Year-end Sale % OFF 
Abstract
Huntington’s disease (HD) is a life-threatening neurodegenerative disorder. Altered levels and functions of the purinergic ionotropic P2X7 receptors (P2X7Rs) have been found in animal and cellular models of HD, suggesting their possible role in the pathogenesis of the disease; accordingly, the therapeutic potential of P2X7R antagonists in HD has been proposed. Here we further investigated the effects of P2X7R ligands in in vitro and ex vivo HD experimental models. In ST14A/Q120 rat striatal cells, we found a reduction of P2X7R expression; however, the P2X7R agonist 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate (BzATP) induced cellular death, and this effect was fully reversed by the antagonist periodate-oxidized adenosine 5′-triphosphate (OxATP). Moreover, in corticostriatal slices from symptomatic R6/2 mice, BzATP reduced the synaptic transmission to a larger extent than in wild-type (WT) mice. Such an effect was accompanied by a concomitant increase of the paired-pulse ratio, suggesting a presynaptic inhibitory action. This was confirmed to be the case, since while the effects of BzATP were unaffected by the P2X7R antagonist OxATP, they were blocked by the adenosine A1 receptor (A1R) antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), suggesting possible BzATP hydrolysis to 2′(3′)-O-(4-benzoylbenzoyl)adenosine (Bz-adenosine) and consequent activation of A1Rs as a mechanism. Taken together, these data point out that 1) P2X7R expression and activity are confirmed to be altered in the presence of HD mutation; 2) in some experimental settings, such an abnormal functioning can be ascribed to presynaptic A1Rs activation.
Highlights
Huntington’s disease (HD) is a genetic neurodegenerative disease characterized by a complex set of movement, psychiatric, and cognitive alterations (Harper and Newcombe, 1992).The disease is caused by a mutation in the exon 1 of the IT-15 gene, located on chromosome 4, encoding for the huntingtin protein (The Huntington’s Disease Collaborative Research Group, 1993)
BzATP-induced toxicity in Q120 cells was blocked by the P2X7R antagonist but not by the A1R antagonist
We evaluated the expression and functioning of P2X7R in HD and validated some results previously reported in different genetic models (Diaz-Hernandez et al, 2009)
Summary
Huntington’s disease (HD) is a genetic neurodegenerative disease characterized by a complex set of movement, psychiatric, and cognitive alterations (Harper and Newcombe, 1992).The disease is caused by a mutation in the exon 1 of the IT-15 gene, located on chromosome 4, encoding for the huntingtin (htt) protein (The Huntington’s Disease Collaborative Research Group, 1993). Despite the ubiquitous expression of mutant and normal htt protein, the neurodegeneration mainly involves the striatum, with neuronal death selectively occurring in medium-sized spiny neurons (MSNs) and, to a lesser extent, in the cortex (Vonsattel et al, 1985). Since these brain areas represent the paradigmatic site of the corticostriatal glutamatergic pathway, a role for an altered glutamate receptor signaling, and consequent excitotoxicity, has been proposed to explain MSN vulnerability (Levine et al, 1999; Cepeda et al, 2001; Zeron et al, 2002; Martire et al, 2007)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
