After CNS axonal injuries, medical treatments to enhance recovery from neurological deficits are extremely limited. Non-permissive environments for axonal growth at least partially contribute to growth failure in the adult CNS. Specifically, several groups of inhibitory molecules strongly suppress axonal extension following CNS lesions, including chondroitin sulfate proteoglycans (CSPGs) generated by glial scars. CSPGs are the principal inhibitory components of glial scars and form a major barrier to regenerating axons. Although several strategies have been reported, digestion of CSPGs with local application of bacterial chondroitinase ABC is the major in vivo approach to surmount growth inhibition of CSPGs after CNS injuries. Important disadvantages, however, preclude the use of this enzyme as a therapeutic option for axonal injury patients, including incomplete removal of inhibitory components from CSPGs, short-period of enzymatic activity at body temperature and inability to cross the blood-brain barrier. In this proposal, we aim to develop novel strategies for treating CNS axonal injury based on inhibition of CSPGs alone or in combination with our previously identified approaches. We hypothesize that peptide antagonists of CSPGs will augment both morphological and functional recovery in a mouse model of CNS injury. Using a bioinformatics approach to define the conserved elements of several CSPGs, we have identified two selective peptide antagonists for CSPGs. Our preliminary studies suggest that these peptides at low nanomolar concentrations principally overcome neurite growth restrictions of CSPGs in neuronal cultures. Systemic application of a CSPG-blocking peptide significantly improves behavioral recovery in CNS axon-injured mice in vivo. In this study, we will characterize the therapeutic potential of these CSPG antagonistic peptides in mouse spinal cord injury (SCI) model. In addition to CSPGs, a number of inhibitory molecules contribute to axonal growth suppression intracellularly mediated via activation of convergent RhoA or glycogen synthase kinase 32 (GSK-32). Recently, we have demonstrated that inactivation of RhoA with ibuprofen or GSK-32 with lithium overcomes growth inhibition of different molecules and significantly promotes axonal growth of descending motor neurons and locomotor recovery in SCI rodents. Thus, we also aim to stimulate a more dramatic axonal regeneration in SCI mice by combining a CSPG-blocking peptide with RhoA-inhibiting ibuprofen or GSK-32-inactivating lithium, two drugs widely used in humans. The use of our novel antagonists for CSPGs, alone or in combination with ibuprofen or lithium, may significantly advance our ability to treat CNS axonal injuries in adult mammals by promoting axonal regeneration and functional recovery.
We aim to develop novel therapies for CNS axonal injuries based on strong inhibitory properties of chondroitin sulfate proteoglycans, a group of extracellular matrix molecules generated by reactive glial scars. Development of novel peptide antagonists for these axonal growth inhibitors may advance our ability to treat CNS axonal injuries in the adult mammals. We hope that the translation of our novel therapeutic strategies from neuronal cultures in vitro to mouse model in vivo will ultimately lead to key strategies in patients with spinal cord injury and other CNS lesions.
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