Data for this review were identified from the personal files of the authors and by search using Medline. The search terms were “Huntington's disease”, “excitotoxicity”, “mitochondria”, “adenosine receptors”, “A1 receptors”, “A2A receptors”, “neuroprotection”, “ischaemia”, “Parkinson's disease”, and “review”. Only papers published in English were reviewed.
ReviewAdenosine receptors and Huntington's disease: implications for pathogenesis and therapeutics
Section snippets
Genetic models of HD and physiological effects of the mutation
Many genetic models of HD are available (eg, transgenic mice and knock-in animals and models in which mutated huntingtin is ectopically expressed in the striatum after injection of lentiviruses that code for the mutated gene; table 1).8 Mice that express exon 1 of human huntingtin with many (141–157) CAG repeats provided the first transgenic model of HD, R6. These mice have motor disturbances and die early but have minimum cell death in the striatum.9 These mice were characterised by the
Adenosine and adenosine receptors
Purines, such as adenosine, ADP, and ATP are crucial cellular components used as a source of energy or as parts of nucleic acids. Besides these vital cellular functions, purines are released into the extracellular space where they act as important signalling molecules that mediate biological effects through purine receptors: P1 (adenosine) receptors and P2 (ATP and ADP) receptors.48, 49, 50
Adenosine is particularly important in excitable tissues—such as the brain—in which it reduces cellular
Neuroprotection, adenosine, and adenosine receptors
Modulation of adenosine receptors has important effects on neuronal survival in several conditions, such as hypoxia, ischaemia, and seizures. Many researchers have suggested the use of A1-receptor agonists and A2A-receptor antagonists as neuroprotective agents.49, 76 However, in the case of HD, there is still a lot to learn about he role of adenosine receptors. Because A1 receptors are expressed on striatal cells as well as on striatal afferent fibres coming from the cortex or the substantia
Neuroprotection and A1 receptors
Excessive neuronal activation caused by excitatory amino acids is implicated in several neurodegenerative diseases (eg, amyotrophic lateral sclerosis, Parkinson's disease, and HD), and A1 receptor agonists may have beneficial effects in these disorders. However, most data have been collected from studies on cerebral ischaemia in which adenosine concentrations increase substantially.78, 79
Adenosine and selective A1-receptor agonists reduce neuronal damage in in vitro models of ischaemia, whereas
Neuroprotection and A2A receptors
Blockade of A2A receptors has been shown to be beneficial in models of various neurological disorders such as epilepsy,103 ischaemia,104, 105 HD,71 and Parkinson's disease. Studies in Parkinson's disease106 have suggested an association between the disorder and consumption of dietary compounds that inhibit A2A receptors, such as caffeine. Blockade of A2A receptors stimulates motor activity,72, 107 and increases the effects of levodopa in patients with Parkinson's disease.108 In animal models, A
Clinical perspectives
The modulation of adenosine receptors to slow down the neurodegenerative process in HD has great therapeutic potential. However, further pharmacological work is needed to find the optimum benefit/risk ratio. The potential side-effects and neurobiological constraints are quite different for A1 and A2A receptors.
There are several physiological limitations to the use of A1 agonists. First, such compounds do not have equal capacities to cross the blood–brain barrier.133 In addition to the
Search strategy and selection criteria
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2016, Handbook of Behavioral NeuroscienceCitation Excerpt :The same complex profile has emerged in experimental models of HD, in which both A2A receptor agonists and antagonists have shown beneficial effects, depending on the model used, the type of pharmacological treatment, and the period of drug administration (see Popoli et al., 2007, 2008, for review). For instance, pharmacological blockade or genetic inactivation of A2A receptors resulted in neuroprotection in pathogenetic models of HD (Blum et al., 2003; Fink et al., 2004; Popoli et al., 2002), but the deletion of A2A receptors in genetic HD models worsened the survival and motor function of mice (Mievis et al., 2011). Even more intriguingly, a recent retrospective analysis in HD patients suggested that consumption of caffeine, a nonselective A2A antagonist, is associated with an earlier disease onset (Simonin et al., 2013).
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