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 |
| |
Authors: | Sara Ebrahimi Nasrabady Anujaianthi Kuzhandaivel Miranda Mladinic Andrea Nistri |
| |
Institution: | (1) Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy;(2) Spinal Person Injury Neurorehabilitation Applied Laboratory (SPINAL), Istituto di Medicina Fisica e Riabilitazione, Udine, Italy; |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed SpringerLink 等数据库收录! |
|