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NEUROPHARMACOLOGY

Novel Isoquinolinone-Derived Inhibitors of Poly(ADP-ribose) Polymerase-1: Pharmacological Characterization and Neuroprotective Effects in an in Vitro Model of Cerebral Ischemia

Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Firenze, Italy (A.C., E.M., M.C., R.P., R.B., D.E.P.G., F.M.); and Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Perugia, Italy (E.C., G.C., M.M., R.P.)

Excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme catalyzing the transfer of ADP-ribose units from NAD to acceptor proteins, induces cellular energy failure by NAD and ATP depletion and has been proposed to play a causative role in a number of pathological conditions, including ischemia/reperfusion injury. In this study, we used an in vitro enzyme activity assay to characterize a series of newly synthesized isoquinolinone derivatives as potential PARP-1 inhibitors. Several compounds displayed powerful inhibitory activity: thieno[2,3-c]isoquinolin-5-one (TIQ-A) displayed a submicromolar IC₅₀ of 0.45 ± 0.1 µM, whereas the 5-hydroxy and 5-methoxy TIQ-A derivatives had IC₅₀ values of 0.39 ± 0.19 and 0.21 ± 0.12 µM, respectively. We then examined the neuroprotective effects of the newly characterized compounds in cultured mouse cortical cells exposed to 60 min of oxygen and glucose deprivation (OGD). When PARP-1 inhibitors were present in the incubation medium during OGD and the subsequent 24-h recovery period, they significantly attenuated neuronal injury. TIQ-A provided neuroprotection even when added to the culture 30 min after OGD and was able to reduce the early activation of PARP induced by OGD as detected by flow cytometry. When the IC₅₀ values observed in the PARP-1 activity assay for selected compounds were compared with their IC₅₀ values for the neuroprotective activity, a significant correlation (r = 0.93, P < 0.01) was observed. Our results suggest that TIQ-A and its derivatives are a new class of neuroprotectants that may be helpful in studies aimed at understanding the involvement of PARP-1 in physiology and pathology.

Address correspondence to: Prof. Flavio Moroni, Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Viale Pieraccini, 6, 50139 Firenze, Italy. E-mail: flavio.moroni{at}unifi.it

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