1 / 41

Adenosine A2A receptors and Parkinson’s disease

Adenosine A2A receptors and Parkinson’s disease. Institute of Pharmacology and Neurosciences, Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Portugal anaseb@fm.ul.pt. Catania Summer School July 2007. Parkinson’s disease is a basal ganglia disease.

adair
Download Presentation

Adenosine A2A receptors and Parkinson’s disease

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Adenosine A2A receptors and Parkinson’s disease Institute of Pharmacology and Neurosciences, Faculty of Medicine and Institute of Molecular Medicine, University of Lisbon, Portugal anaseb@fm.ul.pt Catania Summer School July 2007

  2. Parkinson’s disease is a basal ganglia disease http://stemcells.nih.gov/StaticResources/info/scireport/images/figure82.jpg

  3. A2A receptors are predominantly located in the striatum From: Schwarzschild MA, Agnati L, Fuxe K, Chen JF, Morelli M. Trends Neurosci. 2006, 29:647-54. Why the interest in adenosine receptors?

  4. s R A2A co-activated A1 - Neuronal communication - + A2A But not only… Adenosine A1 and A2A receptors in the hippocampus Total Non-Spec. A2A mRNA A1 A2A receptor A1 Cunha, Johansson, der Ploeg, Sebastião, Ribeiro & Fredholm (1994) Brain Res, 649, 208-216

  5. Adenosine receptor distribution in the CNS Hippocampus Thalamus Neocortex Olfactory bulb A1 A2A Cerebellum A1 A2A A2A A3 A1 A2A A2A A1 A1 A2A A1 A1 A3 Amygdala Nucleus tractus solitarius A1 Striatumpallidal GABAergic neurons (caudate-putamen, nucleus accumbens, tuberculum olfactorium) A1 A2A A1 Substantia nigra Spinal cord (dorsal horn) Ribeiro, Sebastião & deMendonça (2003), Prog Neurobiol. 68, 377-392

  6. A1 receptor Inhibitory  q A2A receptor  Excitatory Cell localization in the brain axon glia e.g. astrocyte Pre- A1 A1 A2A A2A Post- A2A A1 Sebastião & Ribeiro, 1996, Prog Neurobiol,48,167-189 Adenosine receptors are GPCR Gi/o  A1 i/o  High affinity A2A Gs  s  A2B Low affinity Gq? Low affinity in rats High affinity in humans A3

  7. Why such interest in adenosine?

  8. 8004 men whose intake was determined in 1965 and who were followed up over 30 years ATP Highly consumed adenosine receptor antagonists S-adenosil-homocisteine ATP ADP 1 adenosine AMP 3 ATP 2 homocisteine inosine 4 R 5 R 6 9 10 inosine 7, 8 ATP Honolulu Heart Programme ADP AMP adenosine Adenosine ADENOSINE AND ATP ARE PRESENT IN ALL CELLS (metabolic functions) ADENOSINE AND ATP ARE RELEASED BY THE CELLS ADENOSINE AND ATP ACT EXTRACELLULARLY TO MODULATE CELL ACTIVITY

  9. Where are the A2A receptors in the striatum? Predominantly R: Predominantly in the medium spiny GABAergic neurones of the indirect pathway From: Ferré, Fredholm, Morelli, Popoli and Fuxe, 1997, 20, 482-487

  10. An action particularly relevant when dopaminergic tonus is decreased (i.e. Low D2 inhibition of A2A) From: Schwarzschild MA, Agnati L, Fuxe K, Chen JF, Morelli M. Trends Neurosci. 2006, 29:647-54. From: Ferré, Fredholm, Morelli, Popoli and Fuxe, 1997, 20, 482-487 Postsynaptic A2A receptors in medium spiny GABAergic neurones Inhibition of inhibitory dopamine D2 receptors

  11. A2AR and Parkinson’s disease Trends Neurosci. 2006 Nov;29(11):647-54. Targeting adenosine A2A receptors in Parkinson's disease. Schwarzschild MA, Agnati L, Fuxe K, Chen JF, Morelli M.

  12. Presynaptic A2A receptors in dopaminergic nerve terminals

  13. A2A receptors are absent from dopaminergic nerve terminals A bit of history.... Effects of adenosine A1 and A2 receptor activation on electrically evoked dopamine and acetylcholine release from rat striatal slices. Jin S, Johansson B, Fredholm BB J Pharmacol Exp Ther. 1993 Nov;267(2):801-8 ‘CGS 21680 (an A2A receptor agonist) never caused any stimulation of DA release’

  14. A2AR TyrOH merged But… Domaminergic terminals are endowed with adenosine A2A receptors Isolated nerve endings of the striatum Hypothesis: A2A receptors in striatal nerve terminals have other roles rather than modulating DA release Gomes et al., in preparation

  15. cAMP Adenosine A2A receptors as fine tuners of neuronal signalling Sebastião & Ribeiro (2000) Trends Pharmacol Sci. 21, 341-346 Do A2A receptors modulate actions of receptors for neurotrophic factors in dopaminergic nerve terminals?

  16. GDNF, a promising neurotrophic factor for Parkinson’s disease Ann Neurol. 2005, 57:298-302. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P, Gill SS. Nat Med. 2005, 11:703-4. Glial cell line-derived neurotrophic factor induces neuronal sprouting in human brain. Love S, Plaha P, Patel NK, Hotton GR, Brooks DJ, Gill SS. Do A2A receptors in dopaminergic nerve terminals modulate GDNF actions?

  17. GDNF enhances dopamine release from isolated nerve endings (synaptosomes) GDNF enhances dopamine release from striatal slices

  18. The facilitation of dopamine release by GDNF Is fully abolished upon adenosone A2A receptor blockade Is facilitated by adenosine A2A receptor activation A2AR activated A2AR activated A2AR blocked A2AR blocked Striatal slices (with GABAergic blockade) Isolated striatal nerve endings Gomes, Vaz, Ribeiro & Sebastião, Brain Research, 2006, 1113: 129-136

  19. Morphological evidence? 1. Are there GDNF receptors in nerve endings in the striatum? 2. Do GDNF and A2A receptors co-localize in the striatum? 3. Do they co-localize with dopaminergic markers?

  20. The GDNF receptor complex

  21. Ret Syn merged GFR1 Syn merged The GDNF receptor co-localizes with presynaptic markers

  22. Ret TyrOH GFR1 TyrOH GFR1 TyrOH merged merged The GDNF receptor co-localizes with dopaminergic markers

  23. A2AR TyrOH Ret merged merged A2AR GFR1 TyrOH A few dopaminergic terminals possess both A2A and GDNF receptors

  24. Are GDNF receptors in other nerve terminals in the striatum?

  25. merged vGluT 1/2 Ret merged vGAT Ret Ret merged vAChT GFR1 VGLUT 1/2 merged GFR1 merged VGAT GFR1 merged vAchT GDNF receptors are also abundant in glutamatergic nerve terminals

  26. GDNF receptors are predominantly located in dopaminergic and glutamatergic nerve terminals in striatum • GDNF enhances dopamine release Role of GDNF upon glutamate release?

  27. GDNF enhances glutamate release in the striatum only when A2A receptors are activated

  28. Dopamine Glutamate

  29. s R BDNF deficits have been implicated in several neurodegenerative diseases • Eur J Neurosci. 2006 Feb;23(3):649-58. • Reduced expression of the TrkB receptor in Huntington's disease mouse models and in human brain. • Gines S, Bosch M, Marco S, Gavalda N, Diaz-Hernandez M, Lucas JJ, Canals JM, Alberch J. • .Departament de Biologia Cel.lular i Anatomia Patologica, Facultat de Medicina, Universitat de Barcelona, Casanova 143, E-08036 Barcelona, Spain. Pharmacogenomics J. 2006 Jan-Feb;6(1):8-15 The expanding role of BDNF: a therapeutic target for Alzheimer's disease? Fumagalli F, Racagni G, Riva MA. Department of Pharmacological Sciences, Center of Neuropharmacology, University of Milan, Milan, Italy What about other neurotrophic factors?

  30. s R ADO AK ADO AMP ITU A2A receptors blocked (ZM241385) Endogenously released ADO is able to trigger a BDNF action Diógenes et al.,2004 - J Neurosci, 24, 2905-2913

  31. s With PKA blocked Post-synaptic cAMP does not trigger BDNF action cAMP Mechanism? Cyclic AMP/PKA is required to trigger BDNF action

  32. survival Fast signalling differentiation BDNF signalling through trkB receptors Adapted from Lee et al (2002) Cytokine Growth Factor Rev, 13, 11

  33. The enhancement of NMT caused by CGS 21680 requires PKA but not PLC activity PLC inhibitor PLC inhibitor PKA inhibitor 140 PKA inhibitor * 120 caused by BDNF % Change of EPP amplitude ** ** 100 ** 80 - + + + + CGS 21680 (10nM) - ZM 241385 (50nM) - + - - H - 89 (1µM) - - - - + U73122 (5µM) - - - + - A2A receptors triggering of a BDNF action by A2A receptors: mechanism The enhancement of NMT caused by BDNF in the presence of CGS 21680 requires PKA and PLC activity Pousinha, Diógenes, Ribeiro & Sebastião, 2006 – Neurosc Letts, in the press

  34. P (+) PLCγ (+) PKA Adenosine A2A receptors trigger a BDNF action on nerve terminals Proposed mechanism Trk B ATP ACh ADO ACh ATP A2A BDNF ADO Na+ K+ end plate potential Skeletal muscle fiber

  35. ACh (-) Ch d a b c e SP SP SR SR SLM SLM (+) Inhibition by BDNF requires tonic activation of adenosine A2A receptors BDNF actions on cholinergic currents? Catarina Fernandes António Pinto Duarte

  36. Switch off : Switch on: Libertação do NT Transportadores para NT Resposta eléctrica Acção do NT Receptores 8’ 8

  37. BDNF and adenosine transport in astrocytes BDNF enhances GABA transport BDNF enhances adenosine transport BDNF BDNF *** BDNF with A2A-R blocked *** BDNF with A2A-R blocked % [3H]uridine uptake BDNF (5 min) CGS (15 min) SCH (20 min) K252a (20 min) - - - - + - - - + + - - + - + - + - - + BDNF and GABA transport in astrocytes The facilitation by BDNF requires tonic A2A receptor activation

  38. A2A receptors Trigger or facilitate neurotrophin actions on neurotransmitter release and fast excitatory synaptic transmission on Prevent neurotrophin actions on neurotransmitter release and fast excitatory synaptic transmission off Adenosine A2A receptors as ‘trophic’ receptors? Consequences of their blockade in chronic neurodegenerative diseases suchas as PD?

  39. Work (slightly) in advanced cases of PD Reduction of dyskinesias when paired with a low dose of L-DOPA Bara-Jiminez et al., Neurology, 61, 293-296, 2003; Hauser et al., Neurology, 61, 297-303, 2003. A2A receptor antagonists and PD Good reasons to use: - To decrease the glutamatergic output of the indirect pathway • Work nicely in lesion animal models of PD Good reasons not to use them (at least at early stages of PD): - May prevent the pro-survival action of neurotrophic factors Early stages of PD: A2AR enhancers + ADO release enhancers + mGluR3 agonists (+ mGluR5 antagonists)?

  40. Further issues to think about... • Lower incidence of PD in humans with chronic caffeíne intake (Honolulu study) • Chronic consumption of adenosine receptor antagonists (caffeine) causes up regulation of adenosine receptors The lower incidence of PD in caffeine consumers must be attributed to: upregulation of A2AR or blockade of A2AR?

More Related