Despite advances in promoting axonal regeneration after acute spinal cord injury (SCI), eliciting regeneration and axonal bridging after chronic SCI remains a formidable challenge. Glial scars and inhibitory extracellular matrices that are well-established around a chronic spinal cord lesion site might be important factors in impeding axonal growth. In addition, chronically injured neurons downregulate the expression of regeneration-associated genes and become atrophic.
We have shown that inhibitory factors deposited at sites of chronic SCI do not create impenetrable boundaries, and that inhibition can be balanced by local and diffusible growth signals to generate robust axonal extension even without the resection of chronic scar tissue. Furthermore, combinatorial therapies that stimulate the neuronal cell soma with cAMP and the injured axon with NT-3 can achieve sensory axon regeneration beyond the lesion site in acute SCI.
We are currently testing the hypothesis that these combinatorial approaches are also effective in chronic models of SCI. Our data indicate that chronically-injured sensory neurons are still sensitive to growth factor delivery and conditioning peripheral lesions which increase the intrinsic growth capacity of injured neurons. Furthermore, for animal models to better replicate the pathophysiological conditions on chronic SCI, long-term models of chronic SCI are also under investigation.
Kadoya K, Tsukada S, Blesch A, Lu P, Tuszynski MH. "Post-conditioning" lesions plus NT-3 promote sensory axonal regeneration beyond sites of chronic spinal cord injury, presented at the Annual Meeting of the Society for Neuroscience, October 2006, Atlanta, GA
Lu P, Jones LL, Tuszynski MH. Axon regeneration through scars and into sites of chronic spinal cord injury. Experimental Neurology (2007): 203(1):8-21.
Lu P, Yang H, Jones LL, Filbin MT, Tuszynski MH. Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. Journal of Neuroscience (2004): 24(28):6402-9.
Jones LL, Sajed D, Tuszynski MH. Axonal regeneration through regions of chondroitin sulfate proteoglycan deposition after spinal cord injury: a balance of permissiveness and inhibition. Journal of Neuroscience (2003): 23(28):9276-88.
Ken Kadoya, MD, PhD
Assistant Project Scientist