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Spinal cord injury (SCI) can damage the axons of spinal nerve cells, preventing communication and resulting in paralysis that can affect movement as well as bodily functions such as urination. After SCI, axon regeneration is inhibited, hindering recovery. Research has shown that this inhibition is mediated by compounds called chondroitin sulphate proteoglycans (CSPGs), which block axon growth by interacting with a receptor called protein tyrosine phosphatase sigma (PTPσ). Under the direction of Jerry Silver (Case Western Reserve University School of Medicine, Cleveland, OH), scientists have been working to understand this block in hopes of learning how to circumvent it in order to rescue axon growth and improve functional recovery after SCI. In a paper published recently in Nature, they reported success in removing the CSPG–PTPσ block, restoring locomotor and bladder function in rats that had suffered contusive SCI (doi:10.1038/nature13974; published online 3 December). The key is a drug called intracellular sigma peptide (ISP), which binds PTPσ and relieves CSPG-mediated inhibition of neuronal axon extension.

Rats with SCI were given subcutaneous injections of ISP or of a placebo daily for 7 weeks beginning the day after injury. Several weeks later, rats treated with ISP showed significant improvements in bladder function or in movement. Untreated rats with SCI had less frequent bladder voiding and greater void volume than uninjured rats, but treatment with ISP increased bladder voiding frequency and decreased void volume. Bladder function was more closely analyzed in 15 rats treated with ISP, 10 of which showed evidence of reconnection of bladder functional circuitry. Thirty percent of rats with SCI treated with ISP showed improvements in locomotion, suggestive of recovery of sensorimotor coordination and balance. In total, 21 of 26 rats treated with ISP recovered at least some locomotor or bladder function.

Further analysis showed that the improvements were related to increases in serotonin levels. Serotonin is a neurotransmitter that enables communication among nerve cells. Axon growth induced by ISP flooded the surrounding tissue with serotonin, which amplified the signals being carried by intact nerves in the area. “If you have lots of extra serotonin in the spinal cord, those few nerve connections that are just a whisper will become a roar,” Silver told NPR's Jon Hamilton, “and you can get function back really nicely.”

Modulation of PTPσ may offer a new therapeutic strategy for enhancing functional recovery in humans with SCI and other disorders involving CSPG-mediated inhibition of axon regeneration.