Adenosine as a neuromodulator in neurological diseases

Abstract

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 A(1) receptors is beneficial in epilepsy, chronic pain and cerebral ischemia, inhibition of facilitatory A(2A) 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.

Figure 1. The adenosine cycle

The regulation of extracellular levels of adenosine is largely dependent on the astrocyte-based adenosine cycle. A major source of synaptic adenosine is vesicular release of ATP (in orange circle) followed by its extracellular degradation to adenosine (ADO) via ectonucleotidases. Nucleoside transporters (NT) equilibrate extra- and intracellular levels of adenosine. Intracellular metabolism of adenosine depends on the activity of adenosine kinase (ADK), which, together with 5′-nucleotidase (5′-NT), forms a substrate cycle between AMP and adenosine. Thus, intracellular metabolism of adenosine via ADK drives the influx of adenosine into the cell.

Figure 2. Adenosine kinase – the key regulator to fine-tune neurotransmission

Adenosine kinase as the key sensor and regulator of ambient adenosine, plays a pivotal role in fine-tuning glutamatergic and dopaminergic neurotransmission based on adenosine’s activation of adenosine receptors with opposing activities (A₁R versus A_2AR). Crosstalk between receptors and components of glutamatergic and dopaminergic neurotransmissions allows integrating and fine-tuning these transmitter systems. Thus, any imbalance in the adenosine system will have pathological downstream effects via altered glutamatergic and dopaminergic neurotransmission.