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

Authors

  • Sara E. Nasrabady,

    1. Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
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    • S.E.N. and A.K. contributed equally to this work.

  • Anujaianthi Kuzhandaivel,

    1. Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
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    • S.E.N. and A.K. contributed equally to this work.

  • Andrea Nistri

    1. Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy
    2. Spinal Person Injury Neurorehabilitation Applied Laboratory, Istituto di Medicina Fisica e Riabilitazione, Udine, Italy
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Andrea Nistri, 1Neurobiology Sector, as above.
E-mail: nistri@sissa.it

Abstract

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.

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