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

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• 作者：Marta R.S. Carmo^a ; ^b ; Ana Paula F. Menezes^a ; Ana Carla L. Nunes^a ; Anna Pliá ; ssova^b ; ^e ; Anabela P. Rolo^b ; ^c ; Carlos M. Palmeira^b ; ^d ; Rodrigo A. Cunha^b ; ^e ; ^{cunharod@gmail.com" class="auth_mail} ; Paula M. Canas^b ; ¹ ; Geanne M. Andrade^a ; ¹
• 关键词：ATP ; P2X7 receptor ; Parkinson's disease ; Synaptotoxicity ; Neuroprotection ; Microglia ; Astrocytes ; Dopamine
• 刊名：Neuropharmacology
• 出版年：June, 2014
• 年：2014
• 卷：81
• 期：Complete
• 页码：142-152
• 全文大小：2158 K

文摘

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聽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聽vitro models exploring synaptotoxicity (striatal synaptosomes) and neurotoxicity (dopamine-differentiated neuroblastoma SH-SY5Y cells). P2X7R were present in striatal dopaminergic terminals, and BBG (100聽nM) prevented the 6-OHDA-induced synaptosomal dysfunction. P2X7R were also co-localized with tyrosine hydroxylase in SH-SY5Y cells, where BBG (100聽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.