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Neurotoxicity Research

, Volume 3, Issue 6, pp 545–556 | Cite as

Adenosine A2A receptor antagonists: Potential therapeutic and neuroprotective effects in parkinson’s disease

  • M. Morelli
  • J. Wardas
Article

Abstract

The most effective treatment of Parkinson’s disease (PD) is, at present, the dopamine precursor L-3,4-dihydroxyphenyl-alanine (L-DOPA), however a number of disadvantages such as a loss of drug efficacy and severe side-effects (psychoses, dyskinesias and on-off phenomena) limit long-term, effective utilisation of this drug. Recent experimental studies in which selective antagonists of adenosine A2A receptors were used, have shown an improvement in motor disabilities in animal models of PD. The A2A antagonist [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-(4, 3-e)-l,2,4-triazolo(l,5-c)pyrimidine] (SCH 58261) potentiated the contralateral turning behavior induced by a threshold dose of L-DOPA or direct dopamine receptor agonists in unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, an effect accompanied by an increase in Foslike-immunoreactivity in neurons of the lesioned striatum. Likewise, other A2A receptor antagonists such as (3,7-dimethyl-1-propargylxanthine) (DMPX), [E-8-(3,4-dimethoxystyryl)-1,3-dipropy1-7-methylxan-thine] (KF 17837) and [E-1,3-diety1-8(3,4-dimethox-ystyry1-7-methy1-3,7-dhydro-1H-purine-2,6-dione] (KW 6002) antagonized catalepsy induced by haloperidol or reserpine in the rat, whereas in non-human primate models of PD, KW 6002 reduced the rigidity and improved the disability score of MPTP-treated marmosets and cynomolgus monkeys. Moreover, in contrast to L-DOPA, selective A2A receptor antagonists administered chronically did not produce dyskinesias and did not evoke tolerance in 6-OHDA and MPTP models of PD. An additional therapeutic potential of adenosine A2A antagonists emerged from studies showing neuroprotective properties of these compounds in animal models of cerebral ischemia and excitotoxicity, as well as in the (1-methy1-4-pheny1-1,2,3,6-tetrahydropyridine) (MPTP) model of PD. Adenosine A2A receptor antagonists by reversing motor impairments in animal models of PD and by contrasting cell degeneration are some of the most promising compounds for the treatment of PD.

Keywords

Parkinson’s disease adenosine A2A receptor antagonists neuroprotection dopamine D1 and D2 receptors turning behavior dyskinesia striatum 

Abbreviations

AC

adenylate cyclase

AD

adenosine

cAMP

cyclic adenosine monophosphate

CGS 15943

5-amino-9-chloro-2-(2-furyl)-l,2,4-triazolo[1,5-c]quinazoline

CGS 21680

2-[4-(2-carbonyl-ethyl)-phenethylammo]-5′-N-ethyl-carboxamidoadenosine

CP

caudate-putamen

CP 66713

4-amino-l-phenyl-[l,2,4]-triazolo[4,3-a]quinoxaline

CSC

8-(3-chlorostyryl)caffeine

DA

dopamine

DMPX

3,7-dimethyl-l-propargylxanthine

DYN

dynorphin

ENK

enkephalin

GABA

γ-aminobutyric acid

Glu

glutamic acid

GP

globus pallidus

2-HE-NECA

2-hexyl-5′-N-ethylcarbox-amidoadenosine

KF17837

(E)-l,3-dipropyl-8-(3,4-dimethox-ystyryl)-7-methyl-3,7-dihydro-lH-purine-2,6-dione

KW 6002

(E)-l,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-lH-purine-2,6-dione

L-DOPA

L-3,4-dihydroxy-phenylalanine

MPTP

l-methyl-4-phenyl-l,2,3,6-tetrahydro-pyridine

6-OHDA

6-hydroxydopamine

PD

Parkinson’s disease

SCH 58261

5-amino-7-(2-phenylethyl-2-(2-furyl)-pyrazolo[4,3-e]-l,2,4-triazolo[l,5-c ]pyrimidine

SNr

substantia nigra pars reticulata

SP

substance P

STN

subthalamic nucleus

Th

thalamus

ZM 241385

4-(2-[7-amino-2-(2-furyl)l,2,4-triazolo[2,3-a][l,3,5]triazin-5-ylamino]ethylphenol

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© Springer 2001

Authors and Affiliations

  1. 1.Department of ToxicologyUniversity of Cagliari, Palazzo delle ScienzeCagliariItaly
  2. 2.Department of Neuropsychopharmacology, Institute of PharmacologyPolish Academy of SciencesKrakowPoland

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