Role of ABT888, a Novel Poly(ADP-Ribose) Polymerase (PARP) Inhibitor in Countering Autophagy and Apoptotic Processes Ass
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Role of ABT888, a Novel Poly(ADP-Ribose) Polymerase (PARP) Inhibitor in Countering Autophagy and Apoptotic Processes Associated to Spinal Cord Injury Giovanna Casili 1 & Michela Campolo 1 & Marika Lanza 1 & Alessia Filippone 1 & Sarah Scuderi 1 & Salvatore Messina 1 & Alessio Ardizzone 1 & Emanuela Esposito 1 & Irene Paterniti 1 Received: 30 April 2020 / Accepted: 22 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Accidents are the cause of some 50 deaths per 100,000 population each year; some 3% of these are from traumatic spinal cord injury (SCI), a damage that causes temporary or permanent motor deficits, often leading to permanent neurological alterations. The activation of poly(ADP-ribose) polymerase (PARP) as DNA damage response, together with autophagy and apoptosis processes contributes to the secondary injury processes seen after SCI. Thus, in the present study, a mouse compression model of SCI was used to determine whether the treatment with ABT888, as PARP-1/2 inhibitor, could restore the neuronal damage induced by SCI. Mice were orally administered with ABT888 (at a dose of 25 mg/kg) 1 h and 6 h after SCI induction. Histological analysis, myeloperoxidase (MPO) activity, and Basso Mouse scale (BMS) were performed. The expression of autophagy-related proteins and apoptosis-inducing factors was quantified in the cytosolic fraction from spinal cord tissue collected after 24 h after SCI. TUNEL assay was performed in SCI-tissues 24 h after damage. ABT888 treatment significantly reduced histological damage and neutrophilic infiltration, improving motor skills. PARP-1/2 inhibition by ABT888 slowed cell death, decreasing autophagy-activation proteins. These results showed that ABT888, inhibiting PARP-1/2 activity, through a reduction in the apoptosis-autophagy machinery, plays a protective role after SCI, suggesting a new insight into the potential application of ABT888 as novel candidate in SCI therapies. Keywords Spinal cord injury . Autophagy . Apoptosis . PARP-1 . PARP-2
Introduction Spinal cord injury (SCI) is a serious and debilitating health problem that usually causes lifelong disability and leads to neurological dysfunction at and/or below the level of the injury [1]. The pathology of SCI includes local edema, ischemia, reactive oxygen species (ROS) formation that contributes to tissue injury observed during inflammation, and posttraumatic inflammatory reactions after SCI [2]. ROS and peroxynitrite also cause DNA damage, which results in the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) [3]. PARP activation is a physiological response, but an excess of its levels produces ATP depletion, leading to * Irene Paterniti [email protected] 1
Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’alcontres, 31, 98166 Messina, Italy
irreversible cellular energy failure and cell death [4]. PARP-1/ 2 is recruited to DNA strand breaks and leading to polymerization of PAR, pla
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