Another "string to the bow" of PJ34, a potent poly(ADP-Ribose)polymerase inhibitor: an antiplatelet effect through P2Y12 antagonism?
BACKGROUND: Neuro- and vasoprotective effects of poly(ADP-ribose)polymerase (PARP) inhibition have been largely documented in models of cerebral ischemia, particularly with the potent PARP inhibitor PJ34. Furthermore, after ischemic stroke, physicians are faced with incomplete tissue reperfusion and...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4203827?pdf=render |
| _version_ | 1811210826567122944 |
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| author | Marie Lechaftois Elise Dreano Bruno Palmier Isabelle Margaill Catherine Marchand-Leroux Christilla Bachelot-Loza Dominique Lerouet |
| author_facet | Marie Lechaftois Elise Dreano Bruno Palmier Isabelle Margaill Catherine Marchand-Leroux Christilla Bachelot-Loza Dominique Lerouet |
| author_sort | Marie Lechaftois |
| collection | DOAJ |
| description | BACKGROUND: Neuro- and vasoprotective effects of poly(ADP-ribose)polymerase (PARP) inhibition have been largely documented in models of cerebral ischemia, particularly with the potent PARP inhibitor PJ34. Furthermore, after ischemic stroke, physicians are faced with incomplete tissue reperfusion and reocclusion, in which platelet activation/aggregation plays a key role. Data suggest that certain PARP inhibitors could act as antiplatelet agents. In that context, the present in vitro study investigated on human blood the potential antiplatelet effect of PJ34 and two structurally different PARP inhibitors, DPQ and INO-1001. METHODS AND RESULTS: ADP concentrations were chosen to induce a biphasic aggregation curve resulting from the successive activation of both its receptors P2Y(1) and P2Y(12). In these experimental conditions, PJ34 inhibited the second phase of aggregation; this effect was reduced by incremental ADP concentrations. In addition, in line with a P2Y(12) pathway inhibitory effect, PJ34 inhibited the dephosphorylation of the vasodilator stimulated phosphoprotein (VASP) in a concentration-dependent manner. Besides, PJ34 had no effect on platelet aggregation induced by collagen or PAR1 activating peptide, used at concentrations inducing a strong activation independent on secreted ADP. By contrast, DPQ and INO-1001 were devoid of any effect whatever the platelet agonist used. CONCLUSIONS: We showed that, in addition to its already demonstrated beneficial effects in in vivo models of cerebral ischemia, the potent PARP inhibitor PJ34 exerts in vitro an antiplatelet effect. Moreover, this is the first study to report that PJ34 could act via a competitive P2Y(12) antagonism. Thus, this antiplatelet effect could improve post-stroke reperfusion and/or prevent reocclusion, which reinforces the interest of this drug for stroke treatment. |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T05:01:33Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-9d744c3f5f7e4540a9844ea368effbfc2022-12-22T03:46:58ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01910e11077610.1371/journal.pone.0110776Another "string to the bow" of PJ34, a potent poly(ADP-Ribose)polymerase inhibitor: an antiplatelet effect through P2Y12 antagonism?Marie LechaftoisElise DreanoBruno PalmierIsabelle MargaillCatherine Marchand-LerouxChristilla Bachelot-LozaDominique LerouetBACKGROUND: Neuro- and vasoprotective effects of poly(ADP-ribose)polymerase (PARP) inhibition have been largely documented in models of cerebral ischemia, particularly with the potent PARP inhibitor PJ34. Furthermore, after ischemic stroke, physicians are faced with incomplete tissue reperfusion and reocclusion, in which platelet activation/aggregation plays a key role. Data suggest that certain PARP inhibitors could act as antiplatelet agents. In that context, the present in vitro study investigated on human blood the potential antiplatelet effect of PJ34 and two structurally different PARP inhibitors, DPQ and INO-1001. METHODS AND RESULTS: ADP concentrations were chosen to induce a biphasic aggregation curve resulting from the successive activation of both its receptors P2Y(1) and P2Y(12). In these experimental conditions, PJ34 inhibited the second phase of aggregation; this effect was reduced by incremental ADP concentrations. In addition, in line with a P2Y(12) pathway inhibitory effect, PJ34 inhibited the dephosphorylation of the vasodilator stimulated phosphoprotein (VASP) in a concentration-dependent manner. Besides, PJ34 had no effect on platelet aggregation induced by collagen or PAR1 activating peptide, used at concentrations inducing a strong activation independent on secreted ADP. By contrast, DPQ and INO-1001 were devoid of any effect whatever the platelet agonist used. CONCLUSIONS: We showed that, in addition to its already demonstrated beneficial effects in in vivo models of cerebral ischemia, the potent PARP inhibitor PJ34 exerts in vitro an antiplatelet effect. Moreover, this is the first study to report that PJ34 could act via a competitive P2Y(12) antagonism. Thus, this antiplatelet effect could improve post-stroke reperfusion and/or prevent reocclusion, which reinforces the interest of this drug for stroke treatment.http://europepmc.org/articles/PMC4203827?pdf=render |
| spellingShingle | Marie Lechaftois Elise Dreano Bruno Palmier Isabelle Margaill Catherine Marchand-Leroux Christilla Bachelot-Loza Dominique Lerouet Another "string to the bow" of PJ34, a potent poly(ADP-Ribose)polymerase inhibitor: an antiplatelet effect through P2Y12 antagonism? PLoS ONE |
| title | Another "string to the bow" of PJ34, a potent poly(ADP-Ribose)polymerase inhibitor: an antiplatelet effect through P2Y12 antagonism? |
| title_full | Another "string to the bow" of PJ34, a potent poly(ADP-Ribose)polymerase inhibitor: an antiplatelet effect through P2Y12 antagonism? |
| title_fullStr | Another "string to the bow" of PJ34, a potent poly(ADP-Ribose)polymerase inhibitor: an antiplatelet effect through P2Y12 antagonism? |
| title_full_unstemmed | Another "string to the bow" of PJ34, a potent poly(ADP-Ribose)polymerase inhibitor: an antiplatelet effect through P2Y12 antagonism? |
| title_short | Another "string to the bow" of PJ34, a potent poly(ADP-Ribose)polymerase inhibitor: an antiplatelet effect through P2Y12 antagonism? |
| title_sort | another string to the bow of pj34 a potent poly adp ribose polymerase inhibitor an antiplatelet effect through p2y12 antagonism |
| url | http://europepmc.org/articles/PMC4203827?pdf=render |
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