Abstract
Since proving adenosine triphosphate (ATP) functions as a neurotransmitter in neuron/glia interactions, the purinergic system has been more intensely studied within the scope of the central nervous system. In neurological disorders with associated motor symptoms, including Parkinson's disease (PD), motor neuron diseases (MND), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington's Disease (HD), restless leg syndrome (RLS), and ataxias, alterations in purinergic receptor expression and activity have been noted, indicating a potential role for this system in disease etiology and progression. In neurodegenerative conditions, neural cell death provokes extensive ATP release and alters calcium signaling through purinergic receptor modulation. Consequently, neuroinflammatory responses, excitotoxicity and apoptosis are directly or indirectly induced. This review analyzes currently available data, which suggests involvement of the purinergic system in neuro-associated motor dysfunctions and underlying mechanisms. Possible targets for pharmacological interventions are also discussed.
Highlights
The unexpected discovery and description of non-adrenergic and non-cholinergic inhibitory nerves working through adenosine triphosphate (ATP) and its metabolites gave rise to the introduction of the purinergic system concept in the early 70’s (Burnstock et al, 1970; Burnstock, 1972)
In terms of the variety of extracellular nucleotide-degrading enzymes and purinergic receptors, which assemble as homoor heterocomplexes and vary in composition in different central nervous system (CNS) cell types, more intense research has to be performed to clarify short- and long-term implications of purinergic signaling in amyotrophic lateral sclerosis (ALS)
Taken together, evidence indicates that modulation of purinergic receptor expression and activity could be useful in Parkinson’s disease (PD) treatment in several ways: (1) reducing microglia activation by damaged cells and α-synuclein aggregation through P2X7 and P2Y6 receptors antagonism; (2) preventing α-synuclein aggregation through P2X1 and A2A receptors antagonism; (3) modulating inflammatory scenario through A2A receptors antagonism; or (4) preventing dyskinesia induced by L-DOPA long-term use through combined treatment with A2A receptor antagonists
Summary
The unexpected discovery and description of non-adrenergic and non-cholinergic inhibitory nerves working through adenosine triphosphate (ATP) and its metabolites gave rise to the introduction of the purinergic system concept in the early 70’s (Burnstock et al, 1970; Burnstock, 1972). Purinergic Receptors in Neurological Diseases receptors, membrane nucleotide/nucleoside transporters and channels (e.g., pannexins) as well as ectonucleotidases play important roles in purinergic signaling These are responsible for the exchange of purines between intracellular and extracellular environments and their enzymatic extracellular conversion, respectively (Zimmermann et al, 1998; Zimmermann, 2006; Scemes et al, 2007; Abbracchio et al, 2009; Lapato and TiwariWoodruff, 2017). Large amounts of ATP are released into the extracellular environment, stimulating other purinergic receptors, and signaling cascades widely associated with pathological conditions (Bartlett et al, 2014), such as the A2A receptor, which is activated by adenosine released from damaged cells or produced from ATP hydrolysis (Cunha, 2016).
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