title: Another "string to the bow" of PJ34, a potent poly(ADP-Ribose)polymerase inhibitor: an antiplatelet effect through P2Y12 antagonism?
abstract: 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.
  
  
  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.
authors.affiliation: EA4475-"Pharmacologie de la Circulation Cérébrale", Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Comue Sorbonne Paris Cité, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Lechaftois
authors.affiliation: Inserm UMR S1140, Paris, France; Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Comue Sorbonne Paris Cité, Paris, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Dreano
authors.affiliation: EA4475-"Pharmacologie de la Circulation Cérébrale", Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Comue Sorbonne Paris Cité, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Palmier
authors.affiliation: EA4475-"Pharmacologie de la Circulation Cérébrale", Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Comue Sorbonne Paris Cité, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Margaill
authors.affiliation: EA4475-"Pharmacologie de la Circulation Cérébrale", Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Comue Sorbonne Paris Cité, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Marchand-Leroux
authors.affiliation: Inserm UMR S1140, Paris, France; Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Comue Sorbonne Paris Cité, Paris, France.
authors.forename: Christilla
authors.initials: C
authors.lastname: Bachelot-Loza
authors.affiliation: EA4475-"Pharmacologie de la Circulation Cérébrale", Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Comue Sorbonne Paris Cité, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lerouet
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D001792:Blood Platelets / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D010616:Phenanthrenes / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism
chemical_list: C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; C548576:P2RY12 protein, human; D010616:Phenanthrenes; D010975:Platelet Aggregation Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate