title: The P2X7 receptor antagonist Brilliant Blue G attenuates contralateral rotations in a rat model of Parkinsonism through a combined control of synaptotoxicity, neurotoxicity and gliosis.
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.
authors: Department of Physiology and Pharmacology, Federal University of Ceará, Brazil; CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Portugal.
authors: Marta R S
authors: MR
authors: Carmo
authors: Department of Physiology and Pharmacology, Federal University of Ceará, Brazil.
authors: Ana Paula F
authors: AP
authors: Menezes
authors: Department of Physiology and Pharmacology, Federal University of Ceará, Brazil.
authors: Ana Carla L
authors: AC
authors: Nunes
authors: CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Portugal; FMUC - Faculty of Medicine, University of Coimbra, Portugal.
authors: Anna
authors: A
authors: Pliássova
authors: CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Portugal; Department of Biology, University of Aveiro, Portugal.
authors: Anabela P
authors: AP
authors: Rolo
authors: CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Portugal; Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Portugal.
authors: Carlos M
authors: CM
authors: Palmeira
authors: CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Portugal; FMUC - Faculty of Medicine, University of Coimbra, Portugal. Electronic address: cunharod@gmail.com.
authors: Rodrigo A
authors: RA
authors: Cunha
authors: CNC - Center for Neurosciences and Cell Biology, University of Coimbra, Portugal.
authors: Paula M
authors: PM
authors: Canas
authors: Department of Physiology and Pharmacology, Federal University of Ceará, Brazil.
authors: Geanne M
authors: GM
authors: Andrade
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D007839:Functional Laterality / Q000187:drug effects*; D005911:Gliosis / Q000188:drug therapy; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology; D009043:Motor Activity / Q000187:drug effects*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000209:etiology; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D012394:Rosaniline Dyes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D012394:Rosaniline Dyes; D016627:Oxidopamine; C004692:coomassie Brilliant Blue
keywords: ATP; Astrocytes; Dopamine; Microglia; Neuroprotection; P2X7 receptor; Parkinson's disease; Synaptotoxicity