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Adenosine A2A Receptors and Parkinson’s Disease

  • Micaela Morelli
  • Anna R. Carta
  • Peter Jenner
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 193)

Abstract

The drug treatment of Parkinson’s disease (PD) is accompanied by a loss of drug efficacy, the onset of motor complications, lack of effect on non-motor symptoms, and a failure to modify disease progression. As a consequence, novel approaches to therapy are sought, and adenosine A2A receptors (A2AARs) provide a viable target. A2AARs are highly localized to the basal ganglia and specifically to the indirect output pathway, which is highly important in the control of voluntary movement. A2AAR antagonists can modulate γ-aminobutyric acid (GABA) and glutamate release in basal ganglia and other key neurotransmitters that modulate motor activity. In both rodent and primate models of PD, A2AAR antagonists produce alterations in motor behavior, either alone or in combination with dopaminergic drugs, which suggest that they will be effective in the symptomatic treatment of PD. In clinical trials, the A2AAR antagonist istradefylline reduces “off” time in patients with PD receiving optimal dopaminergic therapy. However, these effects have proven difficult to demonstrate on a consistent basis, and further clinical trials are required to establish the clinical utility of this drug class. Based on preclinical studies, A2AAR antagonists may also be neuroprotective and have utility in the treatment of neuropsychiatric disorders. We are only now starting to explore the range of potential uses of A2AAR antagonists in central nervous system disorders, and their full utility is still to be uncovered.

Keywords

A2A antagonist Clinical trial Dyskinesia Motor dysfunction Basal ganglia MPTP 6-OHDA Neuroprotection 

Abbreviations

AIMs

Abnormal involuntary movements

A2AAR

Adenosine A2A receptor

AUC

Area under the curve

AMPA

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BG

Basal ganglia

COMT

Catechol-O-methyl transferase

CPu

Caudate-putamen

CGI

Clinical global impression

DA

Dopamine

DYN

Dynorphin

ENK

Enkephalin

GABA

γ-Aminobutyric acid

GAD67

Glutamic acid decarboxylase

GP

Globus pallidus

GPe

Globus pallidus, external segment

GPi

Globus pallidus, internal segment

5-HT

5-Hydroxytryptamine

LOCF

Last observation carried forward

KO

Knockout

l-DOPA

3,4-Dihydroxy-l-phenylalanine

LTP/LDP

Long-term potentiation/long-term depression

mGlu5

Metabotropic glutamate subtype 5

MAO B

Monoamine oxidase B

6-OHDA

6-Hydroxydopamine

MPTP

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

PD

Parkinson’s disease

STN

Subthalamus

SNr

Substantia nigra pars reticulata

TJM

Tremulous jaw movement

UPDRS

Unified Parkinson’s disease rating scale

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Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Department of Toxicology and Center of Excellence for Neurobiology of AddictionUniversity of CagliariCagliariItaly
  2. 2.Neurodegenerative Diseases Research CentreSchool of Health and Biomedical SciencesLondonUK

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