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 mu M 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 mu M) 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. (C) 2012 Elsevier Ltd. All rights reserved.
|Titolo:||Unusual increase in lumbar network excitability of the rat spinal cord evoked by the PARP-1 inhibitor PJ-34 through inhibition of glutamate uptake|
|Autori:||Nasrabady, S. E.; Kuzhandaivel, A; Akrami, A; Bianchetti, E; Milanese, M; Bonanno, G; Nistri, A|
|Data di pubblicazione:||2012|
|Digital Object Identifier (DOI):||10.1016/j.neuropharm.2012.04.014|
|Appare nelle tipologie:||1.1 Journal article|