Abstract
Excitotoxicity is considered to be a major pathophysiological mechanism responsible for extensive neuronal death after acute spinal injury. The chief effector of such a neuronal death is thought to be the hyperactivation of intracellular PARP-1 that leads to cell energy depletion and DNA damage with the manifestation of non-apoptotic cell death termed parthanatos. An in vitro lesion model using the neonatal rat spinal cord has recently shown PARP-1 overactivity to be closely related to neuronal losses after an excitotoxic challenge by kainate: in this system the PARP-1 inhibitor 6(5H)-phenanthridinone (PHE) appeared to be a moderate histological neuroprotector. This article investigated whether PHE could actually preserve the function of locomotor networks in vitro from excitotoxicity. Bath-applied PHE (after a 60 min kainate application) failed to recover locomotor network function 24 h later. When the PHE administration was advanced by 30 min (during the administration of kainate), locomotor function could still not be recovered, while basic network rhythmicity persisted. Histochemical analysis showed that, even if the number of surviving neurons was improved with this protocol, it had failed to reach the threshold of minimal network membership necessary for expressing locomotor patterns. These results suggest that PARP-1 hyperactivity was a rapid onset mechanism of neuronal loss after an excitotoxic challenge and that more selective and faster-acting PARP-1 inhibitors are warranted to explore their potential neuroprotective role.
This is a preview of subscription content, log in via an institution to check access.
References
Banasik M, Komura H, Shimoyama M, Ueda K (1992) Specific inhibitors of poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase. J Biol Chem 267:1569–1575
Baranauskas G, Nistri A (1995) Membrane potential oscillations of neonatal rat spinal motoneurons evoked by electrical stimulation of dorsal root fibres. Eur J Neurosci 7:2403–2408
Bracci E, Ballerini L, Nistri A (1996) Localization of rhythmogenic networks responsible for spontaneous bursts induced by strychnine and bicuculline in the rat isolated spinal cord. J Neurosci 16:7063–7076
Bracci E, Beato M, Nistri A (1997) Afferent inputs modulate the activity of a rhythmic burst generator in the rat disinhibited spinal cord in vitro. J Neurophysiol 77:3157–3167
Butt SJ, Lebret JM, Kiehn O (2002) Organization of left-right coordination in the mammalian locomotor network. Brain Res Brain Res Rev 40:107–117
Chiarugi A (2002) Inhibitors of poly(ADP-ribose) polymerase-1 suppress transcriptional activation in lymphocytes and ameliorate autoimmune encephalomyelitis in rats. Br J Pharmacol 137:761–770
Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang ZQ, Dawson TM, Snyder SH, Dawson VL (1997) Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 3:1089–1095
Genovese T, Mazzon E, Muia C, Patel NS, Threadgill MD, Bramanti P, De Sarro A, Thiemermann C, Cuzzocrea S (2005) Inhibitors of poly(ADP-ribose) polymerase modulate signal transduction pathways and secondary damage in experimental spinal cord trauma. J Pharmacol Exp Ther 312:449–457
Koh SH, Park Y, Song CW, Kim JG, Kim K, Kim J, Kim MH, Lee SR, Kim DW, Yu HJ, Chang DI, Hwang SJ, Kim SH (2004) The effect of PARP inhibitor on ischaemic cell death, its related inflammation and survival signals. Eur J Neurosci 20:1461–1472
Kuzhandaivel A, Nistri A, Mladinic M (2010) Kainate-mediated excitotoxicity induces neuronal death in the rat spinal cord in vitro via a PARP-1 dependent cell death pathway (Parthanatos). Cell Mol Neurobiol 30:1001–1012
Li JH, Serdyuk L, Ferraris DV, Xiao G, Tays KL, Kletzly PW, Li W, Lautar S, Zhang J, Kalish VJ (2001) Synthesis of substituted 5[H]phenanthridin-6-ones as potent poly(ADP-ribose)polymerase-1 (PARP1) inhibitors. Bioorg Med Chem Lett 11:1687–1690
Marchetti C, Beato M, Nistri A (2001) Alternating rhythmic activity induced by dorsal root stimulation in the neonatal rat spinal cord in vitro. J Physiol 530:105–112
Margaryan G, Mattioli C, Mladinic M, Nistri A (2010) Neuroprotection of locomotor networks after experimental injury to the neonatal rat spinal cord in vitro. Neuroscience 165:996–1010
Mazzone GL, Margaryan G, Kuzhandaivel A, Nasrabady SE, Mladinic M, Nistri A (2010) Kainate-induced delayed onset of excitotoxicity with functional loss unrelated to the extent of neuronal damage in the in vitro spinal cord. Neuroscience 168:451–462
Narasimhan P, Fujimura M, Noshita N, Chan PH (2003) Role of superoxide in poly(ADP-ribose) polymerase upregulation after transient cerebral ischemia. Brain Res Mol Brain Res 113:28–36
Nistri A, Taccola G, Mladinic M, Margaryan G, Kuzhandaivel A (2010) Deconstructing locomotor networks with experimental injury to define their membership. Ann N Y Acad Sci 1198:242–251
Scott GS, Jakeman LB, Stokes BT, Szabo C (1999) Peroxynitrite production and activation of poly (adenosine diphosphate-ribose) synthetase in spinal cord injury. Ann Neurol 45:120–124
Taccola G, Nistri A (2006) Oscillatory circuits underlying locomotor networks in the rat spinal cord. Crit Rev Neurobiol 18:25–36
Taccola G, Margaryan G, Mladinic M, Nistri A (2008) Kainate and metabolic perturbation mimicking spinal injury differentially contribute to early damage of locomotor networks in the in vitro neonatal rat spinal cord. Neuroscience 155:538–555
Wang Y, Dawson VL, Dawson TM (2009) Poly(ADP-ribose) signals to mitochondrial AIF: a key event in parthanatos. Exp Neurol 218:193–202
Acknowledgments
This study was supported by grants from the government of the Friuli Venezia Giulia Region and the Italian Ministry for Education and Research (MIUR) under their PRIN program. M.M. is a research biologist of the Local Health Authority (ASS4 MedioFriuli).
Author information
Authors and Affiliations
Corresponding author
Additional information
Sara Ebrahimi Nasrabady, and Anujaianthi Kuzhandaivel are joint first authors.
Rights and permissions
About this article
Cite this article
Nasrabady, S.E., Kuzhandaivel, A., Mladinic, M. et al. Effects of 6(5H)-phenanthridinone, an Inhibitor of Poly(ADP-ribose)Polymerase-1 Activity (PARP-1), on Locomotor Networks of the Rat Isolated Spinal Cord. Cell Mol Neurobiol 31, 503–508 (2011). https://doi.org/10.1007/s10571-011-9661-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-011-9661-x