title: Effect of the PARP-1 inhibitor PJ 34 on excitotoxic damage evoked by kainate on rat spinal cord organotypic slices.
abstract: Excitotoxicity triggered by over-activation of glutamate receptors is thought to be an early mechanism of extensive neuronal death with consequent loss of function following lesion of spinal networks. One important process responsible for excitotoxic death is 'parthanatos' caused by hyperactivation of poly(ADP-ribose) polymerase (PARP) enzyme 1. Using rat organotypic spinal slices as in vitro models, the present study enquired if 2-(dimethylamino)-N-(5,6-dihydro-6-oxophenanthridin-2yl)acetamide (PJ 34), a pharmacological inhibitor of PARP-1, could counteract the excitotoxic damage evoked by transient application (1 h) of kainate, a potent analogue of glutamate. Kainate induced dose-dependent (1 μM threshold) neuronal loss (without damage to astrocytes) detected 24 h later via a PARP-1 dependent process that had peaked at 4 h after washout kainate. All spinal regions (ventral, central and dorsal) were affected, even though the largest damage was found in the dorsal area. Whereas PJ 34 did not protect against a large concentration (100 μM) of kainate, it significantly inhibited neuronal losses evoked by 10 μM kainate as long as it was co-applied with this glutamate agonist. When the application of PJ 34 was delayed to the washout time, neuroprotection was weak and regionally restricted. These data suggest that kainate-induced parthanatos developed early and was prevented by PJ 34 only when it was co-applied together with excitotoxic stimulus. Our results highlight the difficulty to arrest parthanatos as a mechanism of spinal neuron death in view of its low threshold of activation by kainate, its widespread distribution, and relatively fast development.
authors.affiliation: Neurobiology Sector, International School for Advanced Studies, Trieste, Italy.
authors.forename: Graciela L
authors.initials: GL
authors.lastname: Mazzone
authors.forename: Andrea
authors.initials: A
authors.lastname: Nistri
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D005260:Female; D007608:Kainic Acid / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010616:Phenanthrenes / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology*; D046509:Tissue Culture Techniques
chemical_list: C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D018696:Neuroprotective Agents; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D007608:Kainic Acid