Abstract
Dopamine replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) is the only temporary therapy for Parkinson’s disease (PD), but it triggers dyskinesia over time. Since dyskinesia is associated with increased neuronal firing that bolsters purinergic signaling, we now tested whether the selective and blood-brain barrier-permeable P2X7 receptor antagonist Brilliant Blue-G (BBG, 22.5–45 mg/kg ip) attenuated behavioral, neurochemical and biochemical alterations in rats turned hemiparkinsonian upon unilateral striatal injection of 6-hydroxydopamine (6-OHDA) and treated daily with L-DOPA (30 mg/kg by gavage) for 22 days. The blockade of P2X7 receptors decreased L-DOPA-induced dyskinesia and motor incoordination in hemiparkinsonian rats. In parallel, BBG treatment rebalanced the altered dopamine D1 and D2 receptor density and signaling as well as some neuroinflammation-associated parameters in the striatum and substantia nigra. These findings herald a hitherto unrecognized role for purinergic signaling in the etiopathology of dyskinesia and prompt P2X7 receptor antagonists as novel candidate anti-dyskinesia drugs.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disease mainly characterized by bradykinesia resulting from dopamine deficits in the striatum and loss of dopamine neurons in the substantia nigra
Dopamine replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) temporarily alleviates PD motor symptoms, it is accompanied by evolving adverse side effects, namely the development of abnormal involuntary movements known as L-DOPA-induced dyskinesia (LID), occurring in up to 80% of patients within 5 years of treatment (Bastide et al, 2015)
We confirmed that a unilateral 6-OHDA injection caused a loss of dopamine neurons (TH, dopamine transporters (DAT) staining) in the striatum and nigra, impairing motor responses consistent with a hemiparkinsonian condition
Summary
Parkinson’s disease (PD) is a neurodegenerative disease mainly characterized by bradykinesia resulting from dopamine deficits in the striatum and loss of dopamine neurons in the substantia nigra. In different animal models of PD, the blockade of ATP-activated P2X7 receptor (P2X7R) attenuates motor dysfunction (Marcellino et al, 2010; Carmo et al, 2014; Ferrazoli et al, 2017; Wang et al, 2017) This likely involves an ability of P2X7R blockade to attenuate neuroinflammation (reviewed in Volonté et al, 2012; Bartlett et al, 2014; JimenezMateos et al, 2019) and neurodegeneration (e.g., Zhang et al, 2005; Arbeloa et al, 2012; Nishida et al, 2012; Gandelman et al, 2013), in particular, dopaminergic dysfunction (Jun et al, 2007; Carmo et al, 2014; Kumar et al, 2017). Based on the previous observations that the bloodbrain barrier permeable and selective P2X7R antagonist, brilliant blue G (BBG), attenuated motor incoordination in a model of Huntington’s disease (Díaz-Hernández et al, 2009), we evaluated if this P2X7R antagonist alleviates LID in a rat model
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