title: Unusual increase in lumbar network excitability of the rat spinal cord evoked by the PARP-1 inhibitor PJ-34 through inhibition of glutamate uptake.
abstract: Overactivity of poly(ADP-ribose) polymerase enzyme 1 (PARP-1) is suggested to be a major contributor to neuronal damage following brain or spinal cord injury, and has led to study the PARP-1 inhibitor 2-(dimethylamino)-N-(5,6-dihydro-6-oxophenanthridin-2yl)acetamide (PJ-34) as a neuroprotective agent. Unexpectedly, electrophysiological recording from the neonatal rat spinal cord in vitro showed that, under control conditions, 1-60 μM PJ-34 per se strongly increased spontaneous network discharges occurring synchronously on ventral roots, persisting for 24 h even after PJ-34 washout. The PARP-1 inhibitor PHE had no similar effect. The action by PJ-34 was reversibly suppressed by glutamate ionotropic receptor blockers and remained after applying strychnine and bicuculline. Fictive locomotion evoked by neurochemicals or by dorsal root stimulation was present 24 h after PJ-34 application. In accordance with this observation, lumbar neurons and glia were undamaged. Neurochemical experiments showed that PJ-34 produced up to 33% inhibition of synaptosomal glutamate uptake with no effect on GABA uptake. In keeping with this result, the glutamate uptake blocker TBOA (5 μM) induced long-lasting synchronous discharges without suppressing the ability to produce fictive locomotion after 24 h. The novel inhibition of glutamate uptake by PJ-34 suggested that this effect may compound tests for its neuroprotective activity which cannot be merely attributed to PARP-1 block. Furthermore, the current data indicate that the neonatal rat spinal cord could withstand a strong, long-lasting rise in network excitability without compromising locomotor pattern generation or circuit structure in contrast with the damage to brain circuits known to be readily produced by persistent seizures.
authors.affiliation: Neuroscience Department, International School for Advanced Studies-SISSA, Trieste, Italy.
authors.forename: Sara Ebrahimi
authors.initials: SE
authors.lastname: Nasrabady
authors.forename: Anujaianthi
authors.initials: A
authors.lastname: Kuzhandaivel
authors.forename: Athena
authors.initials: A
authors.lastname: Akrami
authors.forename: Elena
authors.initials: E
authors.lastname: Bianchetti
authors.forename: Marco
authors.initials: M
authors.lastname: Milanese
authors.forename: Giambattista
authors.initials: G
authors.lastname: Bonanno
authors.forename: Andrea
authors.initials: A
authors.lastname: Nistri
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000494:pharmacology; D002452:Cell Count; D055724:Electrophysiological Phenomena; D004797:Enzyme-Linked Immunosorbent Assay; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D007150:Immunohistochemistry; D008124:Locomotion / Q000187:drug effects; D008161:Lumbosacral Region; D009415:Nerve Net / Q000187:drug effects*; D010616:Phenanthrenes / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1