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eNeuro. 2016 Dec 26;3(6). pii: ENEURO.0270-16.2016. doi: 10.1523/ENEURO.0270-16.2016. eCollection 2016 Nov-Dec.

Inhibition of Poly-ADP-Ribosylation Fails to Increase Axonal Regeneration or Improve Functional Recovery after Adult Mammalian CNS Injury.

Author information

1
Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520; Department of Neurology, Yale University School of Medicine, New Haven, CT 06520.
2
Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, CT 06536; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520; Department of Genetics, Yale University School of Medicine, New Haven CT 06520.
3
Department of Neurology, Yale University School of Medicine , New Haven, CT 06520.

Abstract

After traumatic damage of the brain or spinal cord, many surviving neurons are disconnected, and recovery of function is limited by poor axon regeneration. Recent data have suggested that poly ADP-ribosylation plays a role in limiting axonal regrowth such that inhibition of poly (ADP-ribose) polymerase (PARP) may have therapeutic efficacy for neurological recovery after trauma. Here, we tested systemic administration of the PARP inhibitor, veliparib, and showed effective suppression of PARylation in the mouse CNS. After optic nerve crush injury or dorsal hemisection of the thoracic spinal cord in mice, treatment with veliparib at doses with pharmacodynamic action had no benefit for axonal regeneration or functional recovery. We considered whether PARP gene family specificity might play a role. In vitro mouse cerebral cortex axon regeneration experiments revealed that short hairpin RNA (shRNA)-mediated suppression of PARP1 promoted axonal regeneration, whereas suppression of other PARP isoforms either had no effect or decreased regeneration. Therefore, we examined recovery from neurological trauma in mice lacking PARP1. No increase of axonal regeneration was observed in Parp1-/- mice after optic nerve crush injury or dorsal hemisection of the thoracic spinal cord, and there was no improvement in motor function recovery. Thus, comprehensive in vivo analysis reveals no indication that clinical PARP inhibitors will on their own provide benefit for recovery from CNS trauma.

KEYWORDS:

PARP; axon regeneration; optic nerve regeneration; poly (ADP-ribose); spinal cord injury

PMID:
28032120
PMCID:
PMC5187389
DOI:
10.1523/ENEURO.0270-16.2016
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

S.M.S. is a co-founder of Axerion Therapeutics seeking to develop NgR1-based therapeutics.

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