Recapitulate development to promote axonal regeneration: good or bad approach?

Phil. Trans. R. Soc. B, 2006 · DOI: 10.1098/rstb.2006.1885 · Published: July 28, 2006

Simple Explanation

The adult mammalian central nervous system (CNS) does not spontaneously regenerate after damage, unlike the neonatal CNS. This difference is due to changes in the CNS environment and in the neurons themselves as they develop. The adult CNS environment becomes inhibitory for axonal regeneration due to the formation of a glial scar and the presence of inhibitory molecules in myelin debris. Young neurons, however, can extend axons through these inhibitors. Two developmental events are focused on: changes in the CNS environment and shifts in the neuron’s response. Understanding the molecules involved and how to overcome their inhibition is key to encouraging regeneration and functional recovery after injuries like spinal cord injury.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
The glial scar, formed by reactive astrocytes, is a major component of the inhibitory environment in the adult CNS. These astrocytes express inhibitory chondroitin sulphate proteoglycans (CSPGs).
2
Myelin-associated proteins like Nogo, MAG, and OMgp are inhibitory for regeneration in the adult CNS. These proteins interact with receptors like NgR and p75 to transduce inhibitory signals.
3
Activating the cAMP signaling pathway in neurons can block inhibition by myelin-associated inhibitors and change growth repulsion to attraction for some guidance cues and CSPGs.

Research Summary

The adult mammalian CNS does not spontaneously regenerate after injury due to an inhibitory environment and changes in the neurons themselves. This contrasts with the neonatal CNS, which can regenerate. The inhibitory environment of the adult CNS includes the formation of a glial scar and the presence of myelin-associated inhibitors. Key inhibitory molecules include CSPGs, Nogo, MAG, and OMgp. Strategies to promote regeneration involve blocking inhibitors or their receptors, or changing the neuron from within to no longer interpret the signals as inhibitory. Elevating cAMP levels in neurons is one such approach.

Practical Implications

Therapeutic Targets

Identifying and targeting specific inhibitory molecules and their receptors can lead to the development of drugs that promote axonal regeneration.

Combination Therapies

Combining multiple treatments, such as blocking myelin inhibitors, modulating the immune response, and promoting cAMP signaling, may be more effective than single interventions.

Timing of Intervention

Delivering treatments early after injury, before the glial scar matures, may be crucial for promoting axonal regeneration.

Study Limitations

1
Conflicting results from studies blocking Nogo, Nogo-66, or the NgR receptor make it difficult to determine which approach is most effective.
2
The complexity of the glial scar reaction and the challenges of inducing a permissive environment in old animals are significant hurdles.
3
Achieving successful regeneration requires not only axonal growth but also ensuring correct targeting, synapse formation, and remyelination.

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