Purinergic receptors, cytotoxicity and neurodegeneration
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1
University of Coimbra, Center for Neuroscience of Coimbra, Faculty of Medicine, Portugal
Adenosine is a ubiquitous neuromodulator, i.e. it does not directly trigger neuronal responses but it effectively controls the efficiency of synaptic transmission. Adenosine mainly controls excitatory transmission through the activation of widespread inhibitory A1 receptors (A1Rs) and synaptically located facilitatory A2ARs. ATP is also released in the nervous system where it fulfils a variety of roles that range from neurotransmission, neuromodulation and communication between neurons and astrocytes and astrocytes and microglia. Since stimuli triggering neurodegeneration persistently increase extracellular adenosine and ATP, we explored how they control neurodegeneration.
Pharmacological or genetic A2A receptor (A2AR) blockade abrogated kainate-induced hippocampal gliosis and neurotoxicity, which might result from combined control of glutamate release and neuroinflammation. Chronic caffeine and A2AR (but not A1R) blockade also prevented β-amyloid peptides (Aβ)-induced neurotoxicity and memory loss, possibly through direct neuronal action since it was reproduced in cultured neurons and there was no evident Aβ-induced neuroinflammation. Chronic caffeine also abrogated memory deficits and synaptotoxicity caused by diabetes and chronic stress (as A2AR blockade). Whereas A2ARs seem to play a deleterious role as executioners of synaptotoxicity that precedes overt neurodegeneration and amplifiers of neurodegeneration through neuroinflammation control, A1Rs seem to act as an initial hurl to initiate neurodegeneration, as shown by their key role in preconditioning whereby restraint stress prevented subsequent kainate- or ischemia-induced toxicity. ATP also controls neurotoxicity since P2Y1R antagonists (or siRNA) prevented glutamate- or Aβ-induced synaptotoxicity and memory impairment.
It is concluded that ATP is a direct danger signal in brain degeneration, which is also under opposite control by adenosine A1 and A2ARs, acting through modification of brain metabolism, synaptic viability and neuroinflammation.
Supported by FCT, Fundacao Oriente, Pfizer.
Conference:
3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009.
Presentation Type:
Oral Presentation
Topic:
Symposium 27 – The purinergic system as a target for the development of novel drugs for acute and chronic CNS disorders
Citation:
Cunha
R
(2009). Purinergic receptors, cytotoxicity and neurodegeneration.
Front. Neurosci.
Conference Abstract:
3rd Mediterranean Conference of Neuroscience .
doi: 10.3389/conf.neuro.01.2009.16.095
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Received:
20 Nov 2009;
Published Online:
20 Nov 2009.
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Correspondence:
Rodrigo Cunha, University of Coimbra, Center for Neuroscience of Coimbra, Faculty of Medicine, Coimbra, Portugal, cunharod@gmail.com