Enhanced regeneration and functional recovery after root avulsion by manipulation of proteoglycan receptor protein tyrosine phosphatase-σ

Society for Neuroscience 2015 Nanosymposium SCI Therapeutic Strategies Trauma

Enhanced regeneration and functional recovery after root avulsion by manipulation of proteoglycan receptor protein tyrosine phosphatase-σ

Dr. Jerry Silver reviewing poster presentations

Dr. Jerry Silver reviewing poster presentations

Abstract: Following root avulsion, spinal nerves are physically disconnected from the spinal cord. Severe motor neuron death, scarring in the CNS-PNS transitional zone (TZ) and long distance for axon regrowth together could lead to inefficient regeneration and devastating motor dysfunction. Chondroitin sulfate proteoglycan (CSPG) presents a major barrio for axonal extending in the extracellular matrix of scar tissue and it exerts the inhibitory role via its neuronal receptors, including protein tyrosine phosphatase-σ (PTPσ). Previously, a small peptide mimetic of PTPσ wedge motif, namely Intracellular Sigma Peptide (ISP) was generated and its capabilities to target PTPσ and relieve CSPG inhibition were validated. In the present study, in order to promote axonal regeneration and achieve functional recovery, we systematically administrated ISP for 12 weeks into adult rats with ventral root avulsion (the 5th, 6th and 7th cervical roots) and immediate re-implantation (C6 only). We show that 1) ISP treatment enabled up to 80.7% of injured motor neurons to survive, compared with 61.2% of that in vehicle treated re-implanted rats (p<0.0001, Chi-square test). 2) By facilitating newly formed axons to navigate through the inhibitory CNS-PNS TZ, ISP intervention nearly doubled the number of axons elongating in the peripheral nerve trajectory (p<0.0001, chi-square test). In addition, these axons exhibited bigger axon sizes than those found in vehicle rats (p<0.05, student’s t test). 3) Muscles atrophy was rescued in ISP rats, reflected by their high similarity to intact ones in muscle fiber diameters and motor endplate morphology. By contrast, vehicle muscles displayed shrunk myocytes (p<0.01, z test) and fibrosis. Moreover, number of motor endplates was decreased (p<0.05, chi-square test) and they were more likely to fall into smaller area categories, with lower density of acetylcholine receptors, due to delayed or lack of re-innervation. 4) Importantly, motor functional recovery was remarkably enhanced, suggested by increased averaged score of Terzis grooming test (p<0.05 at 3- and 6-weeks post injury, Mann Whitney U test) and shortened recovery duration. Electromyography further confirmed that improved behavioral performance in ISP rats was associated with healthier motor units, with less spontaneous potentials recorded. Our results show that modulation of PTPσ is a potential therapeutic strategy for root avulsion injury.

Authors: H. LI1, C. W. WONG2, W. LI2, C. RUVEN2, L. HE2, X. WU2, B. LANG3, J. SILVER3, *W. WU4; 1the Univ. of Hong Kong, Hong Kong SAR, Hong Kong; 2HKU, HK, Hong Kong; 3Case Western Reserve Univ., OH, OH; 4The Univ. Of Hong Kong, Hong Kong SAR, Hong Kong

Support: HKSCI 973 program, 2014CB502200

Disclosures: H. Li: None. C.W. Wong: None. W. Li: None. C. Ruven: None. L. He: None. X. Wu: None. Bradley Lang: None. Jerry Silver: None. W. Wu: None.

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