Neuroprotection of locomotor networks after experimental injury to the neonatal rat spinal cord in vitro

Margaryan, G.; Mattioli, Carlos A.; Mladinić, Miranda; Nistri, Andrea

doi:10.1016/j.neuroscience.2009.10.066

Cited by 21 publications

(22 citation statements)

References 42 publications

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“…Full details of the experimental methods have recently been published (Taccola et al 2008;Margaryan et al 2010). In brief, we used neonatal (age: 0-2 days) rat spinal cords with the following protocols: sham preparations were maintained in vitro for up to 24 h in standard Krebs solution (Taccola et al 2008); injured preparations were treated with a maximally effective dose (1 mM) of the glutamate agonist kainate (60 min) followed by wash and maintenance in Krebs solution for 24 h. PHE (60 lM; Sigma, Milan, Italy)-treated preparations received this drug either at the time of kainate washout or after the first 30 min of kainate application.…”

Section: Methodsmentioning

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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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: Methodsmentioning

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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“…Neuronal nuclei (NeuN) monoclonal antibody has been widely used in our lab (Taccola et al 2008;Margaryan et al 2009Margaryan et al , 2010 as a reliable tool to detect differentiated neurons: its neuronal target has been recently identified as Fox-3 (Kim et al 2009). In the present study, we used NeuN to assess the number of surviving neurons after excitotoxicity.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…The protocol of the present experiments was similar to the one of our previous reports (Taccola et al 2008;Margaryan et al 2010) and consisted of applying a temporary, strong excitotoxic stimulus (such as kainate) to find out what happened (and to what cells and for how long) after removal of the excitotoxic agent. This in vitro model was, therefore trying to imitate, despite its intrinsic limitations (lack of vascular supply and of immune system responses), the rapid evolution of acute spinal injury in vivo, in which excitotoxicity is believed to be an early strong contributor to the severe network damage (Choi 1992;Hall and Springer 2004;Park et al 2004).…”

Section: An In Vitro Model Of Spinal Network Damage Induced By Kainatmentioning

confidence: 99%

“…Nonetheless, our recent investigation has shown that such substances chiefly target the white matter of the spinal cord in vitro (Taccola et al 2008). Hence, our aim was to explore if kainateevoked excitotoxicity mainly directed to neurons (Taccola et al 2008;Margaryan et al 2010) was expressed via apoptotic or PARP-1 mechanisms and what timecourse it followed.…”

Section: Introductionmentioning

confidence: 99%

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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)

2010

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Kainate is an effective excitotoxic agent to lesion spinal cord networks, thus providing an interesting model for investigating basic mechanisms of spinal cord injury. The present study aimed at revealing the type and timecourse of cell death in rat neonatal spinal cord preparations in vitro exposed to 1 h excitotoxic insult with kainate. Substantial numbers of neurons rather than glia showed pyknosis (albeit without necrosis and with minimal apoptosis occurrence) already apparent on kainate washout and peaking 12 h later with dissimilar spinal topography. Neurons appeared to suffer chiefly through a process involving anucleolytic pyknosis mediated by strong activation of poly(ADP-ribose)polymerase-1 (PARP-1) that generated poly ADP-ribose and led to nuclear translocation of the apoptotic inducing factor (AIF) with DNA damage. This process had the hallmarks of parthanatos-type neuronal death. The PARP-1 inhibitor 6-5(H)-phenathridione applied immediately after kainate washout significantly prevented pyknosis in a dose-dependent fashion and inhibited PARP-1-dependent nuclear AIF translocation. Conversely, the caspase-3 inhibitor II was ineffective against neuronal damage. Our results suggest that excitotoxicity of spinal networks was mainly directed to neurons and mediated by PARP-1 death pathways, indicating this mechanism as a potential target for neuroprotection to limit the acute damage to the local circuitry.

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“…The acute phase of SCI (due to the primary insult of mechanical, vascular or dysmetabolic nature) rapidly evolves into secondary damage, characterized by excitotoxicity caused by massive release of glutamate, in turn triggering a complex pathophysiological cascade generating toxic compounds (Dumont et al, 2001;Park et al, 2004;Rowland et al, 2008;Forder and Tymianski, 2009;Fatima et al, 2014). Thus, neuroprotection against secondary injury is a major therapeutic target (York et al, 2013;Cox et al, 2014) to preserve the spinal gray (Lipton, 2006;Sa´mano et al, 2012) and white matter containing the long-fiber tracts (Kanellopoulos et al, 2000;Lee et al, 2008;Margaryan et al, 2010;Sun et al, 2010;Cox et al, 2014). Large-scale clinical trials proposed the early i.v.…”

Section: Introductionmentioning

confidence: 99%

A study of methylprednisolone neuroprotection against acute injury to the rat spinal cord in vitro

2016

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Neuroprotection of locomotor networks after experimental injury to the neonatal rat spinal cord in vitro

Cited by 21 publications

References 42 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

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

A study of methylprednisolone neuroprotection against acute injury to the rat spinal cord in vitro

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