Parkinson Disease: Agnati L

Fuxe K, Marcellino D, Genedani S, Agnati L. · Division of Cellular and Molecular Neurochemistry, Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden. · Mov Disord. · Pubmed #17618524 No free full text.

Abstract: Future therapies in Parkinson's disease may substantially build on the existence of intra-membrane receptor-receptor interactions in DA receptor containing heteromeric receptor complexes. The A(2A)/D(2) heteromer is of substantial interest in view of its specific location in cortico-striatal glutamate terminals and in striato-pallidal GABA neurons. Antagonistic A(2A)/D(2) receptor interactions in this heteromer demonstrated at the cellular level, and at the level of the striato-pallidal GABA neuron and at the network level made it possible to suggest A(2A) antagonists as anti-parkinsonian drugs. The major mechanism is an enhancement of D(2) signaling leading to attenuation of hypokinesia, tremor, and rigidity in models of Parkinson's disease with inspiring results in two clinical trials. Other interactions are antagonism at the level of the adenylyl cyclase; heterologous sensitization at the A(2A) activated adenylyl cyclase by persistent D(2) activation and a compensatory up-regulation of A(2A) receptors in response to intermittent Levodopa treatment. An increased dominance of A(2A) homomers over D(2) homomers and A(2A)/D(2) heteromers after intermittent Levodopa treatment may therefore contribute to development of Levodopa induced dyskinesias and to the wearing off of the therapeutic actions of Levodopa giving additional therapeutic roles of A(2A) antagonists. Their neuroprotective actions may involve an increase in the retrograde trophic signaling in the nigro-striatal DA system.

Schwarzschild MA, Agnati L, Fuxe K, Chen JF, Morelli M. · MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA 02129, USA. · Trends Neurosci. · Pubmed #17030429 No free full text.

Abstract: The adenosine A2A receptor has emerged as an attractive non-dopaminergic target in the pursuit of improved therapy for Parkinson's disease (PD), based in part on its unique CNS distribution. It is highly enriched in striatopallidal neurons and can form functional heteromeric complexes with other G-protein-coupled receptors, including dopamine D2, metabotropic glutamate mGlu5 and adenosine A1 receptors. Blockade of the adenosine A2A receptor in striatopallidal neurons reduces postsynaptic effects of dopamine depletion, and in turn lessens the motor deficits of PD. A2A antagonists might partially improve not only the symptoms of PD but also its course, by slowing the underlying neurodegeneration and reducing the maladaptive neuroplasticity that complicates standard 'dopamine replacement' treatments. Thus, we review here a prime example of translational neuroscience, through which antagonism of A2A receptors has now entered the arena of clinical trials with realistic prospects for advancing PD therapeutics.

Fuxe K, Manger P, Genedani S, Agnati L. · Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. · J Neural Transm Suppl. · Pubmed #17017512 No free full text.

Abstract: The discovery of the nigrostriatal DA system in the rat was made possible by the highly specific and sensitive histochemical fluorescence method of Falck and Hillarp in combinations with electrolytic lesions in the substantia nigra and removal of major parts of the neostriatum. Recent work on DA neuron evolution shows that in the Bottlenose Dolphin the normal DA cell groups of the substantia nigra are very cell sparse, while there is a substantial expansion of the A9 medial and A10 lateral subdivisions forming an impressive "ventral wing" in the posterior substantia nigra. The nigrostriatal DA pathway mainly operates via Volume Transmission. Thus, DA diffuses along concentration gradients in the ECF to reach target cells with high affinity DA receptors. A novel feature of the DA receptor subtypes is their physical interaction in the plasma membrane of striatal neurons forming receptor mosaics (RM) with the existence of two types of RM. The "functional decoding unit" for DA is not the single receptor, but rather the RM that may affect not only the integration of signals in the DA neurons but also their trophic conditions. In 1991 A2A receptor antagonists were indicated to represent novel antiparkinsonian drugs based on the existence of A2A/D2 receptor-receptor interactions and here P2X receptor antagonists are postulated to be neuroprotective drugs in treatment of Parkinson's Disease.

Antonelli T, Fuxe K, Agnati L, Mazzoni E, Tanganelli S, Tomasini MC, Ferraro L. · Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, 44100 Ferrara, Italy. · J Neurol Sci. · Pubmed #16765381 No free full text.

Abstract: Dual probe microdialysis was used to study A2A/D2 receptor interactions in the striato-pallidal GABA pathway in a model of Parkinson's Disease. The A2A agonist CGS21680 and/or the D2-like agonist quinpirole were perfused via reverse microdialysis into the DA denervated striatum and the effects on globus pallidus (GP) extracellular GABA levels were evaluated. CGS21680 alone produced in the DA denervated striatum a transient rise of GP GABA levels. Quinpirole perfused alone into the DA denervated striatum reduced GP GABA levels, which was not only counteracted by coperfused CGS21680, but led to an enhancement of the GABA levels, which was larger than that seen with CGS21680 alone. These results may reflect existence not only of antagonistic A2A/D2 interactions but also of the appearance of D2/A2A interactions increasing the A2A signaling at the level of the adenylate cyclase. Such actions diminish the therapeutic efficacy of L-dopa and D2 agonists. L-dopa induced dyskinesias could be caused by changes in the balance of A2A/D2 heteromers vs A2A homomers expressed at the surface membrane, where A2A homomers dominate with abnormal increases in A2A signaling. This may lead to stabilization of abnormal receptor mosaics (high order hetero-oligomers) leading to formation of abnormal motor programs contributing to dyskinesia development.