The effect of systemic PTEN antagonist peptides on axon growth and functional recovery after spinal cord injury

Yosuke Ohtake, Dongsun Park, P. M. Abdul-Muneer, Hui Li, Bin Xu, Kartavya Sharma, George M. Smith, Michael E. Selzer, Shuxin Li

Research output: Contribution to journalArticle

48 Scopus citations

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 invivo. 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.

Original languageEnglish (US)
Pages (from-to)4610-4626
Number of pages17
JournalBiomaterials
Volume35
Issue number16
DOIs
StatePublished - May 2014

Keywords

  • Axon regeneration
  • Functional recovery
  • Intrinsic growth capacity
  • PTEN antagonist peptide
  • Spinal cord injury

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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    Ohtake, Y., Park, D., Abdul-Muneer, P. M., Li, H., Xu, B., Sharma, K., Smith, G. M., Selzer, M. E., & Li, S. (2014). The effect of systemic PTEN antagonist peptides on axon growth and functional recovery after spinal cord injury. Biomaterials, 35(16), 4610-4626. https://doi.org/10.1016/j.biomaterials.2014.02.037