correlate with motor symptoms in PD patients who were previously either not pharmacologically treated or were treated with a wide spectrum of drugs and not restricted to only L-dopa (Varani et al., 2010). Therefore, A2AR upregulation in PD, which tonically inhibits D2R (see above), together with the low dopamine content in the striatum, a consequence of the death of dopaminergic neurons from the substantia nigra, contribute to a synergistic impairment of D2R function.

It remains to be clarified whether upregulation of A2ARs levels in PD is a hallmark of the disease or is a consequence of dopaminergic terminal drop-off in the striatum. This issue has been quite controversial, as increased striatal levels of A2ARs were shown in 6-hydroxidopamine (6-OHDA)-treated rats, as a consequence of dopamine denervation (Pinna et al., 2002), and also in 6-OHDA-treated rats with intermittent L-dopa treatment (Tomiyama et al., 2004).

3. Clinical trials with A2AR antagonists in PD

L-dopa remains the most effective treatment for symptomatic relief of PD, although its pharmacological administration over time induces motor dysfunctions such as dyskinesias (Obeso et al., 2000). One of the strategies to reduce these is the administration of

non-dopaminergic drugs that modulate dopaminergic neurotransmission. Indeed, A2AR has emerged as a potential pharmacological target in PD, as its relationship with the dopaminergic system has been clearly demonstrated (Ferré et al., 2002). There have been several clinical trials with A2AR antagonists, such as istradefylline (also known as KW-6002), confirming that their administration to PD patients reduces the “OFF” time and dyskinesias induced by L-dopa treatment (Bara-Jimenez et al., 2003; Factor et al., 2010; Hauser et al., 2003, 2008; LeWitt et al., 2008b; Mizuno et al., 2010; Stacy et al., 2008). As A2ARs expression levels are nearly exclusive of the striatum, the use of specific antagonists for these receptors could promote a specific brain-area effect (Brooks et al., 2008). Interestingly, it has recently been described how KW-6002 preferentially targets the A2AR within the postsynaptic A2AR/D2R oligomer located at the MSNs, thus potentiating D2R-mediated motor activation (Orru et al., 2011). Therefore, although the use of istradefylline as a monotheraphy in PD has not been statistically demonstrated (Fernandez et al., 2010), its administration as a coadjuvant seems to allow a reduction in the L-dopa dose.

As mentioned before, there are heteromers formed by A2AR, D2R and mGluR5 in striatal GABAergic neurons or MSNs (Cabello et al., 2009). It is proposed that the increase in glutamate and adenosine extracellular levels activates A2AR and mGluR5, both synergizing and promoting the inhibition of D2Rs (Ferré et al., 2007). Interestingly, it has been demonstrated in a rat model of PD that the simultaneous inhibition of A2AR and mGluR5 synergistically reverses the parkinsonian deficits in these animals (Coccurello et al., 2004). In this line, the use of mGluR type I antagonists as a therapy for PD has been proposed (Bonsi et al., 2007). Overall, this explains why pharmaceutical companies are going after either single compounds or combinations of drugs that will simultaneously antagonize A2AR and mGluR5.

4. Brain DNA methylation

Studies in mice deficient in enzymes that control DNA methylation and the results of folate-free diets have established an important role for methylation in the development of the nervous system (Waterland & Jirtle, 2003). In fact, the manipulation of methylation and acetylation affects neuronal vulnerability in experimental models of neurodegenerative diseases (El-Maarri, 2003). It has also been proposed that memory processes are highly related with the level of neuronal methylation (Day & Sweatt, 2010; Liu et al., 2009).

DNA methylation is a normal process that occurs during mammal embryo development, and it is also implicated in X-chromosome inactivation and repression of proviral genes and endogenous transposons. This chemical modification is one of the most important epigenetic mechanisms in gene silencing in mammals. It is characterized by the methylation of cytosines that precede guanines in the well-known CpG sites. Those genome CpG-rich regions are called CpG islands (CGIs); they present a size between 200 bp and several kilobases. In general, these active gene promoter regions are not methylated, while the inactive gene promoter regions are fully methylated. Most CGIs are found in 5' UTR regions and in the first exon, although they can be found in regions distal to the transcription start site and in intronic regions. In normal tissues, CGIs are usually non-methylated, while they are methylated in tumorous cells, especially in tumor repressor genes (Illingworth & Bird, 2009; Jones, 1999).

Methylation of CpG sites is achieved by the action of DNA metyltransferases (Dnmt) which catalyze the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to DNA. The human DNA Methylome map has recently been published, annotating those genes found methylated in normal tissues and in human diseases such as Alzheimer’s disease (AD) and schizophrenia (SZ) (Ballestar & Esteller, 2008). DNA methylation in the CpG sites interferes with gene expression in two ways. The first is interference with the binding of transcription factors to DNA through the methyl group. The second is caused by the binding of specific proteins, such as MeCP2, MBD1 and MBD2, to methyl CpG sites (methyl-CpG-binding proteins, MBDs). These MBDs recruit histone-modifying and chromatin-remodeling complexes to methylated sites (Portela & Esteller, 2010). The importance of these proteins is demonstrated by Rett syndrome, a disease causing severe mental dysfunction and brought on by MeCP2 mutations (Amir et al., 1999).

The role of DNA methylation in the brain is an emerging field of research. Neuronal DNA methylation is modified with lifespan, and the analysis of 12 loci related with AD has revealed an age-specific epigenetic drift in the percentage of DNA methylation (Siegmund et al. 2007; Wang et al., 2008). Moreover, the degree of gene methylation varies among the different cerebral regions, and it has been reported that DNA methyltransferase 1 (Dnmt1) expression levels are different in the various cerebral regions (Ladd-Acosta et al., 2007). Interestingly, Dnmt 1 is increased in the cortical interneurons where the GAD67 gene is suppressed in SZ patients (Veldic et al., 2004, 2005).

Finally, epigenetic therapies such as the use of demethylating agents are widely established in the treatment of tumors (Herranz & Esteller, 2006), but their use in neurodegeneration is poorly studied. In this line, S-adenosylmethionine (SAM) is a methyl group donor molecule necessary for DNA methylation which is reduced in AD (Linnebank et al., 2010; Morrison et al., 1996). There have been proposals to use it as a therapy for AD (Scarpa et al., 2003). Its administration to cell lines down-regulates PSEN1 and reduces β-amyloid production. In contrast, deprivation of SAM up-regulates PSEN1, increasing β-amyloid deposits in APP transgenic mice (Fuso et al., 2005, 2008). Interestingly, mice treated with L-methionine downregulate GAD67 and reelin levels by increasing DNA methylation of their respective gene promoter regions (Tremolizzo et al., 2002).

5. Endogenous SAM biosynthesis cycle and alterations in PD

SAM is the main biological methyl donor molecule in the methionine metabolic cycle, which is involved in the methylation of DNA, and protein, lipid and polyamine synthesis. Moreover, it is a precursor of glutathione in the liver and also perhaps in the brain (Vitvitsky et al, 2006). When SAM is demethylated, it is transformed into S-adenosylhomocysteine (SAH) which in turn is hydrolysed into homocysteine (HCY) and adenosine. To prevent the accumulation of HCY, it is remethylated to form methionine (Chiang et al., 1996; Lu, 2000) (see Figure 1). The SAM/SAH ratio is also known as methylation potential and its endogenous maintenance is very important.

L-dopa is the conventional drug used in the treatment of PD to minimize the lack of endogenous dopamine in these patients (Lewitt, 2008a; Tolosa et al., 1998). However, chronic treatment with L-dopa has been associated with hyperhomocysteinemia in plasma, peripheral tissues and brain of PD patients, as L-dopa metabolism requires S-adenosylmethionine (SAM) as a methyl donor (Lu, 2000; Müller et al., 2009a; Nutt, 2008; O’Suilleabhain et al, 2004; Zoccolella et al., 2006, 2009, 2010). Interestingly, it has been shown that L-dopa treatment in mice depletes the brain SAM content (Liu et al., 2000). In addition, elevated plasma homocysteine (Hcy) levels have been related to cognitive and motor impairment and have also been associated with the pathogenesis of other neurological diseases such as stroke and AD (Morris, 2003; Quadri et al., 2004; Seshadri et al., 2002). Interestingly, some polymorphisms described in MTHFR gene (methylenetetrahydrofolate reductase) have been associated with a reduction in its enzymatic activity, promoting an increase in the Hcy levels in L-dopa-treated PD patients (Frosst et al., 1995; Yasui et al., 2000). Vitamin B6 enhances the direct flow of Hcy to cysteine, the precursor of gutathione. Deficits in vitamin B6 induce oxidative stress and, in turn, enhance Hcy (Obeid et al., 2009). Therefore, several factors have been related with hyperhomocysteinemia and a concomitant reduction in the SAM levels in blood and cerebrospinal fluid of L-dopa-treated PD patients (Cheng et al., 1997). These include the following: 1. An excessive production of S-adenosylhomocysteine (SAH) when L-dopa is metabolized by catechol-O-methyltransferase (COMT), depleting the SAM levels an in turn decreasing the SAM/SAH ratio; 2. Reduced MTHFR enzymatic activity; and 3. Vitamin B12 or folic acid deficits (Dos Santos et al., 2009; Miller et al., 2003; Müller et al., 2001, 2009b; Woitalla et al., 2004). In this context, some clinical trials have been carried out using decarboxylase and COMT inhibitors (for instance, carbidopa and entacapone/tolcapone, respectively) or vitamin B12 and folate supplementation to reduce Hcy levels in PD patients (Müller et al., 2003, 2006; Zoccolella et al., 2007).


Figure 1.

SAM biosynthesis cycle

6. Epigenetic study of ADORA2A

A2AR gene (ADORA2A) is localized to chromosome 22 (Le et al., 1996; MacCollin et al., 1994; Peterfreund et al., 1996). It consists of two coding exons (exon 2 and 3) separated by a single intron of nearly 7 Kb. The exon 1 is a non-coding exon which is located at 5′ upstream exon 2 and presents 6 tissue-specific isoforms: h1A-h1F (Yu et al., 2004) (Figure 2A). Interestingly, differential expression of these isoforms has been reported in granulocytes of patients suffering from sepsis, indicating that 5′ UTR plays an important regulatory role in A2AR expression (Kreth et al., 2008). We recently identified a functional CGI surrounding the h1E isoform, demonstrating that DNA methylation controls basal ADORA2A expression in several cell lines and that it is one of the molecular mechanisms responsible for A2ARs’ differential expression levels in specific human brain areas, such as the putamen and the cerebellum (Buira et al., 2010a, 2010b). Interestingly, we showed that A2AR expression levels can be modulated by SAM treatment in SH-SY5Y (human neuroblastoma) and U87MG (human glioblastoma) cell lines. In this context, A2ARs levels have been reported to be upregulated in PD patients (Calon et al., 2004; Varani et al., 2010). Therefore, we postulated that SAM treatment could represent a therapeutical tool to reduce A2ARs levels in these patients. This is based on the fact that the DNA methylation profile of striatal ADORA2A in PD patients is lower than the one found in SH-SY5Y and U87MG cells (Figure 2B). Therefore, as A2ARs cell surface levels are reduced in these cells after SAM treatment, due to an increase in the DNA methylation profile of ADORA2A (Buira et al., 2010a), it is also plausible that the same mechanism of action could play a role in the striatum of PD patients.


Figure 2.

A, Scaled representation of 5’ UTR region of human ADORA2A gene, containing 6 isoforms of non-coding exon 1 (1A-1F). Two CGIs surrounding exon 1E were recently described (Buira et al., 2010b). The translational start site (ATG) is indicated with an arrow. B, DNA methylation percentage (mean ± SD) of a locus located in the CGIs of exon 1E of 8 human post-mortem putamens of PD (black bars) and in two cell lines (black line, SH-SY5Y, n=3; dotted lines, U87-MG, n=3).

7. Clinical trials with SAM

SAM has been widely used for the treatment of liver diseases, as it increases the glutathione content (Friedel et al. 1989). Interestingly, SAM has antidepressant properties and its long term tolerability is excellent, presenting few side effects (Bell et al., 1988; Bottiglieri & Hyland, 1994; Delle Chiaie et al., 2002; Kagan et al., 1990; Lipinski et al., 1984; Papakostas, 2009, 2010). Moreover, SAM administration in patients with depression and dementia, intravenously or orally, has shown that it crosses the blood-brain barrier, and as a result, it is detected at increased levels in the cerebrospinal fluid (Bottiglieri et al., 1990).

Impaired transmethylation potential in L-dopa-treated PD patients has been proposed (De Bonis et al., 2010). The authors argue that a possible global DNA hypomethylation in hyperhomocysteinemic PD patients could be responsible for a generalized gene expression dysregulation and for playing a role in the outcome of the pathology. In accordance with this, another study has shown improved cognitive function in PD patients with a higher SAM/SAH ratio and higher plasma vitamin B6 (Obeid et al., 2009). It is noteworthy that SAM treatment improved depression of PD patients in an open-label clinical trial (Di Rocco et al., 2000). In fact, vitamin dietary supplementation, including SAM, has been shown to be effective in patients with early and moderate stages of AD (Chan et al., 2008; Panza et al., 2009; Remington et al., 2009; Shea and Chan, 2008). Moreover, SAM supplementation also presented antioxidant properties in an AD animal model (Cavallaro et al., 2010). In line with this, oxidative stress is also present in early-stages of PD (Ferrer et al., 2010), which points up the benefits of SAM administration in this pathology as an adjunctive treatment.

8. Conclusions and proposals for future PD interventions

As mentioned in the introduction, it is noteworthy that inactivation of A2ARs enhances the affinity of D2Rs for dopamine, this being the probable mechanism underlying the prodopaminergic effect of A2ARs antagonists in several clinical trials with PD patients. In this chapter, we have examined the literature which, in combination with our studies based on ADORA2A transcriptional regulation, has led us to propose SAM treatment as an epigenetic tool to modulate the increased expression of A2ARs in PD.

It is obvious that SAM treatment presents a broad spectrum of gene targets, and not only tumor supressor genes. However, it has been reported that SAM treatment promotes a decrease in the growth of hepatocellular carcinoma cells and liver cancer in animal models, hypothesising the methylation and repression of oncogenic gene promoters by this drug (Cai et al., 1998; Pascale et al., 1992). However, the existence of several clinical trials with SAM and the reduced number of side-effects in its administration must be taken into account. Based on our studies, and bearing in mind the restrictive expression of A2ARs in the brain (mainly in 95% of striatal neurons), we postulate that SAM treatment would have a “specific” effect on A2ARs in the brain. This would be especially true in a cerebral region where it colocalizes with D2Rs, which in turn present reduced activity due to the low dopamine content in PD. Then, although SAM treatment would reduce the expression of hypomethylated genes, its effect on A2ARs might represent significant activation of D2Rs.

Thus, the possible beneficial role of SAM in these patients should be examined in randomized controlled studies, examining supplementation to L-dopa (allowing a reduction of its dose) and to A2ARs antagonists (such as istradefylline), or in triple administration with both current therapies.

9. Acknowledgements

We are very grateful to Dr. Sandra Pérez Buira, Dr. José Luis Albasanz, Guido Dentesano and Jesús Moreno for their contributions to the study of ADORA2A transcriptional regulation. We thank T. Yohannan for editorial help. The experimental work described in the present chapter was funded by grants from the Ministerio de Ciencia e Innovación, (PI05/1631, CP08/00095, BFU2008-00138), the European Union through the Marie-Curie Research Training Network PRAIRIES (Contract MRTN-CT-2006-035810), the Consejería de Educación y Ciencia (PCI08-0125), the Consejería de Sanidad-FISCAM (PI-2007/50 and G-2007-C/13) of the Junta de Comunidades de Castilla-La Mancha and the Fundació La Marató de TV3 (092330, 090331).


1 - J. L. Albasanz, A. Rodríguez, I. Ferrer, M. Martín, 2007 Up-regulation of adenosine A1 receptors in frontal cortex from Pick’s disease cases. The European journal of neuroscience, 26 12 35013508
2 - J. L. Albasanz, S. Perez, M. Barrachina, I. Ferrer, M. Martín, 2008 Up-regulation of adenosine receptors in the frontal cortex in Alzheimer’s disease. Brain pathology, 18 2 211219
3 - R. E. Amir, Veyver. I. B. Van den, M. Wan, C. Q. Tran, U. Francke, H. Y. Zoghbi, 1999 Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics, 23 2 185188
4 - E. Angulo, V. Casadó, J. Mallol, E. I. Canela, F. Viñals, I. Ferrer, C. Lluis, R. Franco, 2003 A1 adenosine receptors accumulate in neurodegenerative structures in Alzheimer disease and mediate both amyloid precursor protein processing and tau phosphorylation and translocation. Brain pathology, 13 4 440451
5 - E. Ballestar, M. Esteller, 2008 SnapShot: the human DNA methylome in health and disease. Cell, 135 6 11441144
6 - W. Bara-Jimenez, A. Sherzai, T. Dimitrova, A. Favit, F. Bibbiani, M. Gillespie, M. J. Morris, M. M. Mouradian, T. N. Chase, 2003 Adenosine A(2A) receptor antagonist treatment of Parkinson’s disease. Neurology, 61 3 293296
7 - K. M. Bell, L. Plon, W. E. Bunney, Jr , S. G. Potkin, 1988 S-adenosylmethionine treatment of depression: a controlled clinical trial. The American journal of psychiatry, 145 9 11101114
8 - P. Bonsi, D. Cuomo, B. Picconi, G. Sciamanna, A. Tscherter, M. Tolu, G. Bernardi, P. Calabresi, A. Pisani, 2007 Striatal metabotropic glutamate receptors as a target for pharmacotherapy in Parkinson’s disease. Amino acids, 32 2 189195
9 - T. Bottiglieri, P. Godfrey, T. Flynn, M. W. Carney, B. K. Toone, E. H. Reynolds, 1990 Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. Journal of neurology, neurosurgery, and psychiatry, 53 12 10961098
10 - T. Bottiglieri, K. Hyland, 1994 S-adenosylmethionine levels in psychiatric and neurological disorders: a review. Acta neurologica Scandinavica. Supplementum, 154 1926
11 - D. J. Brooks, M. Doder, S. Osman, S. K. Luthra, E. Hirani, S. Hume, H. Kase, J. Kilborn, S. Martindill, A. Mori, 2008 Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain. Synapse, 62 9 671681
12 - S. P. Buira, J. L. Albasanz, G. Dentesano, J. Moreno, M. Martín, I. Ferrer, M. Barrachina, 2010a DNA methylation regulates adenosine A(2A) receptor cell surface expression levels. Journal of neurochemistry, 112 5 12731285
13 - S. P. Buira, G. Dentesano, J. L. Albasanz, J. Moreno, M. Martín, I. Ferrer, M. Barrachina, 2010b DNA methylation and Yin Yang-1 repress adenosine A2A receptor levels in human brain. Journal of neurochemistry, 115 1 283295
14 - N. Cabello, J. Gandía, D. C. Bertarelli, M. Watanabe, C. Lluís, R. Franco, S. Ferré, R. Luján, F. Ciruela, 2009 Metabotropic glutamate type 5, dopamine D2 and adenosine A2a receptors form higher-order oligomers in living cells. Journal of neurochemistry, 109 5 14971507
15 - J. Cai, Z. Mao, J. J. Hwang, S. C. Lu, 1998 Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. Cancer research, 58 7 14441450
16 - F. Calon, M. Dridi, O. Hornykiewicz, P. J. Bédard, A. H. Rajput, T. Di Paolo, 2004 Increased adenosine A2A receptors in the brain of Parkinson’s disease patients with dyskinesias. CalonF.DridiM.HornykiewiczO.BédardP. J.RajputA. H.Di PaoloT. (2004). Increased adenosine A2A receptors in the brain of Parkinson’s disease patients with dyskinesias. Brain, Vol.127, No.Pt 5, pp. 1075-1084, 127 No.Pt 5, 10751084
17 - P. M. Canas, L. O. Porciúncula, G. M. Cunha, C. G. Silva, N. J. Machado, J. M. Oliveira, C. R. Oliveira, R. A. Cunha, 2009 Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. The Journal of neuroscience, 29 47 1474114751
18 - R. A. Cavallaro, A. Fuso, V. Nicolia, S. Scarpa, 2010 S-adenosylmethionine prevents oxidative stress and modulates glutathione metabolism in TgCRND8 mice fed a B-vitamin deficient diet. Journal of Alzheimer’s disease, 20 4 9971002
19 - M. D. Cerqueira, 2004 The future of pharmacologic stress: selective A2A adenosine receptor agonists. The American journal of cardiology, 94 2A 33D40D
20 - A. Chan, J. Paskavitz, R. Remington, S. Rasmussen, T. B. Shea, 2008 Efficacy of a vitamin/nutriceutical formulation for early-stage Alzheimer’s disease: a 1-year, open-label pilot study with a 16-month caregiver extension. American journal of Alzheimer’s disease and other dementias, 23 6 571585
21 - H. Cheng, C. Gomes-Trolin, S. M. Aquilonius, A. Steinberg, C. Löfberg, J. Ekblom, L. Oreland, 1997 Levels of L-methionine S-adenosyltransferase activity in erythrocytes and concentrations of S-adenosylmethionine and S-adenosylhomocysteine in whole blood of patients with Parkinson’s disease. Experimental neurology, 145 2Pt1 580585
22 - P. K. Chiang, R. K. Gordon, J. Tal, G. C. Zeng, B. P. Doctor, K. Pardhasaradhi, P. P. Mc Cann, 1996 S-Adenosylmethionine and methylation. The FASEB journal, 10 4 471480
23 - F. Ciruela, V. Casadó, R. J. Rodrigues, R. Luján, J. Burgueño, M. Canals, J. Borycz, N. Rebola, S. R. Goldberg, J. Mallol, A. Cortés, E. I. Canela, J. F. López-Giménez, G. Milligan, C. Lluis, R. A. Cunha, S. Ferré, R. Franco, 2006 Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. The Journal of neuroscience, 26 7 20802087
24 - F. Ciruela, M. Gómez-Soler, D. Guidolin, D. O. Borroto-Escuela, L. F. Agnati, K. Fuxe, V. Fernández-Dueñas, 2011 Adenosine receptor containing oligomers: Their role in the control of dopamine and glutamate neurotransmission in the brain. Biochimica et biophysica acta, 1808 5 12451255
25 - R. Coccurello, N. Breysse, M. Amalric, 2004 Simultaneous blockade of adenosine A2A and metabotropic glutamate mGlu5 receptors increase their efficacy in reversing Parkinsonian deficits in rats. Neuropsychopharmacology, 29 8 14511461
26 - R. A. Cunha, 2005 Neuroprotection by adenosine in the brain: From A(1) receptor activation to A (2A) receptor blockade. Purinergic signalling, 1 2 111134
27 - J. J. Day, J. D. Sweatt, 2010 DNA methylation and memory formation. Nature neuroscience, 13 11 13191323
28 - M. L. De Bonis, A. Tessitore, M. T. Pellecchia, K. Longo, A. Salvatore, A. Russo, D. Ingrosso, V. Zappia, P. Barone, P. Galletti, G. Tedeschi, 2010 Impaired transmethylation potential in Parkinson’s disease patients treated with L-Dopa. Neuroscience letters, 468 3 287291
29 - Chiaie. R. Delle, P. Pancheri, P. Scapicchio, 2002 Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. The American journal of clinical nutrition, 76 5 1172S1176S
30 - A. Di Rocco, J. D. Rogers, R. Brown, P. Werner, T. Bottiglieri, 2000 S-Adenosyl-Methionine improves depression in patients with Parkinson’s disease in an open-label clinical trial. Movement disorders, 15 6 12251229
31 - A. de Mendonça, A. M. Sebastião, J. A. Ribeiro, 2000 Adenosine: does it have a neuroprotective role after all? Brain research. Brain research reviews, 33 2-3 , 258274
32 - Santos. E. F. Dos, E. N. Busanello, A. Miglioranza, A. Zanatta, A. G. Barchak, C. R. Vargas, J. Saute, C. Rosa, M. J. Carrion, D. Camargo, A. Dalbem, Costa. J. C. da, Miguel. S. R. de Sousa, Rieder. C. R. de Mello, M. Wajner, 2009 Evidence that folic acid deficiency is a major determinant of hyperhomocysteinemia in Parkinson’s disease. Metabolic brain disease, 4 2 257269
33 - T. V. Dunwiddie, S. A. Masino, 2001 The role and regulation of adenosine in the central nervous system. Annual review of neuroscience, 24 3155
34 - O. El -Maarri, 2003 DNA methylation and human diseases. Advances in experimental medicine and biology, 544 135144
35 - M. El Yacoubi, J. Costentin, J. M. Vaugeois, 2003 Adenosine A2A receptors and depression. Neurology, 61 11 Suppl 6, S82S87
36 - S. Factor, M. H. Mark, R. Watts, L. Struck, A. Mori, R. Ballerini, N. M. Sussman, 600. Istradefylline, U. S-0, Group. Study, 2010 A long-term study of istradefylline in subjects with fluctuating Parkinson’s disease. Parkinsonism & related disorders, 16 6 423426
37 - H. H. Fernandez, D. R. Greeley, R. M. Zweig, J. Wojcieszek, A. Mori, N. M. Sussman, 600, U. S-0, Group. Study, 2010 Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism & related disorders, 16 1 1620
38 - S. Ferré, M. Karcz-Kubicha, B. T. Hope, P. Popoli, J. Burgueño, M. A. Gutiérrez, V. Casadó, K. Fuxe, S. R. Goldberg, C. Lluis, R. Franco, F. Ciruela, 2002 Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: implications for striatal neuronal function. Proceeding of the National Academy of Sciences of the United States of America, 99 18 1194011945
39 - S. Ferré, F. Ciruela, A. S. Woods, C. Lluis, R. Franco, 2007 Functional relevance of neurotransmitter receptor heteromers in the central nervous system. Trends in Neuroscience, 30 9 440446
40 - I. Ferrer, A. Martinez, R. Blanco, E. Dalfó, M. Carmona, 2010 Neuropathology of sporadic Parkinson disease before the appearance of parkinsonism: preclinical Parkinson disease. Journal of neural transmission, 2010 Sep 23. [Epub ahead of print]
41 - B. B. Fredholm, T. V. Dunwiddie, 1988 How does adenosine inhibit transmitter release? Trends in pharmacological sciences, 9 4 130134
42 - B. B. Fredholm, I. Jzerman, A. P. , K. A. Jacobson, K. N. Klotz, J. Linden, 2001 International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacological reviews, 53 4 527552
43 - H. A. Friedel, K. L. Goa, P. Benfield, 1989 S-adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs, 38 3 389416
44 - P. Frosst, H. J. Blom, R. Milos, P. Goyette, C. A. Sheppard, R. G. Matthews, G. J. Boers, Heijer. M. den, L. A. Kluijtmans, Heuvel. L. P. van den, et al. 1995 A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature genetics, 10 1 111113
45 - A. Fuso, L. Seminara, R. A. Cavallaro, F. D’Anselmi, S. Scarpa, 2005 S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Molecular and cellular neurosciences, 28 1 195204
46 - A. Fuso, V. Nicolia, R. A. Cavallaro, L. Ricceri, F. D’Anselmi, P. Coluccia, G. Calamandrei, S. Scarpa, 2008 B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-beta deposition in mice. Molecular and cellular neurosciences, 37 4 731746
47 - K. Fuxe, L. F. Agnati, K. Jacobsen, J. Hillion, M. Canals, M. Torvinen, B. Tinner-Staines, W. Staines, D. Rosin, A. Terasmaa, P. Popoli, G. Leo, V. Vergoni, C. Lluis, F. Ciruela, R. Franco, S. Ferré, 2003 Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson’s disease. Neurology, 61 11 S19S23
48 - R. A. Hauser, J. P. Hubble, D. D. Truong, U. Istradefylline, 001 Study Group. (2003). Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD. Neurology, 61 3 297303
49 - R. A. Hauser, L. M. Shulman, J. M. Trugman, J. W. Roberts, A. Mori, R. Ballerini, N. M. Sussman, 600. Istradefylline, U. S-0, Group. Study, 2008 Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Movement disorders, 23 15 21772185
50 - M. Herranz, M. Esteller, 2006 New therapeutic targets in cancer: the epigenetic connection. Clinical & translational oncology, 8 4 242249
51 - R. S. Illingworth, A. P. Bird, 2009 CpG islands--’a rough guide’. FEBS letters, 583 11 17131720
52 - P. A. Jones, 1999 The DNA methylation paradox. Trends in genetics, 15 1 3437
53 - B. L. Kagan, D. L. Sultzer, N. Rosenlicht, R. H. Gerner, 1990 Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. The American journal of psychiatry, 147 5 591595
54 - S. Kreth, C. Ledderose, I. Kaufmann, G. Groeger, M. Thiel, 2008 Differential expression of 5’-UTR splice variants of the adenosine A2A receptor gene in human granulocytes: identification, characterization, and functional impact on activation. The FASEB journal, 22 9 32763286
55 - C. Ladd-Acosta, J. Pevsner, S. Sabunciyan, R. H. Yolken, M. J. Webster, T. Dinkins, P. A. Callinan, J. B. Fan, J. B. Potash, A. P. Feinberg, 2007 DNA methylation signatures within the human brain. American journal of human genetics, 81 6 13041315
56 - F. Le , A. Townsend-Nicholson, E. Baker, G. R. Sutherland, P. R. Schofield, 1996 Characterization and chromosomal localization of the human A2a adenosine receptor gene: ADORA2A. Biochemical and biophysical research communications, 223 2 461467
57 - P. A. Lewitt, 2008a Levodopa for the treatment of Parkinson’s disease. The New England journal of medicine, 359 23 24682476
58 - P. A. Le Witt, M. Guttman, J. W. Tetrud, P. J. Tuite, A. Mori, P. Chaikin, N. M. Sussman, 600, U. S-0, Group. Study, 2008b Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Annals of neurology, 63 3 295302
59 - J. Linden, 2001 Molecular approach to adenosine receptors: receptor-mediated mechanisms of tissue protection. Annual review of pharmacology and toxicology, 41 775787
60 - M. Linnebank, J. Popp, Y. Smulders, D. Smith, A. Semmler, M. Farkas, L. Kulic, G. Cvetanovska, H. Blom, B. Stoffel-Wagner, H. Kölsch, M. Weller, F. Jessen, 2010 S-adenosylmethionine is decreased in the cerebrospinal fluid of patients with Alzheimer’s disease. Neuro-degenerative diseases, 7 6 373378
61 - J. F. Lipinski, B. M. Cohen, F. Frankenburg, M. Tohen, C. Waternaux, R. Altesman, B. Jones, P. Harris, 1984 Open trial of S-adenosylmethionine for treatment of depression. The American journal of psychiatry, 141 3 448450
62 - L. Liu, T. van Groen, I. Kadish, T. O. Tollefsbol, 2009 DNA methylation impacts on learning and memory in aging. Neurobiology of aging, 30 4 549560
63 - X. X. Liu, K. Wilson, C. G. Charlton, 2000 Effects of L-dopa treatment on methylation in mouse brain: implications for the side effects of L-dopa. Life sciences, 66 23 22772288
64 - S. C. Lu, 2000 S-Adenosylmethionine. The international journal of biochemistry & cell biology, 32 4 391395
65 - Collin. M. Mac, R. Peterfreund, Donald. M. Mac, J. S. Fink, J. Gusella, 1994 Mapping of a human A2a adenosine receptor (ADORA2) to chromosome 22. Genomics, 20 2 332333
66 - S. A. Masino, L. Diao, P. Illes, N. R. Zahniser, G. A. Larson, B. Johansson, B. B. Fredholm, T. V. Dunwiddie, 2002 Modulation of hippocampal glutamatergic transmission by ATP is dependent on adenosine a(1) receptors. The Journal of pharmacological and experimental therapeutics, 303 1 356363
67 - J. W. Miller, J. Selhub, M. R. Nadeau, C. A. Thomas, R. G. Feldman, P. A. Wolf, 2003 Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status. Neurology, 60 7 11251129
68 - Y. Mizuno, K. Hasegawa, T. Kondo, S. Kuno, M. Yamamoto, Istradefylline. Japanese, Group. Study, 2010 Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease: a randomized, controlled study. Movement disorders, 25 10 14371443
69 - M. S. Morris, 2003 Homocysteine and Alzheimer’s disease. Lancet neurology, 2 7 425428
70 - L. D. Morrison, D. D. Smith, S. J. Kish, 1996 Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease. Journal of neurochemistry, 67 3 13281331
71 - T. Müller, D. Woitalla, B. Hauptmann, B. Fowler, W. Kuhn, 2001 Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson’s disease. Neuroscience letters, 308 1 5456
72 - T. Müller, D. Woitalla, W. Kuhn, 2003 Benefit of folic acid supplementation in parkinsonian patients treated with levodopa. Journal of neurology, neurosurgery, and psychiatry, 74 4 549
73 - T. Müller, W. Kuhn, 2006 Tolcapone decreases plasma levels of S-adenosyl-L-homocysteine and homocysteine in treated Parkinson’s disease patients. European journal of clinical pharmacology, 62 6 447450
74 - T. Müller, W. Kuhn, 2009a Homocysteine levels after acute levodopa intake in patients with Parkinson’s disease. Movement disorders, 24 9 13391343
75 - T. Müller, S. Muhlack, 2009b Peripheral COMT inhibition prevents levodopa associated homocysteine increase. Journal of neural transmission, 116 10 12531256
76 - J. G. Nutt, 2008 Pharmacokinetics and pharmacodynamics of levodopa. Movement disorders, 23 3 S580S584
77 - R. Obeid, A. Schadt, U. Dillmann, P. Kostopoulos, K. Fassbender, W. Herrmann, 2009 Methylation status and neurodegenerative markers in Parkinson disease. Clinical chemistry, 55 10 18521860
78 - J. A. Obeso, C. W. Olanow, J. G. Nutt, 2000 Levodopa motor complications in Parkinson’s disease. Trends in neurosciences, 23 10 S2S7
79 - M. Orru, J. Bakešová, M. Brugarolas, C. Quiroz, V. Beaumont, S. R. Goldberg, C. Lluís, A. Cortés, R. Franco, V. Casadó, E. I. Canela, S. Ferré, 2011 Striatal pre- and post-synaptic profile of adenosine A(2A) receptor antagonists. PLoS One, 6 1 e16088
80 - P. E. O’Suilleabhain, V. Sung, C. Hernandez, L. Lacritz, R. B. Dewey, Jr , T. Bottiglieri, R. Diaz-Arrastia, 2004 Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive associations. Archives of neurology, 61 6 865868
81 - A. Ohta, M. Sitkovsky, 2001 Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature, 414 6866 916920
82 - F. Panza, V. Frisardi, C. Capurso, A. D’Introno, A. M. Colacicco, G. Vendemiale, A. Capurso, V. Solfrizzi, 2009 Possible role of S-adenosylmethionine, S-adenosylhomocysteine, and polyunsaturated fatty acids in predementia syndromes and Alzheimer’s disease. Journal of Alzheimer’s disease, 16 3 467470
83 - G. I. Papakostas, 2009 Evidence for S-adenosyl-L-methionine (SAM-e) for the treatment of major depressive disorder. The Journal of clinical psychiatry, 70 5 1822
84 - G. I. Papakostas, D. Mischoulon, I. Shyu, J. E. Alpert, M. Fava, 2010 S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. The American journal of psychiatry, 167 8 942948
85 - R. M. Pascale, V. Marras, M. M. Simile, L. Daino, G. Pinna, S. Bennati, M. Carta, M. A. Seddaiu, G. Massarelli, F. Feo, 1992 Chemoprevention of rat liver carcinogenesis by S-adenosyl-L-methionine: a long-term study. Cancer research, 52 18 49794986
86 - R. A. Peterfreund, Collin. M. Mac, J. Gusella, J. S. Fink, 1996 Characterization and expression of the human A2a adenosine receptor gene. Journal of neurochemistry, 66 1 362368
87 - A. Pinna, C. Corsi, A. R. Carta, V. Valentini, F. Pedata, M. Morelli, 2002 Modification of adenosine extracellular levels and adenosine A(2A) receptor mRNA by dopamine denervation. European journal of pharmacology, 446 1-3 , 7582
88 - S. Perez-Buira, M. Barrachina, A. Rodriguez, J. L. Albasanz, M. Martín, I. Ferrer, 2007 Expression levels of adenosine receptors in hippocampus and frontal cortex in argyrophilic grain disease. Neuroscience letters, 423 Vol.3, 194199
89 - A. Portela, M. Esteller, 2010 Epigenetic modifications and human disease. Nature biotechnology, 28 10 10571068
90 - P. Quadri, C. Fragiacomo, R. Pezzati, E. Zanda, G. Forloni, M. Tettamanti, U. Lucca, 2004 Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. The American journal of clinical nutrition, 80 1 114122
91 - C. Quiroz, R. Luján, M. Uchigashima, A. P. Simoes, T. N. Lerner, J. Borycz, A. Kachroo, P. M. Canas, M. Orru, M. A. Schwarzschild, D. L. Rosin, A. C. Kreitzer, R. A. Cunha, M. Watanabe, S. Ferré, 2009 Key modulatory role of presynaptic adenosine A2A receptors in cortical neurotransmission to the striatal direct pathway. ScientificWorldJournal, 9 13211344
92 - V. Ralevic, G. Burnstock, 1998 Receptors for purines and pyrimidines. Pharmacological reviews, 50 3 413492
93 - R. Remington, A. Chan, J. Paskavitz, T. B. Shea, 2009 Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage Alzheimer’s disease: a placebo-controlled pilot study. American journal of Alzheimer’s disease and other dementias, 24 1 2733
94 - J. A. Ribeiro, A. M. Sebastião, A. de Mendonça, 2002 Adenosine receptors in the nervous system: pathophysiological implications. Progress in neurobiology, 68 6 377392
95 - R. J. Rodrigues, T. M. Alfaro, N. Rebola, C. R. Oliveira, R. A. Cunha, 2005 Co-localization and functional interaction between adenosine A(2A) and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum. Journal of neurochemistry, 92 3 433441
96 - A. Rodríguez, M. Martín, J. L. Albasanz, M. Barrachina, J. C. Espinosa, J. M. Torres, I. Ferrer, 2006 Adenosine A1 receptor protein levels and activity is increased in the cerebral cortex in Creutzfeldt-Jakob disease and in bovine spongiform encephalopathy-infected bovine-PrP mice. Journal of neuropathology and experimental neurology, 65 10 964975
97 - S. Satoh, H. Matsumura, O. Hayaishi, 1998 Involvement of adenosine A2A receptor in sleep promotion. European journal of pharmacology, 351 2 155162
98 - S. Scarpa, A. Fuso, F. D’Anselmi, R. A. Cavallaro, 2003 Presenilin 1 gene silencing by S-adenosylmethionine: a treatment for Alzheimer disease? FEBS letters, 541 1-3 , 145148
99 - S. N. Schiffmann, F. Libert, G. Vassart, J. J. Vanderhaeghen, 1991 Distribution of adenosine A2 receptor mRNA in the human brain. Neuroscience letters, 130 2 177181
100 - S. N. Schiffmann, G. Fisone, R. Moresco, R. A. Cunha, S. Ferré, 2007 Adenosine A2A receptors and basal ganglia physiology. Progress in neurobiology, 83 5 277292
101 - A. M. Sebastião, J. A. Ribeiro, 1996 Adenosine A2 receptor-mediated excitatory actions on the nervous system. Progress in neurobiology, 48 3 167189
102 - S. Seshadri, A. Beiser, J. Selhub, P. F. Jacques, I. H. Rosenberg, R. B. D’Agostino, P. W. Wilson, P. A. Wolf, 2002 Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. The New England journal of medicine, 346 7 476483
103 - T. B. Shea, A. Chan, 2008 S-adenosyl methionine: a natural therapeutic agent effective against multiple hallmarks and risk factors associated with Alzheimer’s disease. Journal of Alzheimer’s disease, 13 1 6770
104 - K. D. Siegmund, C. M. Connor, M. Campan, T. I. Long, D. J. Weisenberger, D. Biniszkiewicz, R. Jaenisch, P. W. Laird, S. Akbarian, 2007 DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS One, 2 9 e895
105 - M. Stacy, D. Silver, T. Mendis, J. Sutton, A. Mori, P. Chaikin, N. M. Sussman, 2008 A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology, 70 23 22332240
106 - T. W. Stone, S. Ceruti, M. P. Abbracchio, 2009 Adenosine receptors and neurological disease: neuroprotection and neurodegeneration. Handbook of experimental pharmacology, 193 535587
107 - E. Tolosa, M. J. Martí, F. Valldeoriola, J. L. Molinuevo, 1998 History of levodopa and dopamine agonists in Parkinson’s disease treatment. Neurology, 50 6 Suppl 6, S2S10
108 - M. Tomiyama, T. Kimura, T. Maeda, H. Tanaka, K. Kannari, M. Baba, 2004 Upregulation of striatal adenosine A2A receptor mRNA in 6-hydroxydopamine-lesioned rats intermittently treated with L-DOPA. Synapse, 52 3 218222
109 - L. Tremolizzo, G. Carboni, W. B. Ruzicka, C. P. Mitchell, I. Sugaya, P. Tueting, R. Sharma, D. R. Grayson, E. Costa, A. Guidotti, 2002 An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proceeding of the National Academy of Sciences of the United States of America, 99 26 1709517100
110 - D. Van Calker, M. Müller, B. Hamprecht, 1979 Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells. Journal of neurochemistry, 33 5 9991005
111 - K. Varani, F. Vincenzi, A. Tosi, S. Gessi, I. Casetta, G. Granieri, P. Fazio, E. Leung, Lennan. S. Mac, E. Granieri, P. A. Borea, 2010 A2A adenosine receptor overexpression and functionality, as well as TNF-alpha levels, correlate with motor symptoms in Parkinson’s disease. The FASEB journal, 24 2 587598
112 - M. Veldic, H. J. Caruncho, W. S. Liu, J. Davis, R. Satta, D. R. Grayson, A. Guidotti, E. Costa, 2004 DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. Proceeding of the National Academy of Sciences of the United States of America, 101 1 348353
113 - M. Veldic, A. Guidotti, E. Maloku, J. M. Davis, E. Costa, 2005 In psychosis, cortical interneurons overexpress DNA-methyltransferase 1. Proceeding of the National Academy of Sciences of the United States of America, 102 6 21522157
114 - V. Vitvitsky, M. Thomas, A. Ghorpade, H. E. Gendelman, R. Banerjee, 2006 A functional transsulfuration pathway in the brain links to glutathione homeostasis. The Journal of biological chemistry, 281 47 3578535793
115 - S. C. Wang, B. Oelze, A. Schumacher, 2008 Age-specific epigenetic drift in late-onset Alzheimer’s disease. PLoS One, 3 7 e2698
116 - R. A. Waterland, R. L. Jirtle, 2003 Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Molecular and cellular biology, 23 15 52935300
117 - D. Woitalla, W. Kuhn, T. Müller, 2004 MTHFR C677T polymorphism, folic acid and hyperhomocysteinemia in levodopa treated patients with Parkinson’s disease. Journal of neural transmission, 68 1520
118 - K. Yasui, H. Kowa, K. Nakaso, T. Takeshima, K. Nakashima, 2000 Plasma homocysteine and MTHFR C677T genotype in levodopa-treated patients with PD. Neurology, 55 3 437440
119 - L. Yu, M. C. Frith, Y. Suzuki, R. A. Peterfreund, T. Gearan, S. Sugano, M. A. Schwarzschild, Z. Weng, J. S. Fink, J. F. Chen, 2004 Characterization of genomic organization of the adenosine A2A receptor gene by molecular and bioinformatics analyses. Brain research, 1000 1-2 , 156173
120 - S. Zoccolella, P. Lamberti, G. Iliceto, C. Dell’Aquila, C. Diroma, A. Fraddosio, S. V. Lamberti, E. Armenise, G. Defazio, M. de Mari, P. Livrea, 2006 Elevated plasma homocysteine levels in L-dopa-treated Parkinson’s disease patients with dyskinesias. Clinical chemistry and laboratory medicine, 44 7 863866
121 - S. Zoccolella, G. Iliceto, M. de Mari, P. Livrea, P. Lamberti, 2007 Management of L-Dopa related hyperhomocysteinemia: catechol-O-methyltransferase (COMT) inhibitors or B vitamins? Results from a review. Clinical chemistry and laboratory medicine, 45 12 16071613
122 - S. Zoccolella, C. dell’Aquila, G. Abruzzese, A. Antonini, U. Bonuccelli, M. Canesi, S. Cristina, R. Marchese, C. Pacchetti, R. Zagaglia, G. Logroscino, G. Defazio, P. Lamberti, P. Livrea, 2009 Hyperhomocysteinemia in levodopa-treated patients with Parkinson’s disease dementia. Movement disorders, 24 7 10281033
123 - S. Zoccolella, S. V. Lamberti, G. Iliceto, A. Santamato, P. Lamberti, G. Logroscino, 2010 Hyperhomocysteinemia in L-dopa treated patients with Parkinson’s disease: potential implications in cognitive dysfunction and dementia? Current medicinal chemistry, 17 28 32533261