title: The effect of systemic PTEN antagonist peptides on axon growth and functional recovery after spinal cord injury.
abstract: Knockout studies suggest that PTEN limits the regenerative capacities of CNS axons as a dominant antagonist of PI3 kinase, but the transgenic approach is not feasible for treating patients. Although application of bisperoxovanadium may block PTEN function, it is a general inhibitor of phosphotyrosine phosphatases and may target enzymes other than PTEN, causing side effects and preventing firm conclusions about PTEN inhibition on regulating neuronal growth. A pharmacological method to selectively suppress PTEN post-injury could be a valuable strategy for promoting CNS axon regeneration. We identified PTEN antagonist peptides (PAPs) by targeting PTEN critical functional domains and evaluated their efficacy for promoting axon growth. Four PAPs (PAP 1-4) bound to PTEN protein expressed in COS7 cells and blocked PTEN signaling in vivo. Subcutaneous administration of PAPs initiated two days after dorsal over-hemisection injury significantly stimulated growth of descending serotonergic fibers in the caudal spinal cord of adult mice. Systemic PAPs induce significant sprouting of corticospinal fibers in the rostral spinal cord and limited growth of corticospinal axons in the caudal spinal cord. More importantly, PAP treatment enhanced recovery of locomotor function in adult rodents with spinal cord injury. This study may facilitate development of effective therapeutic agents for CNS injuries.
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ohtake
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Dongsun
authors.initials: D
authors.lastname: Park
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: P M Abdul
authors.initials: PMA
authors.lastname: Muneer
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Neurology, UT Southwestern Medical Center, Dallas, TX 75390-8813, USA.
authors.forename: Kartavya
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Neuroscience, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Smith
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Neurology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Selzer
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA. Electronic address: Shuxin.li@temple.edu.
authors.forename: Shuxin
authors.initials: S
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009416:Nerve Regeneration / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D020127:Recovery of Function / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000073718:Pancreatitis-Associated Proteins; D010455:Peptides; C000612141:REG3A protein, human; D051059:PTEN Phosphohydrolase
keywords: Axon regeneration; Functional recovery; Intrinsic growth capacity; PTEN antagonist peptide; Spinal cord injury