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Cerebral Vasodilator Property of Poly(ADP-Ribose) Polymerase Inhibitor (PJ34) in the Neonatal and Adult Mouse Is Mediated by the Nitric Oxide Pathway.

Philippe BonninChristiane Charriaut-MarlangueJulien PansiotAlexandre BoutignyJean-Marie LaunayValerie C Besson
Published in: International journal of molecular sciences (2020)
The poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 has been reported to improve endothelial dysfunction in the peripheral system. We addressed the role of PJ34 on the vascular tone and vasoreactivity during development in the mouse brain. Blood flows were measured in the basilar trunk using ultrasonography. Cerebral vasoreactivity or vasodilation reserve was estimated as a percentage increase in mean blood flow velocities (mBFV) recorded under normoxia-hypercapnia in control and after PJ34 administration. Non-selective and selective eNOS and nNOS inhibitors were used to evaluate the role of NO-pathway into the hemodynamic effects of PJ34. PJ34 increased mBFVs from 15.8 ± 1.6 to 19.1 ± 1.9 cm/s (p = 0.0043) in neonatal, from 14.6 ± 1.4 to 16.1 ± 0.9 cm/s (p = 0.0049) in adult, and from 15.7 ± 1.7 to 17.5 ± 2.0 cm/s (p = 0.0024) in aged mice 48 h after administration. These PJ34 values were similar to those measured in age-matched control mice under normoxia-hypercapnia. This recruitment was mediated through the activation of constitutive NO synthases in both the neonatal (38.2 ± 6.7 nmol/min/mg protein) and adult (31.5 ± 4.4 nmol/min/mg protein) brain, as compared to age-matched control brain (6.9 ± 0.4 and 6.3 ± 0.7 nmol/min/mg protein), respectively. In addition, quite selective eNOS inhibitor was able to inhibit the recruitment. PJ34 by itself is able to increase cerebral blood flow through the NO-pathway activation at least over 48 h after a single administration.
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