Inhibition of central axon regeneration: perspective from chondroitin sulfate proteoglycans in lamprey spinal cord injury

Neural Regeneration Research, 2022 · DOI: 10.4103/1673-5374.335144 · Published: September 1, 2022

Spinal Cord Injury Regenerative Medicine Genetics

Simple Explanation

After spinal cord injury (SCI), axon regeneration fails, leading to paralysis. Chondroitin sulfate proteoglycans (CSPGs) are secreted at the injury site and were initially considered a physical barrier. These CSPGs interact with receptors, initiating inhibitory signaling that prevents regeneration. Studies show that removing CSPGs with chondroitinase ABC (ChABC) reduces their inhibitory effects and promotes axon growth and functional recovery. ChABC treatment enhances axon sprouting after SCI. Experiments in lampreys, which have identifiable reticulospinal (RS) neurons, show that CSPG digestion reduces apoptotic signaling and enhances axon regeneration after spinal cord transection.

Study Duration

Not specified

Participants

Lampreys and Mammalian models

Evidence Level

Not specified

Key Findings

1
Digestion of CSPGs with ChABC reduces retrograde apoptotic signaling and enhances true axon regeneration in lampreys after spinal cord transection.
2
Upregulation of PTPσ mRNA in RS neurons after SCI is partly due to the actions of elevated CSPGs at the injury site, indicating a retrograde effect.
3
ChABC treatment promotes axonal regeneration after SCI and is accompanied by enhanced Akt activation, protecting RS neurons from retrograde apoptosis.

Research Summary

CSPGs inhibit axon regeneration after SCI by interacting with receptors like PTPσ, LAR, and NgRs, activating RhoA and inactivating Akt signaling pathways. ChABC treatment can remove CSPGs, reactivate the Akt signaling pathway, promote axon regeneration, and reduce retrograde neuronal apoptotic signaling after SCI. A successful approach to promoting CNS axon regeneration should combine manipulations of both intracellular and extracellular mechanisms.

Practical Implications

Targeting CSPGs for SCI Therapy

Modulating CSPG levels or CSPG receptor activities could promote axon regeneration after SCI.

Combination Therapies

Combining manipulations of both intracellular and extracellular mechanisms may enhance recovery from SCI.

ChABC Delivery Methods

Optimizing delivery methods for ChABC, such as nanoparticles or synthetic scaffolds, could improve its efficacy in treating SCI.

Study Limitations

1
Effects of NG2/CSPG4 on axon regeneration are inconsistent.
2
Mammalian models may exhibit collateral sprouting, complicating the assessment of true regeneration.
3
Thermo-instability of ChABC limits its long-lasting efficacy in vivo.

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