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Inhibitors of poly(ADP-ribose) polymerase modulate signal transduction pathways and secondary damage in experimental spinal cord trauma.
J Pharmacol Exp Ther. 2005 Feb; 312(2):449-57.JP

Abstract

Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with stroke and neurotrauma. The aim of our study was to evaluate the therapeutic efficacy of in vivo inhibition of PARP in an experimental model of spinal cord trauma, which was induced by the application of vascular clips (force of 24g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration (measured as an increase in myeloperoxidase activity), and apoptosis (measured by terminal deoxynucleotidyltransferase-mediated UTP end labeling coloration). Infiltration of spinal cord tissue with neutrophils was associated with a marked increase in immunoreactivity for poly(ADP-ribose) (PAR), index of PARP activation, in the spinal cord tissue. These inflammatory events were associated with the activation of nuclear factor-kappaB (NF-kappaB) at 4 h after spinal cord damage. Treatment of the mice with the PARP inhibitors 3-aminobenzamide (3-AB) or 5-aminoisoquinolinone (5-AIQ) significantly reduced the degree of 1) spinal cord inflammation and tissue injury (histological score), 2) PAR formation, 3) neutrophil infiltration, and 4) apoptosis. Treatment with these PARP inhibitors also reduced DNA binding of NF-kappaB and inhibitory kappaB degradation. In a separate set of experiments, we have also demonstrated that PARP inhibitors significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with PARP inhibitors reduces the development of inflammation and tissue injury events associated with spinal cord trauma.

Authors+Show Affiliations

Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valeria, Gazzi, 98100 Messina, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15452194

Citation

Genovese, Tiziana, et al. "Inhibitors of poly(ADP-ribose) Polymerase Modulate Signal Transduction Pathways and Secondary Damage in Experimental Spinal Cord Trauma." The Journal of Pharmacology and Experimental Therapeutics, vol. 312, no. 2, 2005, pp. 449-57.
Genovese T, Mazzon E, Muià C, et al. Inhibitors of poly(ADP-ribose) polymerase modulate signal transduction pathways and secondary damage in experimental spinal cord trauma. J Pharmacol Exp Ther. 2005;312(2):449-57.
Genovese, T., Mazzon, E., Muià, C., Patel, N. S., Threadgill, M. D., Bramanti, P., De Sarro, A., Thiemermann, C., & Cuzzocrea, S. (2005). Inhibitors of poly(ADP-ribose) polymerase modulate signal transduction pathways and secondary damage in experimental spinal cord trauma. The Journal of Pharmacology and Experimental Therapeutics, 312(2), 449-57.
Genovese T, et al. Inhibitors of poly(ADP-ribose) Polymerase Modulate Signal Transduction Pathways and Secondary Damage in Experimental Spinal Cord Trauma. J Pharmacol Exp Ther. 2005;312(2):449-57. PubMed PMID: 15452194.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibitors of poly(ADP-ribose) polymerase modulate signal transduction pathways and secondary damage in experimental spinal cord trauma. AU - Genovese,Tiziana, AU - Mazzon,Emanuela, AU - Muià,Carmelo, AU - Patel,Nimesh S A, AU - Threadgill,Michael D, AU - Bramanti,Placido, AU - De Sarro,Angelina, AU - Thiemermann,Christoph, AU - Cuzzocrea,Salvatore, Y1 - 2004/09/27/ PY - 2004/9/29/pubmed PY - 2005/3/19/medline PY - 2004/9/29/entrez SP - 449 EP - 57 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 312 IS - 2 N2 - Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with stroke and neurotrauma. The aim of our study was to evaluate the therapeutic efficacy of in vivo inhibition of PARP in an experimental model of spinal cord trauma, which was induced by the application of vascular clips (force of 24g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration (measured as an increase in myeloperoxidase activity), and apoptosis (measured by terminal deoxynucleotidyltransferase-mediated UTP end labeling coloration). Infiltration of spinal cord tissue with neutrophils was associated with a marked increase in immunoreactivity for poly(ADP-ribose) (PAR), index of PARP activation, in the spinal cord tissue. These inflammatory events were associated with the activation of nuclear factor-kappaB (NF-kappaB) at 4 h after spinal cord damage. Treatment of the mice with the PARP inhibitors 3-aminobenzamide (3-AB) or 5-aminoisoquinolinone (5-AIQ) significantly reduced the degree of 1) spinal cord inflammation and tissue injury (histological score), 2) PAR formation, 3) neutrophil infiltration, and 4) apoptosis. Treatment with these PARP inhibitors also reduced DNA binding of NF-kappaB and inhibitory kappaB degradation. In a separate set of experiments, we have also demonstrated that PARP inhibitors significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with PARP inhibitors reduces the development of inflammation and tissue injury events associated with spinal cord trauma. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15452194/Inhibitors_of_poly_ADP_ribose__polymerase_modulate_signal_transduction_pathways_and_secondary_damage_in_experimental_spinal_cord_trauma_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15452194 DB - PRIME DP - Unbound Medicine ER -