CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Role of adenosine A2A receptors in Parkinson's disease

Summary

Parkinson’s disease (PD), a chronic progressive neurodegenerative disorder, is characterized by a massive dopaminergic neuron degeneration of the substantia nigra pars compacta (SNc) which results in severe motor disturbances that include muscular rigidity, bradykinesia, resting tremor and postural and gait abnormalities. The most effective treatment for parkinsonian patients is the replacement therapy with the dopamine precursor L-DOPA. L-DOPA chronic treatment, after a few years, leads to several side effects as “wearing-off”, “on-off” and dyskinesia. As a consequence, alternative therapeutic approaches to ameliorate PD symptoms without inducing motor complications and to counteract neurodegeneration are one of the main target of active research in PD.

Our research activity is aimed at evaluating symptomatic and neuroprotective potential of adenosine A2A antagonist drugs.

Some results

These studies have evidenced that stimulation of adenosine A2A receptors negatively influences dopamine-mediated motor responses in animal models of PD, whereas blockade of A2A receptors play a positive role in the symptomatic treatment of PD. In particular in PD model of unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, A2A receptor antagonists positively modulate motor responses induced by L-DOPA as well as D1 and D2 agonists. Moreover, in this PD model a chronic treatment with A2A antagonist plus a lower dose of L-DOPA showed a low dyskinetic potential as compared to L-DOPA alone.

In parallel, we have evaluated, by in vivo microdialysis, extracellular levels of dopamine and glutamate after caffeine (A1 and A2A antagonist) or selective A2A antagonist administration. More recently, we have showed that blockade of A2A receptors is effective in antagonizing specific motor deficit induced by dopamine neuron degeneration, such as initiation of movement and sensory-motor integration deficits, even without L-DOPA combined administration. On the basis of ours and other group studies positive clinical trials of A2A antagonists in Parkinsonian patients have been performed.

Publications

  • Pinna A, Tronci E, Schintu N, Simola N, Volpini R, Pontis S, Cristalli G, Morelli M (2010) A new ethyladenine antagonist of adenosine A(2A) receptors: behavioral and biochemical characterization as an antiparkinsonian drug. Neuropharmacology 58:613-23.
  • Pinna A (2009) Novel investigational adenosine A2A receptor antagonists for Parkinson's disease. Expert Opin Investig Drugs 18:1619-31.
  • Simola N, Morelli M, Pinna A (2008) Adenosine A2A receptor antagonists and Parkinson's disease: state of the art and future directions. Curr. Pharm. Des. 14:1475-89.
  • Pinna A, Pontis S, Borsini F, Morelli M (2007) Adenosine A2A receptor antagonists improve deficits in initiation of movement and sensory motor integration in the unilateral 6-hydroxydopamine rat model of Parkinson's disease. Synapse 61:606-14.
  • Tronci E, Simola N, Borsini F, Schintu N, Frau L, Carminati P, Morelli M (2007) Characterization of the antiparkinsonian effects of the new adenosine A2A receptor antagonist ST1535: acute and subchronic studies in rats. Eur. J. Pharmacol. 566:94-102.
  • Simola N, Fenu S, Baraldi PG, Tabrizi MA, Morelli M (2006) Involvement of globus pallidus in the antiparkinsonian effects of adenosine A(2A) receptor antagonists. Exp. Neurol. 202:255-7.
  • Pinna A, Wardas J, Simola N, Morelli M (2005) New therapies for the treatment of Parkinson's disease: adenosine A2A receptor antagonists. Life Sci. 77:3259-67.
  • Pinna A, Volpini R, Cristalli G, Morelli M (2005) New adenosine A2A receptor antagonists: actions on Parkinson's disease models. Eur. J. Pharmacol. 512:157-64.
  • Pinna A, Corsi C, Carta AR, Valentini V, Pedata F, Morelli M (2002) Modification of adenosine extracellular levels and adenosine A(2A) receptor mRNA by dopamine denervation. Eur. J. Pharmacol. 446:75-82.

Collaborations

  • Prof. Baraldi, Department of Pharmaceutical Sciences, University of Ferrara.
  • Dr. Franco Borsini, Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Pomezia (Rome).
  • Prof. Gloria Cristalli, Department of Chemical Sciences, University of Camerino.
  • Prof. Felicita Pedata, Department of Preclinical and Clinical Pharmacology, University of Florence.

 

PI photo

Annalisa Pinna

Contact information

email  E-mail

email  +39 070 6758662

Participating staff

Micaela Morelli

Anna R. Carta

Lucia Frau

Nicola Simola