Beneficial effects of PJ34 and INO-1001, two novel water-soluble poly(ADP-ribose) polymerase inhibitors, on the consequences of traumatic brain injury in rat.
Traumatic brain injury produces peroxynitrite, a powerful oxidant which triggers DNA strand breaks, leading to the activation of poly(ADP-ribose)polymerase-1 (PARP-1). We previously demonstrated that 3-aminobenzamide, a PARP inhibitor, is neuroprotective in a model of traumatic brain injury induced by fluid percussion in rat, suggesting that PARP-1 could be a therapeutic target. In order to confirm this hypothesis, we investigated the effects of PJ34 and INO-1001, two PARP inhibitors from structural classes other than benzamide, on the post-traumatic consequences. Pre- and post-treatments with PJ34 (30 mg/kg/day) and INO-1001 (10 mg/kg/day) decrease the neurological deficit at 3 days post-injury and this deficit is still reduced at 7 days. These neurological recovery-promoting effects are associated with the inhibition of PARP-1 activation caused by trauma, as demonstrated by abolishment of immunostaining of poly(ADP-ribose). Thus, the present work strengthens strongly the concept that PARP-1 inhibition may be a suitable approach for the treatment of brain trauma.
Besson
Valérie C
VC
Laboratoire de Pharmacologie de la Circulation Cérébrale, UPRES EA 2510, Université René Descartes, 4, avenue de l'Observatoire, F-75006 Paris, France.
Zsengellér
Zsuzsanna
Z
Plotkine
Michel
M
Szabó
Csaba
C
Marchand-Verrecchia
Catherine
C
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D024161:Collagen Type XI / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012995:Solubility; D016896:Treatment Outcome
D024161:Collagen Type XI; D004791:Enzyme Inhibitors; C491685:INO 1001; D007211:Indoles; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D018696:Neuroprotective Agents; D010616:Phenanthrenes; D011064:Poly Adenosine Diphosphate Ribose; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases