Kainate-Mediated Excitotoxicity Induces Neuronal Death in the Rat Spinal Cord In Vitro via a PARP-1 Dependent Cell Death Pathway (Parthanatos)

Kuzhandaivel, Anujaianthi; Nistri, Andrea; Mladinić, Miranda

doi:10.1007/s10571-010-9531-y

Cited by 60 publications

(69 citation statements)

References 84 publications

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“…A similar process has also been suggested to occur in the spinal cord after an acute lesion (Scott et al 1999;Genovese et al 2005;Kuzhandaivel et al 2010). Our in vitro model using the rat-isolated spinal cord subjected to a transient excitotoxic stimulus by the glutamate receptor agonist kainate has demonstrated substantial neuronal losses attributable to parthanatos (with preservation of glia) that was attenuated by the PARP-1 inhibitor 6(5H)-phenanthridinone (PHE; Kuzhandaivel et al 2010). Nonetheless, this observation needs validation with electrophysiological recording to prove whether locomotor network activity in vitro is preserved as well.…”

Section: Introductionmentioning

confidence: 66%

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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

et al. 2011

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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.

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Section: Introductionmentioning

confidence: 66%

“…During the process of neuronal excitotoxicity, hyperactivation of the intracellular enzyme poly(ADP-ribose)polymerase-1 (PARP-1) is thought to be a major step to trigger a non-apoptotic form of cell death termed parthanatos (Narasimhan et al 2003;Wang et al 2009;Kuzhandaivel et al 2010).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…We previously used a less selective antagonist of PARP-1, namely PHE, and observed analogous results on the rat isolated spinal cord (Kuzhandaivel et al 2010b). Since PJ 34 is reported to be also an inhibitor of metalloproteinases (Nicolescu et al 2009), we cannot exclude the possibility that this effect contributed to the current data.…”

Section: Neuroprotection By Pj 34mentioning

confidence: 69%

“…Our previous data demonstrated that, in the rat isolated spinal cord, neurons showed PAR-immunopositivity and pyknotic nuclei 24 h after a large concentration (1 mM) of kainate (Kuzhandaivel et al 2010b). Thus, we first investigated whether kainate induced strong expression of PAR also in organotypic slices and what timecourse this phenomenon might follow.…”

Section: Time and Concentration Dependence Of Kainate Excitotoxicity mentioning

confidence: 93%

“…PARP-1-mediated neuronal death is believed to be a common mechanism triggered by ischaemia and injury, and can be classified as 'parthanatos' (Andrabi et al 2008). This process involves generation of high concentrations of poly-ADP-ribose (PAR), which is toxic to the cell energy metabolism of spinal networks (Kuzhandaivel et al 2010b). In this model, intracellular production of PAR leads to nuclear translocation of the apoptotic inducing factor (AIF) with subsequent DNA damage: partial neuroprotection can be observed by application of the PARP-1 inhibitor 6-5(H)-phenanthridione (PHE; Kuzhandaivel et al 2010b).…”

Section: Introductionmentioning

confidence: 99%

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Effect of the PARP-1 Inhibitor PJ 34 on Excitotoxic Damage Evoked by Kainate on Rat Spinal Cord Organotypic Slices

Mazzone

Nistri

2010

Cell Mol Neurobiol

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Excitotoxicity triggered by over-activation of glutamate receptors is thought to be an early mechanism of extensive neuronal death with consequent loss of function following lesion of spinal networks. One important process responsible for excitotoxic death is 'parthanatos' caused by hyperactivation of poly(ADP-ribose) polymerase (PARP) enzyme 1. Using rat organotypic spinal slices as in vitro models, the present study enquired if 2-(dimethylamino)-N-(5,6-dihydro-6-oxophenanthridin-2yl)acetamide (PJ 34), a pharmacological inhibitor of PARP-1, could counteract the excitotoxic damage evoked by transient application (1 h) of kainate, a potent analogue of glutamate. Kainate induced dose-dependent (1 μM threshold) neuronal loss (without damage to astrocytes) detected 24 h later via a PARP-1 dependent process that had peaked at 4 h after washout kainate. All spinal regions (ventral, central and dorsal) were affected, even though the largest damage was found in the dorsal area. Whereas PJ 34 did not protect against a large concentration (100 μM) of kainate, it significantly inhibited neuronal losses evoked by 10 μM kainate as long as it was co-applied with this glutamate agonist. When the application of PJ 34 was delayed to the washout time, neuroprotection was weak and regionally restricted. These data suggest that kainate-induced parthanatos developed early and was prevented by PJ 34 only when it was co-applied together with excitotoxic stimulus. Our results highlight the difficulty to arrest parthanatos as a mechanism of spinal neuron death in view of its low threshold of activation by kainate, its widespread distribution, and relatively fast development.

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Postnatal developmental profile of neurons and glia in motor nuclei of the brainstem and spinal cord, and its comparison with organotypic slice cultures

Cifra

Mazzone

Nani

et al. 2012

Developmental Neurobiology

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In vitro preparations of the neonatal rat spinal cord or brainstem are useful to investigate the organization of motor networks and their dysfunction in neurological disease models. Long-term spinal cord organotypic cultures can extend our understanding of such pathophysiological processes over longer times. It is, however, surprising that detailed descriptions of the type (and number) of neurons and glia in such preparations are currently unavailable to evaluate cell-selectivity of experimental damage. The focus of the present immunohistochemical study is the novel characterization of the cell population in the lumbar locomotor region of the rat spinal cord and in the brainstem motor nucleus hypoglossus at 0-4 postnatal days, and its comparison with spinal organotypic cultures at 2-22 days in vitro. In the nucleus hypoglossus, neurons were 40% of all cells and 80% of these were motoneurons. Astrocytes (35% of total cells) were the main glial cells, while microglia was <10%. In the spinal gray matter, the highest neuronal density was in the dorsal horn (>80%) and the lowest in the ventral horn (≤57%) with inverse astroglia numbers and few microglia. The number of neurons (including motoneurons) and astrocytes was stable after birth. Like in the spinal cord, motoneurons in organotypic spinal culture were <10% of ventral horn cells, with neurons <40%, and the rest made up by glia. The present report indicates a comparable degree of neuronal and glial maturation in brainstem and spinal motor nuclei, and that this condition is also observed in 3-week-old organotypic cultures.

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Kainate-Mediated Excitotoxicity Induces Neuronal Death in the Rat Spinal Cord In Vitro via a PARP-1 Dependent Cell Death Pathway (Parthanatos)

Cited by 60 publications

References 84 publications

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

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

Effect of the PARP-1 Inhibitor PJ 34 on Excitotoxic Damage Evoked by Kainate on Rat Spinal Cord Organotypic Slices

Postnatal developmental profile of neurons and glia in motor nuclei of the brainstem and spinal cord, and its comparison with organotypic slice cultures

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