Randomized trial of the adenosine A
            <sub>2A</sub>
            receptor antagonist istradefylline in advanced PD

Hauser, Robert A.; Hubble, Jean; Truong, Daniel

doi:10.1212/01.wnl.0000081227.84197.0b

Cited by 292 publications

(159 citation statements)

References 15 publications

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“…Moreover, on the basis of the apparent protective effect of coffee in PD, adenosine receptor (A 2A ) antagonists have also been tested and there is evidence that they improve parkinsonian symptoms in animal models [670] and clinical trials [671][672][673][674]. Lastly, the more recently indicated protective effect of uric acid, together with its ability to slow disease progression, has led to the initiation of a clinical trial of inosine, a precursor that increases uric acid levels.…”

Section: Comments and Perspectivesmentioning

confidence: 99%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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Section: Comments and Perspectivesmentioning

confidence: 99%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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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

207

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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“…Therefore, a treatment modulating the dopaminergic transmission yet targeting indirectly the dopaminergic receptors might represent a challenging therapeutic alternative. Adenosine A 2A receptor (A 2A ) antagonists provide anti-Parkinsonian benefit in nonhuman primate model of PD (Kanda et al, 1998;Grondin et al, 1999;Morelli and Wardas, 2001) and have recently been evaluated in patients with L-DOPA-treated PD (Hauser et al, 2003;Baja-Jimenez et al, 2003). In contrast to the widespread distribution of other adenosine receptor subtypes (A 1 , A 2B , and A 3 ), the A 2A receptor subtypes shows a quite specific localization in the basal ganglia largely restricted to the striatum (Svenningsson et al, 1999;Fredholm et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats

Coccurello

Breysse

Amalric

2004

Neuropsychopharmacol

118

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Recent evidence suggest that antagonism of adenosine A 2A receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A 2A and the glutamate subtype 5 metabotropic receptors (mGlu 5 ) synergistically stimulates DARPP-32 phosphorylation and c-fos expression in the striatum. This study therefore tested the effects of a joint blockade of these receptors to alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions in the striatum produced akinetic deficits in rats trained to release a lever after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A 2A and mGlu 5 receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP (1.5 mg/kg) separately or in combination reduced the increase of delayed responses and RTs induced by 6-OHDA lesions, while the same treatment had no effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and immediate recovery of akinesia, which was found to be more efficient than the separate blockade of these receptors. These results demonstrate that the combined inactivation of A 2A and mGlu 5 receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.

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Randomized trial of the adenosine A _2A receptor antagonist istradefylline in advanced PD

Abstract: Istradefylline was generally well tolerated and reduced "off" time as assessed by home diaries. Severity of dyskinesia was unchanged, but "on" time with dyskinesia increased.

Cited by 292 publications

References 15 publications

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

The adenosine kinase hypothesis of epileptogenesis

Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats

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Randomized trial of the adenosine A 2A receptor antagonist istradefylline in advanced PD

Abstract: Istradefylline was generally well tolerated and reduced "off" time as assessed by home diaries. Severity of dyskinesia was unchanged, but "on" time with dyskinesia increased.

Cited by 292 publications

References 15 publications

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

The adenosine kinase hypothesis of epileptogenesis

Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats

Contact Info

Product

Resources

About

Randomized trial of the adenosine A _2A receptor antagonist istradefylline in advanced PD