Inhibitors of Poly(ADP-Ribose) Polymerase Modulate Signal Transduction Pathways and Secondary Damage in Experimental Spinal Cord Trauma

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-B (NF-B) 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-B and inhibitory B 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.Post-traumatic inflammatory reactions may play an important role in the secondary injury processes after spinal cord injury (SCI) (Bartholdi and Schwab, 1995). The primary traumatic mechanical injury to the spinal cord causes the death of a number of neurons that cannot be recovered or regenerated to date. However, neurons continue to die for hours after SCI, and this represents a potentially avoidable event. This secondary neuronal death is determined by a large number of cellular, molecular, and biochemical cascades. One such cascade that has been touted to contribute importantly to the evolution of this secondary damage is the local inflammatory response in the injured spinal cord. Although the neuraxis is considered somehow privileged under an immunological point of view and poorly influenced by inflammatory processes, a large body of recent data suggests the presence of a local inflammatory response and that aspects of this response to injury amplify the secondary damage (Popovich et al., 1994). The cardinal features of inflammation, namely infiltration of inflammatory cells (polymorphonuclear neutrophils, macrophages, and lymphocytes), release Article, publication date, and citation information can be found at

Oleuropein an Olive Oil Compound in Acute and Chronic Inflammation Models: Facts and Perspectives

“…In this report, an intense immunostaining of nitrotyrosine formation also suggested that a structural alteration of joint had occurred, most probably due to the formation of highly reactive nitrogen derivatives ROS produce strand breaks in DNA, which triggers energy-consuming DNA repair mechanisms and activates the nuclear enzyme poly(ADP-ribosyl) polymerase (PARP). There is various evidence that the activation of PARP may also play an important role in inflammation (Genovese et al, 2005). Continuous or excessive activation of PARP produces extended chains of ADP-ribose (PAR) on nuclear proteins and results in a substantial depletion of intracellular NAD and subsequently, ATP, leading to cellular dysfunction and, ultimately, cell death (Chiarugi, 2002).…”

Signaling Mechanism of Poly(ADP-Ribose) Polymerase-1 (PARP-1) in Inflammatory Diseases

“…For example, in a spinal cord trauma model, the infiltration of neutrophils in spinal cord tissue was associated with a marked increase in immunoreactivity for PARs, an index of PARP activation; and treatment with PARP-1 inhibitors reduced the tissue inflammation and injury events associated with spinal cord trauma. 50 In another study, 51 PARP-1-deficient or wild-type mice treated with PARP-1 inhibitors [PJ34 (N-[6-oxo-5,6-dihydro-phenanthridin-2-yl]-N,N-dimethylactamide) or 3AB (3-aminobenzaminde)] were subjected to heat exposure as a model to study heat stroke. The PARP-1 inhibition increased the expression of 27-and 70-kDA heat shock proteins, and heat stroke-induced liver injury was attenuated in PARP-1-deficient mice when compared with findings in wild-type mice.…”

IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis

“…Excessive activation of PARP in response to extensive DNA damage has been associated with the depletion of NAD + , which causes cell death through energy depletion (22). It was recently reported that ONOO --induced toxicity in spinal cord neurons is associated with DNA strand breakage and prevented by PARP inhibition (23).…”