Looking downstream: the role of cyclic AMP-regulated genes in axonal regeneration

Front. Mol. Neurosci., 2015 · DOI: 10.3389/fnmol.2015.00026 · Published: June 18, 2015

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Elevation of intracellular cyclic AMP (cAMP) levels has proven to be one of the most effective means of overcoming inhibition of axonal regeneration by myelin-associated inhibitors such as myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte myelin glycoprotein. The effects of cAMP are transcription-dependent and are mediated through the activation of protein kinase A (PKA) and the transcription factor cyclic AMP response element binding protein (CREB). This leads to the induction of a variety of genes, several of which have been shown to overcome myelin-mediated inhibition in their own right.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
ArgI activity was sufficient to mediate this response.
2
Delivery of IL-6 was found to promote both neurite outgrowth in the presence of myelin-associated inhibitors and in vivo axonal regeneration in the injured spinal cord
3
SLPI can promote axonal regeneration in the injured mammalian CNS.

Research Summary

It has become increasingly clear that there is no single pathway, protein, or drug that can promote robust axonal regeneration in the injured CNS, but our microarray analysis of the conditioning lesion effect has provided us with valuable insight into the spectrum of genes that are modulated to produce axonal regeneration. In the case of ArgI, IL-6, SLPI, and MT-I/II, each protein can overcome inhibition by myelin and promote modest axonal regeneration, but all four have uniquely different mechanisms for overcoming the inhibitory environment of the CNS By continuing to investigate the effects of these cAMP-regulated genes on axonal growth, we will advance our understanding of endogenous repair mechanisms, move closer to the ultimate goal of developing methods to enhance them and produce clinical benefit for patients with spinal cord injury.

Practical Implications

Therapeutic Potential of Arginase I

ArgI and its products, particularly spermidine, could be leveraged to directly promote axonal regeneration in vivo, representing a potential therapeutic target for spinal cord injury.

IL-6 as a Pro-Regenerative Agent

The pro-regenerative and neuroprotective functions of IL-6, especially when delivered intravitreally, suggest potential therapeutic use in promoting axonal regeneration after optic nerve crush and other CNS injuries.

SLPI as a Therapeutic Target

SLPI's ability to reverse inhibition by CNS myelin, promote regeneration in the optic nerve, and suppress Smad2 expression indicates its potential as a therapeutic target for spinal cord injury.

Study Limitations

1
The precise mechanisms of IL-6-dependent axonal regeneration require further elucidation.
2
The physiological role of metallothioneins (MTs) is poorly defined, despite extensive study.
3
Combinatorial effects of IL-6, ArgI, SLPI and/or MT-I/II, as well as other growth-promoting agents such as BDNF, need to be examined to develop effective treatments for spinal cord injury.

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