Adenosine as a neuromodulator in neurological diseases

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Adenosine is a modulator of brain function uniquely positioned to integrate excitatory and inhibitory neurotransmission. The past few years brought a wealth of new data fostering our understanding of how the adenosine system is involved in the pathogenesis of neurological diseases. Thus, dysregulation of the adenosine system is implicated in epileptogenesis and cell therapies have been developed to locally augment adenosine in an approach to prevent seizures. While activation of inhibitory adenosine A1 receptors is beneficial in epilepsy, chronic pain and cerebral ischemia, inhibition of facilitatory A2A receptors has profound neuroprotective effects, which are currently exploited in clinical trials in Parkinson's disease. A new era of adenosine-based therapies has begun, with the prospect to cover a wide range of 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.

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