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

• Published in: Biomaterials 2014-05, Vol.35 (16), p.4610-4626
• Main Authors: Ohtake, Yosuke, Park, Dongsun, Abdul-Muneer, P.M, Li, Hui, Xu, Bin, Sharma, Kartavya, Smith, George M, Selzer, Michael E, Li, Shuxin
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Amino Acid Sequence; Animals; Axon regeneration; Axons - drug effects; Axons - pathology; Cercopithecus aethiops; COS Cells; Dentistry; Female; Functional recovery; Humans; Intrinsic growth capacity; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Nerve Regeneration - drug effects; Neurogenesis - drug effects; Pancreatitis-Associated Proteins; Peptides - chemistry; Peptides - therapeutic use; PTEN antagonist peptide; PTEN Phosphohydrolase - antagonists & inhibitors; PTEN Phosphohydrolase - metabolism; Recovery of Function - drug effects; Spinal Cord - drug effects; Spinal Cord - physiopathology; Spinal Cord Injuries - drug therapy; Spinal Cord Injuries - physiopathology; Spinal cord injury
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2014.02.037

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.