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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

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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.

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Authors and Affiliations

  1. Department of Chemical, Biological, Pharmacological and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’alcontres, 31, 98166, Messina, Italy

    Giovanna Casili, Michela Campolo, Marika Lanza, Alessia Filippone, Sarah Scuderi, Salvatore Messina, Alessio Ardizzone, Emanuela Esposito & Irene Paterniti

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  1. Giovanna Casili
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Contributions

GC: conceptualization, data curation, formal analysis, and writing-original draft; MC: conceptualization, data curation, methodology, and resources; ML: formal analysis, investigation; AF: investigation, methodology; SS: methodology; AA: software; EE: conceptualization, resources, funding acquisition, and supervision; and IP: conceptualization, validation, resources, visualization, and project administration.

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Correspondence to Irene Paterniti.

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Casili, G., Campolo, M., Lanza, M. et al. Role of ABT888, a Novel Poly(ADP-Ribose) Polymerase (PARP) Inhibitor in Countering Autophagy and Apoptotic Processes Associated to Spinal Cord Injury. Mol Neurobiol 57, 4394–4407 (2020). https://doi.org/10.1007/s12035-020-02033-x

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