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1.
Front Mol Neurosci ; 13: 111, 2020.
Article in English | MEDLINE | ID: mdl-32848592

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.

2.
Neuropharmacology ; 81: 142-52, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24508709

ABSTRACT

Parkinson's disease (PD) involves an initial loss of striatal dopaminergic terminals evolving into a degeneration of dopaminergic neurons in the substantia nigra (SN), which can be modeled by 6-hydroxydopamine (6-OHDA) administration. Since ATP is a danger signal acting through its P2X7 receptors (P2X7R), we now tested if a blood-brain barrier-permeable P2X7R antagonist, Brilliant Blue G (BBG), controlled the 6-OHDA-induced PD-like features in rats. BBG (45 mg/kg) attenuated the 6-OHDA-induced: 1) increase of contralateral rotations in the apomorphine test, an effect mimicked by another P2X7R antagonist A438079 applied intra-cerebroventricularly; 2) short-term memory impairment in the passive avoidance and cued version of the Morris Water maze; 3) reduction of dopamine content in the striatum and SN; 4) microgliosis and astrogliosis in the striatum. To grasp the mechanism of action of BBG, we used in vitro models exploring synaptotoxicity (striatal synaptosomes) and neurotoxicity (dopamine-differentiated neuroblastoma SH-SY5Y cells). P2X7R were present in striatal dopaminergic terminals, and BBG (100 nM) prevented the 6-OHDA-induced synaptosomal dysfunction. P2X7R were also co-localized with tyrosine hydroxylase in SH-SY5Y cells, where BBG (100 nM) attenuated the 6-OHDA-induced neurotoxicity. This suggests that P2X7R contribute to PD pathogenesis through a triple impact on synaptotoxicity, gliosis and neurotoxicity, highlighting the therapeutic potential of P2X7R antagonists in PD.


Subject(s)
Functional Laterality/drug effects , Motor Activity/drug effects , Neurotoxicity Syndromes/drug therapy , Parkinsonian Disorders/drug therapy , Purinergic P2X Receptor Antagonists/therapeutic use , Rosaniline Dyes/therapeutic use , Animals , Avoidance Learning/drug effects , Brain/drug effects , Brain/metabolism , Cell Line, Tumor , Disease Models, Animal , Exploratory Behavior/drug effects , Gliosis/drug therapy , Male , Maze Learning/drug effects , Memory Disorders/drug therapy , Memory Disorders/etiology , Neurotoxicity Syndromes/etiology , Oxidopamine/toxicity , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/physiopathology , Purinergic P2X Receptor Antagonists/pharmacology , Rats , Rats, Wistar , Reaction Time/drug effects , Rosaniline Dyes/pharmacology
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