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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS066114-02
Application #
8063891
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Owens, David F
Project Start
2010-05-01
Project End
2012-07-31
Budget Start
2011-05-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$129,918
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Neurology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Ohtake, Yosuke; Saito, Atsushi; Li, Shuxin (2018) Diverse functions of protein tyrosine phosphatase ? in the nervous and immune systems. Exp Neurol 302:196-204
Ohtake, Yosuke; Kong, Weimin; Hussain, Rashad et al. (2017) Protein tyrosine phosphatase ? regulates autoimmune encephalomyelitis development. Brain Behav Immun 65:111-124
Ohtake, Yosuke; Wong, Daniella; Abdul-Muneer, P M et al. (2016) Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons. Sci Rep 6:37152
Ohtake, Yosuke; Li, Shuxin (2015) Molecular mechanisms of scar-sourced axon growth inhibitors. Brain Res 1619:22-35
Xu, Bin; Park, Dongsun; Ohtake, Yosuke et al. (2015) Role of CSPG receptor LAR phosphatase in restricting axon regeneration after CNS injury. Neurobiol Dis 73:36-48
Ohtake, Yosuke; Hayat, Umar; Li, Shuxin (2015) PTEN inhibition and axon regeneration and neural repair. Neural Regen Res 10:1363-8
Ohtake, Yosuke; Park, Dongsun; Abdul-Muneer, P M et al. (2014) The effect of systemic PTEN antagonist peptides on axon growth and functional recovery after spinal cord injury. Biomaterials 35:4610-26
Li, H; Park, D; Abdul-Muneer, P M et al. (2013) PI3K? inhibition alleviates symptoms and increases axon number in experimental autoimmune encephalomyelitis mice. Neuroscience 253:89-99
Sharma, Kartavya; Selzer, Michael E; Li, Shuxin (2012) Scar-mediated inhibition and CSPG receptors in the CNS. Exp Neurol 237:370-8
Xing, Bin; Li, Hui; Wang, Hongyu et al. (2011) RhoA-inhibiting NSAIDs promote axonal myelination after spinal cord injury. Exp Neurol 231:247-60

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