Neurological and Histological Consequences Induced by <i>In Vivo</i> 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

<div><p>Poly(ADP-ribose)polymerase and sirtuin 1 are both NAD⁺-dependent enzymes. <i>In vitro</i> 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 <i>in vitro</i>. <i>In vitro</i> 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 <i>in vivo</i> 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 <i>in vivo</i> cerebral oxidative stress. Furthermore sirtuin 1 activation is involved in the beneficial effects of poly(ADP-ribose)polymerase inhibition after <i>in vivo</i> cerebral oxidative stress.</p>