title: 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 vitromouse 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 inParp1-/-mice after optic nerve crush injury or dorsal hemisection of the thoracic spinal cord, and there was no improvement in motor function recovery. Thus, comprehensivein vivoanalysis reveals no indication that clinical PARP inhibitors will on their own provide benefit for recovery from CNS trauma.
authors.affiliation: 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.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Yuichi
authors.identifier: 0000-0002-2861-603X
authors.initials: Y
authors.lastname: Sekine
authors.affiliation: 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.
authors.forename: Alexandra B
authors.initials: AB
authors.lastname: Byrne
authors.affiliation: Department of Neurology, Yale University School of Medicine , New Haven, CT 06520.
authors.forename: William B J
authors.identifier: 0000-0001-6263-2167
authors.initials: WB
authors.lastname: Cafferty
authors.affiliation: 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.
authors.forename: Marc
authors.identifier: 0000-0002-3068-068X
authors.initials: M
authors.lastname: Hammarlund
authors.affiliation: 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.
authors.forename: Stephen M
authors.identifier: 0000-0001-8188-3092
authors.initials: SM
authors.lastname: Strittmatter
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000201:enzymology; D001562:Benzimidazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D013904:Thoracic Vertebrae
chemical_list: D001562:Benzimidazoles; D007527:Isoenzymes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: PARP; axon regeneration; optic nerve regeneration; poly (ADP-ribose); spinal cord injury