Studies of locomotor network neuroprotection by the selective poly(ADP-ribose) polymerase-1 inhibitor PJ-34 against excitotoxic injury to the rat spinal cord in vitro

• Published in: The European journal of neuroscience Vol. 33; no. 12; pp. 2216 - 2227
• Main Authors: Nasrabady, Sara E., Kuzhandaivel, Anujaianthi, Nistri, Andrea
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2011
• Subjects: Animals; Animals, Newborn; Cell Death - drug effects; central pattern generator; Electric Stimulation; Excitatory Amino Acid Agonists - toxicity; fictive locomotion; In Vitro Techniques; kainate; kainic acid; Kainic Acid - toxicity; Locomotion - drug effects; Locomotion - physiology; Membrane Potentials - drug effects; Membrane Potentials - physiology; motoneuron; Neuroprotective Agents - therapeutic use; parthanatos; Phenanthrenes - therapeutic use; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - metabolism; Rats; Rats, Wistar; Spinal Cord Injuries - chemically induced; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - physiopathology; Spinal Cord Injuries - prevention & control
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2011.07714.x

Delayed neuronal destruction after acute spinal injury is attributed to excitotoxicity mediated by hyperactivation of poly(ADP‐ribose) polymerase‐1 (PARP‐1) that induces ‘parthanatos’, namely a non‐apoptotic cell death mechanism. With an in vitro model of excitotoxicity, we have previously observed parthanatos of rat spinal cord locomotor networks to be decreased by a broad spectrum PARP‐1 inhibitor. The present study investigated whether the selective PARP‐1 inhibitor N‐(6‐oxo‐5,6‐dihydrophenanthridin‐2‐yl)‐(N,N‐dimethylamino)acetamide.HCl (PJ‐34) not only protected networks from kainate‐evoked excitotoxicity, but also prevented loss of locomotor patterns recorded as fictive locomotion from lumbar (L) ventral roots (VRs) 24 h later. PJ‐34 (60 μm) blocked PARP‐1 activation and preserved dorsal, central and ventral gray matter with maintained reflex activity even after a large dose of kainate. Fictive locomotion could not, however, be restored by either electrical stimulation or bath‐applied neurochemicals (N‐methyl‐D‐aspartate plus 5‐hydroxytryptamine). A low kainate concentration induced less histological damage that was widely prevented by PJ‐34. Nonetheless, fictive locomotion was observed in just over 50% of preparations whose histological profile did not differ (except for the dorsal horn) from those lacking such a rhythm. Our data show that inhibition of PARP‐1 could amply preserve spinal network histology after excitotoxicity, with return of locomotor patterns only when the excitotoxic stimulus was moderate. These results demonstrated divergence between histological and functional outcome, implying a narrow borderline between loss of fictive locomotion and neuronal preservation. Our data suggest that either damage of a few unidentified neurons or functional network inhibition was critical for ensuring locomotor cycles.