title: Effects of 6(5H)-phenanthridinone, an inhibitor of poly(ADP-ribose)polymerase-1 activity (PARP-1), on locomotor networks of the rat isolated spinal cord.
abstract: Excitotoxicity is considered to be a major pathophysiological mechanism responsible for extensive neuronal death after acute spinal injury. The chief effector of such a neuronal death is thought to be the hyperactivation of intracellular PARP-1 that leads to cell energy depletion and DNA damage with the manifestation of non-apoptotic cell death termed parthanatos. An in vitro lesion model using the neonatal rat spinal cord has recently shown PARP-1 overactivity to be closely related to neuronal losses after an excitotoxic challenge by kainate: in this system the PARP-1 inhibitor 6(5H)-phenanthridinone (PHE) appeared to be a moderate histological neuroprotector. This article investigated whether PHE could actually preserve the function of locomotor networks in vitro from excitotoxicity. Bath-applied PHE (after a 60 min kainate application) failed to recover locomotor network function 24 h later. When the PHE administration was advanced by 30 min (during the administration of kainate), locomotor function could still not be recovered, while basic network rhythmicity persisted. Histochemical analysis showed that, even if the number of surviving neurons was improved with this protocol, it had failed to reach the threshold of minimal network membership necessary for expressing locomotor patterns. These results suggest that PARP-1 hyperactivity was a rapid onset mechanism of neuronal loss after an excitotoxic challenge and that more selective and faster-acting PARP-1 inhibitors are warranted to explore their potential neuroprotective role.
authors.affiliation: Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy.
authors.forename: Sara Ebrahimi
authors.initials: SE
authors.lastname: Nasrabady
authors.forename: Anujaianthi
authors.initials: A
authors.lastname: Kuzhandaivel
authors.forename: Miranda
authors.initials: M
authors.lastname: Mladinic
authors.forename: Andrea
authors.initials: A
authors.lastname: Nistri
mesh_terms: D000818:Animals; D055724:Electrophysiological Phenomena / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007608:Kainic Acid; D008124:Locomotion / Q000187:drug effects*; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D009498:Neurotoxins; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C040601:phenanthridone; D011065:Poly(ADP-ribose) Polymerases; D007608:Kainic Acid