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

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.

Mechanisms underlying cell death in ischemia-like damage to the rat spinal cord in vitro

“…23, 28, 29 PAR was already strongly increased 3 h after the end of PM+Mg 2+ application, suggesting a narrow time window before irreversible cell damage could occur (demonstrated by colocalization of PAR and pyknosis). When PJ34 is administered early during the lesion protocol, a degree of functional neuroprotection is observed 36 in accordance with the present data. In general, the present results suggest that the presence of Mg 2+ during the ischemic-like protocol aggravated the damage to the white matter cells by promoting the activation of at least one major cell death pathway, namely, parthanatos.…”

A study of the potential neuroprotective effect of riluzole on locomotor networks of the neonatal rat spinal cord in vitro damaged by excitotoxicity

“…2B). In analogy with previous studies (Taccola et al, 2008;Margaryan et al, 2009Margaryan et al, , 2010Nasrabady et al, 2011aNasrabady et al, ,b, 2012, fictive locomotion could consistently be detected in sham (untreated) preparations kept for 24 h in vitro (see example in the left panel of Fig. 2C).…”

“…Since kainate-evoked damage chiefly occurs within the first 2-3 h after its washout Nasrabady et al, 2011a), we thought that neuroprotection by riluzole might be targeted to this crucial time period as long as the action of riluzole could be washed out by 24 h and fictive locomotion observed again. Hence, we first explored if 3-h riluzole application per se could allow us to observe functional activity 24 h later.…”

Molecular Mechanisms Underlying Cell Death in Spinal Networks in Relation to Locomotor Activity After Acute Injury in vitro

“…As a delayed pharmacological approach becomes desirable to combat excitotoxicity, PARP-1 inhibitors like 6,5-( H )phenanthridinone (PHE) and 2-(dimethylamino)- N -(5,6-dihydro-6-oxophenanthridin-2yl) acetamide (PJ-34; Abdelkarim et al, 2001) have been tested (Nasrabady et al, 2011a, b; Mazzone and Nistri, 2011b). As shown in Figure 3C, PHE exerts histological neuroprotection, but it cannot preserve locomotor network function (Kuzhandaivel et al, 2010b; Nasrabady et al, 2011a).…”

“…As shown in Figure 3C, PHE exerts histological neuroprotection, but it cannot preserve locomotor network function (Kuzhandaivel et al, 2010b; Nasrabady et al, 2011a). PJ-34 (60 μM) applied 30 min after the start of kainate administration and maintained for 24 h can preserve spinal network histology with return of locomotor patterns only when the excitotoxic stimulus is moderate (Nasrabady et al, 2011b).…”