Novel approaches to modulate CSPG inhibition for enhancing recovery after spinal cord injury
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Problem: Components of the glial scar (CSPGs) inhibit axon regeneration and plasticity
Target: Deactivating and inhibiting these molecules could facilitate a restructuring of nervous tissue (plasticity)
Goal: Increased plasticity could lead to enhanced functional recovery
Chondroitinase ABC (ChABC) is a successful and many-times validated treatment for experimental spinal cord injury (SCI). It removes a sugar particle which
(i) prevents the regeneration of nerve fibre across the injury site and
(ii) limit plasticity in an anatomal structure called perineuronal nets (PNNs). Plasticity allows the reshaping of the nervous system to adapt and compensate for the lost neural functions.
However, the use of ChABC is technically difficult and invasive, and the effect is short-lived. Here, the team proposes potential alternative ways of cancelling the inhibition of these sugar particles. These new strategies are more practicable and effective for a longer time during which the effect of rehabilitation will be greatly enhanced. They have identified, and are continuing the development of several novel substances which are able to replace ChABC for its action, but without the accompanying drawbacks.
These substances work through two main principles:
a) modify a specific region in the sugar particle
b) modulate the PNN structure
Three candidate substances are now at the stage ready to be applied in SCI models to test for their safety and effectiveness in promoting regeneration and plasticity. In parallel, they shall continue the development of other small molecules which inhibit the production of these inhibitory sugars. The team aims to determine if the candidates can boost any functional recovery after SCI by harnessing both regeneration and plasticity in a less invasive and more sustainable manner.
Perineuronal nets (PNNs, in yellow), a sugar-rich structure, wrapping the surface of a neuron in culture. Removal of the PNNs boosts plasticity.