title: Neurological and histological consequences induced by in vivo cerebral oxidative stress: evidence for beneficial effects of SRT1720, a sirtuin 1 activator, and sirtuin 1-mediated neuroprotective effects of poly(ADP-ribose) polymerase inhibition.
abstract: Poly(ADP-ribose)polymerase and sirtuin 1 are both NAD(+)-dependent enzymes. In vitro oxidative stress activates poly(ADP-ribose)polymerase, decreases NAD(+) level, sirtuin 1 activity and finally leads to cell death. Poly(ADP-ribose)polymerase hyperactivation contributes to cell death. In addition, poly(ADP-ribose)polymerase inhibition restores NAD(+) level and sirtuin 1 activity in vitro. In vitro sirtuin 1 induction protects neurons from cell loss induced by oxidative stress. In this context, the role of sirtuin 1 and its involvement in beneficial effects of poly(ADP-ribose)polymerase inhibition were evaluated in vivo in a model of cerebral oxidative stress induced by intrastriatal infusion of malonate in rat. Malonate promoted a NAD(+) decrease that was not prevented by 3-aminobenzamide, a poly(ADP-ribose)polymerase inhibitor, at 4 and 24 hours. However, 3-aminobenzamide increased nuclear SIRT1 activity/expression ratio after oxidative stress. Malonate induced a neurological deficit associated with a striatal lesion. Both were reduced by 3-aminobenzamide and SRT1720, a sirtuin 1 activator, showing beneficial effects of poly(ADP-ribose)polymerase inhibition and sirtuin 1 activation on oxidative stress consequences. EX527, a sirtuin 1 inhibitor, given alone, modified neither the score nor the lesion, suggesting that endogenous sirtuin 1 was not activated during cerebral oxidative stress. However, its association with 3-aminobenzamide suppressed the neurological improvement and the lesion reduction induced by 3-aminobenzamide. The association of 3-aminobenzamide with SRT1720, the sirtuin 1 activator, did not lead to a better protection than 3-aminobenzamide alone. The present data represent the first demonstration that the sirtuin 1 activator SRT1720 is neuroprotective during in vivo cerebral oxidative stress. Furthermore sirtuin 1 activation is involved in the beneficial effects of poly(ADP-ribose)polymerase inhibition after in vivo cerebral oxidative stress.
authors.affiliation: Université Paris Descartes, Pharmacologie de la Circulation Cérébrale - EA4475, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Gueguen
authors.affiliation: Université Paris Descartes, Pharmacologie de la Circulation Cérébrale - EA4475, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Palmier
authors.affiliation: Université Paris Descartes, Pharmacologie de la Circulation Cérébrale - EA4475, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Plotkine
authors.affiliation: Université Paris Descartes, Pharmacologie de la Circulation Cérébrale - EA4475, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Marchand-Leroux
authors.affiliation: Université Paris Descartes, Pharmacologie de la Circulation Cérébrale - EA4475, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Valérie C
authors.initials: VC
authors.lastname: Besson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000503:physiopathology*; D002227:Carbazoles / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D015151:Immunoblotting; D008297:Male; D008314:Malonates / Q000008:administration & dosage; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018709:Statistics, Nonparametric
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D001549:Benzamides; D002227:Carbazoles; D006576:Heterocyclic Compounds, 4 or More Rings; D008314:Malonates; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C525422:SRT1720; C025160:3-aminobenzamide; C030290:malonic acid; D056564:Sirtuin 1