Adenosine as a neuromodulator in neurological diseases
Introduction
The purine ribonucleoside adenosine controls many brain functions in physiological and pathophysiological conditions via activation of high-affinity A1 or A2A, low-affinity A2B, or low-abundance A3 adenosine receptors (ARs) [1, 2]. Coupling of the receptors to either inhibitory (A1, A3) or stimulatory (A2A, A2B) G-proteins and differential spatial distribution within the brain [1] allow a high degree of complexity in the effects of adenosine and permit the modulation of other neurotransmitter or modulator systems [3]. Because of these multifaceted properties of adenosine, an adenosine-based pharmacopoeia has been established for a variety of conditions [2]. This review covers literature from the past two years, focusing on selected newer trends on the role of adenosine in neurological disease and translation of recent research findings into adenosine-based therapies.
Section snippets
Adenosine: an upstream-regulator of neurotransmission
Inhibitory neuromodulation by adenosine is largely mediated by activation of A1Rs that are coupled to inhibitory Gi or Go containing G-proteins [1, 2]. The consequences of A1R activation are stimulation of adenylyl cyclase, activation of inwardly rectifying K+ channels, inhibition of Ca2+ channels and activation of phospholipase C. As a net result, the release of various neurotransmitters, in particular glutamate, dopamine, serotonin and acetylcholine, is inhibited. Accordingly, preclinical
Astrocytic regulation of synaptic adenosine
Recent findings indicate that synaptic levels of adenosine are largely regulated by astrocytes [10, 11, 12, 13, 14]. The elegant experiments from Phil Haydon's group have documented that – under physiological conditions – the major source of synaptic adenosine is derived from astrocytic vesicular release of ATP, followed by extracellular degradation to adenosine via a cascade of ectonucleotidases [15••]. Using transgenic mice with a defective astrocytic vesicular release system for ATP, the
Adenosine and neurological disease
Given the complex nature and ubiquitous distribution of the adenosine system, any imbalance is expected to lead to neurological disease. The following sections describe recent findings on the role of the adenosine system in neurological diseases (Table 1).
Conclusions
The examples outlined above in a variety of neurological disorders indicate that adenosine concentrations need to be under tight control. Any increases or decreases in ambient adenosine above or below certain thresholds is expected to lead to characteristic pathologies via an imbalance of adenosine receptor mediated secondary effects. Because of interactions with glutamatergic and dopaminergic neurotransmission, adenosine can be regarded as a ‘master regulator’ to integrate and fine-tune
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The work of the author was supported by grant R01 NS047622-01 from the NIH, by the Good Samaritan Hospital Foundation and by the Epilepsy Research Foundation through the generous support of Arlene & Arnold Goldstein Family Foundation.
References (50)
- et al.
Adenosine and brain function
Int Rev Neurobiol
(2005) - et al.
Tonic adenosine A1 and A2A receptor activation is required for the excitatory action of VIP on synaptic transmission in the CA1 area of the hippocampus
Neuropharmacol
(2007) - et al.
The tripartite synapse: roles for gliotransmission in health and disease
Trends Mol Med
(2007) - et al.
Shift of adenosine kinase expression from neurons to astrocytes during postnatal development suggests dual functionality of the enzyme
Neuroscience
(2006) Adenosine and epilepsy: from therapeutic rationale to new therapeutic strategies
Neuroscientist
(2005)- et al.
Adenosine A1 receptor knockout mice develop lethal status epilepticus after experimental traumatic brain injury
J Cereb Blood Flow Metab
(2006) - et al.
Astrogliosis in epilepsy leads to overexpression of adenosine kinase resulting in seizure aggravation
Brain
(2005) - et al.
Adenosine A(2A) receptors, dopamine D(2) receptors and their interactions in Parkinson's disease
Mov Disord
(2007) - et al.
Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production
Neurosci
(2006) - et al.
Caffeine and adenosine A(2a) receptor antagonists prevent beta-amyloid (25–35)-induced cognitive deficits in mice
Exp Neurol
(2007)
The platelet maximum number of A2A-receptor binding sites (Bmax) linearly correlates with age at onset and CAG repeat expansion in Huntington's disease patients with predominant chorea
Neurosci Lett
Involvement of adenosine in the neurobiology of schizophrenia and its therapeutic implications
Prog Neuropsychopharm Biol Psych
Targeting the dopamine D2 receptor in schizophrenia
Expert Opin Ther Targets
Psychosis pathways converge via D2 high dopamine receptors
Synapse
Neurobiology of schizophrenia
Neuron
Disruption of glycine transporter 1 restricted to forebrain neurons is associated with a pro-cognitive and anti-psychotic phenotypic profile
J Neurosci
Adenosine receptors as therapeutic targets
Nat Rev Drug Discov
Adenosine-based cell therapy approaches for pharmacoresistant epilepsies
Neurodegener Dis
Neuroprotection by adenosine in the brain: from A1 receptor activation to A2A receptor blockade
Purinergic Signal
The role of the basal ganglia in habit formation
Nat Rev Neurosci
Blockade of adenosine A(2A) receptors prevents staurosporine-induced apoptosis of rat hippocampal neurons
Neurobiol Dis
Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers
J Neurosci
Adenosine receptor-dopamine receptor interactions in the basal ganglia and their relevance for brain function
Physiol Behav
Adenosine released by astrocytes contributes to hypoxia-induced modulation of synaptic transmission
Glia
Synaptic islands defined by the territory of a single astrocyte
J Neurosci
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