PTPσ inhibitor promotes recovery after spinal cord injury

Recently, researchers from Case Western Reserve University reported a compound called ISP which may promote functional recovery after spinal cord injury[1]. Daily subcutaneous injections of ISP in rats restored neuronal regeneration and improved movements and bladder functions. The researchers are seeking to test the drug in preclinical trials.

Spinal cord injury always results in permanent paralysis owing to the limited neuronal regeneration. At the injury sites, chondroitin sulfate proteoglycans (CSPGs) contribute to glial scar formation. As with scarring in other tissues, the glial scar is the body’s mechanism to protect and begin the healing process in the nervous system. However, CSPGs inhibit axon regeneration. Degrading CSPGs with chondroitinase ABC (ChABC) promotes neural regeneration and functional recovery after spinal cord injury[2].

In 2009, Harvard’s scientists found that protein tyrosine phosphatase σ (PTPσ) is a receptor for CSPGs[3]. As early as 1999, it was reported that dimerization inhibits the activity of PTPσ through the interaction of an inhibitory ‘wedge’ on one monomer with the catalytic domain in the other monomer[4].

ISP is a novel peptide-mimetic of the PTPσ wedge with a TAT domain to facilitate membrane penetration. TAT-conjugated peptides are known to cross biological membranes, including the blood-brain barrier[5].

ISP binds to PTPσ, relieving CSPG-mediated inhibition, and restores the phosphorylation of Erk1/2. The drug promoted the axon to grow though the CSPG barrier in a dose-dependent manner to the same extent as ChABC.

[1] Nature. 2014, doi:10.1038/nature13974.

[2] Nature. 2002, 416(6881), 636-640.

[3] Science. 2009, 326(5952), 592-596.

[4] Nature. 1999, 401(6753), 606-610.

[5] Exp Neurol. 2005, 193(1), 218-227.

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