Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by decreased dopamine bioavailability in the substantia nigra and the striatum. Taking into account that adenosine-5’-triphosphate (ATP) and its metabolites are intensely released in the 6-hydroxydopamine (6-OHDA) animal model of PD, screening of purinergic receptor gene expression was performed. Effects of pharmacological P2Y6 or P2X7 receptor antagonism were studied in preventing or reversing hemiparkinsonian behavior and dopaminergic deficits in this animal model. P2X7 receptor antagonism with Brilliant Blue G (BBG) at a dose of 75 mg/kg re-established the dopaminergic nigrostriatal pathway in rats injured with 6-OHDA. Selective P2Y6 receptor antagonism by MRS2578 prevented dopaminergic neuron death in SH-SY5Y cells in vitro and in vivo in the substantia nigra of rats injured with 6-OHDA. Moreover, in vivo analysis showed that both treatments were accompanied by a reduction of microglial activation in the substantia nigra. Altogether, these data provide evidence that antagonism of P2X7 or P2Y6 receptors results in neuroregenerative or neuroprotective effects, respectively, possibly through modulation of neuroinflammatory responses.
Highlights
Parkinson’s disease (PD) is highly incapacitating and affects nearly 1% of individuals between 65 and 69 years, reaching almost 3% of individuals after 80 years of age (Nussbaum and Ellis, 2003). The pathophysiology of this disease is based on dopaminergic neuron loss in the nigrostriatal pathway and presence of protein aggregates positive for α-synuclein, Abbreviations: 6-OHDA, 6-hydroxydopamine; ATP, adenosine -5 -triphosphate; BBG, Brilliant Blue G; DAMP, Danger Associated Molecular Patterns; MPP+, 1-methyl-4-phenylpyridinium; UDP, uridine-5 -diphosphate
Besides normalizing receptor gene expression data with those of RPL0, that did not differ between experimental groups (Supplementary Figure S2), the fold change of purinergic receptors gene expression is shown in Figure 2 in relation to the respective control hemisphere
P2Y6 receptor gene expression in the samples of 5 weeks post 6-OHDA injury did not present statistical difference in relation to the respective control hemisphere, increased fold change was present as compared to the injured hemisphere after 1 week post-lesion (Figure 2)
Summary
Parkinson’s disease (PD) is highly incapacitating and affects nearly 1% of individuals between 65 and 69 years, reaching almost 3% of individuals after 80 years of age (Nussbaum and Ellis, 2003). The pathophysiology of this disease is based on dopaminergic neuron loss in the nigrostriatal pathway and presence of protein aggregates positive for α-synuclein, Abbreviations: 6-OHDA, 6-hydroxydopamine; ATP, adenosine -5 -triphosphate; BBG, Brilliant Blue G; DAMP, Danger Associated Molecular Patterns; MPP+, 1-methyl-4-phenylpyridinium; UDP, uridine-5 -diphosphate. Antiparkinsonian Effect of Purinergic Receptor Antagonism known as Lewis bodies (Hornykiewicz, 1966). Elucidation of mechanisms of induction, integration and survival of newborn neurons has become important
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