The interruption of spinal circuitry following spinal cord injury disrupts neural activity and is followed by a failure to mount an effective regenerative gene expression response resulting in permanent neurological disability. Functional recovery requires the enhancement of axonal and synaptic plasticity of spared as well as injured fibres, which need to sprout and/or regenerate to form new connections. Here we will investigate whether the combined epigenetic stimulation of the regenerative gene expression program with neuronal activity-dependent enhancement of neuroplasticity and guidance can overcome the current inability to promote neurological recovery in severe and chronic spinal cord injury. This will be carried out by delivering the small molecule CBP/p300 activator CSP-TTK21 in combination with environmental enrichment. We will deliver the CBP/p300 activator CSP-TTK21 weekly between week twelve and twenty following a severe transection model of spinal cord injury in the mouse. Data analysis will assess modifications in regenerative signalling, in motor and sensory axon sprouting and regeneration, in synaptic plasticity as well as in neurological sensorimotor recovery. This approach will advance our mechanistic understanding of regenerative failure and provide insight of whether combining growth promoting strategies with enhancement of neural activity is an effective therapeutic strategy in chronic spinal cord injury.
Oral Administration of a Small Molecule Targeted to Block proNGF Binding to p75 Promotes Myelin Sparing and Functional Recovery after Spinal Cord Injury