Adenosine A
            <sub>2A</sub>
            receptor antagonist treatment of Parkinson’s disease

Bara‐Jimenez, William; Sherzai, Ayesha; Dimitrova, Tzvetelina; Favit, Antonella; Bibbiani, Francesco; Gillespie, Marjorie; Morris, Michael J.; Mouradian, M. Maral; Chase, Thomas N.

doi:10.1212/01.wnl.0000073136.00548.d4

Cited by 318 publications

(166 citation statements)

References 20 publications

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“…The results obtained in animal models of Parkinson's disease strongly support the hypothesis that A 2A receptor antagonists could be useful for the symptomatic treatment of this disease (Ferré et al, 1992). Indeed, clinical trials show that A 2A antagonists potentiate L-DOPA therapy in Parkinson's disease (Bara-Jimenez et al, 2003;Hauser et al, 2003).…”

Section: Adenosine a 2a Receptors In The Ventral Striatum And The Acusupporting

confidence: 62%

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

Ferré

Diamond

Goldberg

et al. 2007

Progress in Neurobiology

127

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Adenosine A 2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A 2A receptor antagonists has shown a significant improvement of the effects of L-DOPA. The present review emphasizes the possible application of A 2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A 2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A 2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A 2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A 1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A 2A receptors. A 2A receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A 1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A 2A receptor knockout mice suggest that A 2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.

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Section: Adenosine a 2a Receptors In The Ventral Striatum And The Acusupporting

confidence: 62%

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

Ferré

Diamond

Goldberg

et al. 2007

Progress in Neurobiology

127

View full text Add to dashboard Cite

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“…Adenosine A2a receptor antagonists have been shown to be neuroprotective agents in animal models of parkinsonism (Shiozaki et al, 1999;Koga et al, 2000;Ikeda et al, 2002;Fink et al, 2004). Potential adverse effects on inflammation (Ohta and Sitkovsky, 2001;Thiel et al, 2005) and coronary artery vasoregulation (Belardinelli et al, 1998) have not limited their safe use in humans with Parkinson's disease (Bara-Jimenez et al, 2003;Kase et al, 2003). Seven transmembrane domain receptors (such as the adenosine A2a receptors) are the most common target of therapeutic drugs (Lefkowitz and Shenoy, 2005), raising the possibility that future agents may be developed that antagonize the pathway by which A2a receptors transactivate Trk receptors.…”

Section: Discussionmentioning

confidence: 99%

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

Mojsilovic-Petrovic¹,

Jeong²,

Crocker³

et al. 2006

J. Neurosci.

131

125

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The death of motor neurons in amyotrophic lateral sclerosis (ALS) is thought to result from the interaction of a variety of factors including excitotoxicity, accumulation of toxic proteins, and abnormal axonal transport. Previously, we found that the susceptibility of motor neurons to excitotoxic insults can be limited by inhibiting signals evoked by brain-derived neurotrophic factor (BDNF) activation of the receptor tyrosine kinase B (TrkB). Here we show that this can be achieved by direct kinase inhibition or by blockade of a transactivation pathway that uses adenosine A2a receptors and src-family kinases (SFKs). Downstream signaling cascades (such as mitogen-activated protein kinase and phosphatidylinositol-3 kinase) are inhibited by these blockers. In addition to protecting motor neurons from excitotoxic insult, these agents also prevent toxicity that follows from the expression of mutant proteins (G85R superoxide dismutase 1; G59S p150 glued ) that cause familial motor neuron disease. TrkB, adenosine A2a receptors, and SFKs associate into complexes in lipid raft and nonlipid raft membranes and the signaling from lipids rafts may be particularly important because their disruption by cholesterol depletion blocks the ability of BDNF to render motor neurons vulnerable to insult. The neuroprotective versatility of Trk antagonism suggests that it may have broad utility in the treatment of ALS patients.

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“…Eventually, the combination of adenosine-augmentation with A 2A R antagonism might be a preferable strategy for therapeutic intervention. In this regard, it needs to be mentioned that a safe A 2A R antagonist KW-6002 is available and already in phase III clinical trials in patients with advanced Parkinson's disease (Bara-Jimenez et al, 2003;Hauser et al, 2003).…”

Section: Adenosine a 2a Receptorsmentioning

confidence: 99%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

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Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the "ADK hypothesis of epileptogenesis": (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and -finally -to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis.

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Adenosine A _2A receptor antagonist treatment of Parkinson’s disease

Abstract: The results support the hypothesis that A(2A) receptor mechanisms contribute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder.

Cited by 318 publications

References 20 publications

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

The adenosine kinase hypothesis of epileptogenesis

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Adenosine A 2A receptor antagonist treatment of Parkinson’s disease

Abstract: The results support the hypothesis that A(2A) receptor mechanisms contribute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder.

Cited by 318 publications

References 20 publications

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

The adenosine kinase hypothesis of epileptogenesis

Contact Info

Product

Resources

About

Adenosine A _2A receptor antagonist treatment of Parkinson’s disease