Abstract
Adenosine is extensively distributed in the central and peripheral nervous systems, where it plays a key role as a neuromodulator. It has long been implicated in the pathogenesis of progressive neurogenerative disorders such as Parkinson’s disease, and there is now growing interest in its role in amyotrophic lateral sclerosis (ALS). The motor neurons affected in ALS are responsive to adenosine receptor function, and there is accumulating evidence for beneficial effects of adenosine A2A receptor antagonism. In this article, we focus on recent evidence from ALS clinical pathology and animal models that support dynamism of the adenosinergic system (including changes in adenosine levels and receptor changes) in ALS. We review the possible mechanisms of chronic neurodegeneration via the adenosinergic system, potential biomarkers and the acute symptomatic pharmacology, including respiratory motor neuron control, of A2A receptor antagonism to explore the potential of the A2A receptor as target for ALS therapy.
Highlights
We review the possible mechanisms of chronic neurodegeneration via the adenosinergic system, the potential of uric acid as a biomarker and the acute symptomatic pharmacology of A2A receptor antagonism to explore the potential of the A2A receptor (A2A R) as target for Amyotrophic lateral sclerosis (ALS) therapy
This leads to activation of downstream targets, such as cAMP response element-binding protein (CREB), that promote transcription of genes related to cell survival and neuronal plasticity [32,33]
Higher levels in mast cells, eosinophils [34,35,47]. Since it was first cloned in the late 1980s [48], the A2A R has been of particular interest in movement disorders such as Parkinson’s disease (PD) because of their selective expression in the brain regions involved in regulating motor control and the pathogenesis of symptomatic motor dysfunction [42]
Summary
RNA dysfunction, protein misfolding and aggregation, mitochondrial dysfunction, neuroinflammation, neuromuscular junction abnormalities, immune system deficiency, cytoskeletal aberrations, growth factor dysfunction, oxidative stress, axonal disruption and apoptosis, excitotoxicity, activation of nucleases and proteases, and abnormal calcium metabolism [4,5,6]. Similar to their generally well-accepted staging theory in Parkinson’s disease (PD) [7], Braak and colleagues have suggested ALS could be a model of corticofugal axonal spread, where motor neuron degeneration initially results from failure of enzymatic machinery at the level of the cell body and proximal parts of the axon that . We review the possible mechanisms of chronic neurodegeneration via the adenosinergic system, the potential of uric acid as a biomarker and the acute symptomatic pharmacology (including phrenic motor facilitation) of A2A receptor antagonism to explore the potential of the A2A receptor (A2A R) as target for ALS therapy
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