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

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.

Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration

“…The ability of Hif3a suppression to increase regeneration is consistent with HIF1 signaling in C. elegans axon regeneration (Alam et al, 2016). Parp1 was previously reported to have a role in C. elegans and mouse regeneration (Byrne et al, 2016), but in vivo evaluation of its role as a target for neural repair in mammals were disappointing (Wang et al, 2016). …”

Intrinsic mechanisms of neuronal axon regeneration

“…This system is conserved across species, as removal of poly(ADP-ribose) from proteins by poly(ADP-ribose) glycohydrolases (PARGs) enhances axon regeneration in C. elegans neurons 85 . Additionally, PARP is locally activated in the injured optic nerve 84 ; however, inhibition of PARP is insufficient to enhance axonal regeneration in either the optic nerve crush injury or thoracic spinal cord injury mouse models 86 . This is consistent with the fact that downstream of Nogo, MAG and CSPGs, other pathways cause growth cone collapse 87 .…”

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

“…As was discussed above, PARP1 and SIRT1 are enzymes that require NAD+ for activity. PARP1 inhibition or elimination did not improve axon regeneration after optic nerve transection in mice (Wang et al, 2016), though treatment started 3 days after injury and there is only a few hours between injury and commencement of Wallerian degeneration.…”