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Symptomatic and Neuroprotective Effects of A2A Receptor Antagonists in Parkinson’s Disease

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Adenosine

Abstract

The motor symptoms of Parkinson’s disease (PD) are due primarily to the degeneration of the dopaminergic nigrostriatal pathway; however other neurotransmitters besides dopamine are affected in the disease. Treatment of PD is largely unsatisfactory due to several side effects such as “on/off,” “wearing-off,” and dyskinesia, associated with dopaminergic chronic therapy. Therefore, new pharmacological approaches based on non-dopaminergic therapy have been recently called for a broadening of therapeutic options beyond traditional dopaminergic drugs. Adenosine A2A receptors have a selective localization in richly dopamine-innervated areas and A2A receptor antagonists can regulate GABA and glutamate release in basal ganglia offering a unique opportunity to modulate basal ganglia functions mediated by dopamine. Indeed, A2A receptor antagonists have been shown to restore motor function and contrast parkinsonian tremor acutely, either alone or in combination with dopaminergic drugs, in experimental models of PD. Moreover, in clinical trials, adenosine A2A receptor antagonists reduce “off” time in patients with PD receiving optimal dopaminergic therapy without the exacerbation of dyskinesia. In addition preclinical data have shown that adenosine A2A receptor antagonists help to prevent neurodegeneration in PD, raising the possibility of their use as disease-modifying agents. With their proposed symptomatic and neuroprotective efficacy, A2A receptor antagonists might be realistic prospects to advance PD therapeutics.

Annalisa Pinna and Nicola Simola have contributed equally to this work.

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Abbreviations

A2AR:

A2A receptors

AMP:

Adenosine monophosphate

ATP:

Adenosine triphosphate

CPu:

Caudate–putamen

CSF:

Cerebrospinal fluid

DDS:

Dopamine-dysregulation syndrome

FDA:

Food and drug administration

GAD67:

Glutamic acid decarboxylase 67

GP:

Globus pallidus

6-OHDA:

6-hydroxydopamine

l-DOPA:

Levo-DOPA

MDMA:

3,4-methylenedioxymethamphetamine

mGlu5:

Metabotropic glutamate receptor 5

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PD:

Parkinson’s disease

PET:

Positron emission tomography

SNr:

Substantia nigra pars reticulata

TJMs:

Tremulous jaw movements

VEGF:

Vascular endothelial growth factor

UPDRS:

Unified PD Rating Scale

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Authors and Affiliations

  1. Department of Biomedical Sciences - Toxicology, University of Cagliari, Via Ospedale, 72, Cagliari, 09124, Italy

    Annalisa Pinna, Nicola Simola, Lucia Frau & Micaela Morelli

  2. CNR, Institute of Neuroscience, Cagliari, Italy

    Annalisa Pinna & Micaela Morelli

  3. Centre of Excellence for Neurobiology of Dependence, University of Cagliari, Cagliari, Italy

    Micaela Morelli

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  1. Annalisa Pinna
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  2. Nicola Simola
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  3. Lucia Frau
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  4. Micaela Morelli
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Correspondence to Micaela Morelli .

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  1. Trinity College, 300 Summit Street, LSC 208, Hartford, 06106, USA

    Susan Masino

  2. Legacy Research Institute, Portland, OR,, 1225 NE 2nd Avenue, Portland, 97232, USA

    Detlev Boison

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Pinna, A., Simola, N., Frau, L., Morelli, M. (2013). Symptomatic and Neuroprotective Effects of A2A Receptor Antagonists in Parkinson’s Disease. In: Masino, S., Boison, D. (eds) Adenosine. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3903-5_18

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