Unusual increase in lumbar network excitability of the rat spinal cord evoked by the PARP-1 inhibitor PJ-34 through inhibition of glutamate uptake

Neuropharmacology
S E NasrabadyAndrea Nistri

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 t...Continue Reading

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Citations

Apr 23, 2013·The FEBS Journal·Torun EkbladAntonio Macchiarulo
Oct 2, 2015·ChemMedChem·Daniela PasseriAntonio Macchiarulo
Aug 8, 2015·PloS One·Antonella CardinaleFrancesca R Fusco
Jul 30, 2016·The European Journal of Neuroscience·Jaspreet KaurAndrea Nistri

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