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

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• 作者：Sara Ebrahimi Nasrabady^a ; Anujaianthi Kuzhandaivel^a ; ¹ ; Athena Akrami^a ; Elena Bianchetti^a ; Marco Milanese^b ; Giambattista Bonanno^b ; ^c ; Andrea Nistri^a ; ^d ; ^{nistri@sissa.it}
• 关键词：Excitotoxicity ; Motoneurons ; Fictive locomotion
• 刊名：Neuropharmacology
• 出版年：2012
• 期刊代码：33_00283908
• 类别：pha
• 出版时间：September, 2012
• 卷：63
• 期：3
• 页码：415-426
• 文件大小：1334 K

摘要

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聽vitro showed that, under control conditions, 1-60聽渭M PJ-34 per se strongly increased spontaneous network discharges occurring synchronously on ventral roots, persisting for 24聽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聽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聽渭M) induced long-lasting synchronous discharges without suppressing the ability to produce fictive locomotion after 24聽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.