Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury

Mol Cell Neurosci, 2005 · DOI: 10.1016/j.mcn.2004.12.008 · Published: May 1, 2005

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Axon growth after spinal injury is limited by myelin-derived proteins acting via the Nogo-66 Receptor (NgR). This study investigates recovery from spinal cord injury (SCI) after inhibiting NgR transgenically with a soluble function-blocking NgR fragment. Mice secreting NgR(310)ecto from astrocytes, after spinal cord injury, show enhanced axonal sprouting into the lumbar spinal cord. This means that more nerve fibers are growing into the damaged area. The ability of the mice to move (locomotion) is improved in the mice that received the treatment, suggesting that blocking NgR can help in recovery from spinal cord injuries.

Study Duration

4 weeks

Participants

Adult female heterozygous-transgenic or littermate wild-type mice (2–6 months of age)

Evidence Level

Not specified

Key Findings

1
Transgenic mice expressing NgR(310)ecto showed increased CST fiber growth into the caudal spinal cord after dorsal over-hemisection compared to wild-type mice.
2
Serotonergic innervation of the caudal spinal cord returns to near normal levels in the injured transgenic mice.
3
Gait analysis revealed that the gait of transgenic mice after SCI is significantly more effective than that of wild-type injured mice and more closely resembles that of uninjured mice.

Research Summary

This study demonstrates that transgenic expression of a secreted function-blocking NgR protein has profound effects after SCI, stimulating both CST and raphespinal fiber growth in the injured spinal cord. NgR inhibition leads to a significant increase in CST fiber growth into the caudal spinal cord, although the density of CST fibers in the lumbar cord remains a small fraction of the pre-injury density. Improved locomotion and gait were observed in the transgenic mice, with cadence and stride lengths nearly resembling uninjured mice, suggesting that soluble NgR protein may provide a therapeutic means to promote recovery after SCI.

Practical Implications

Therapeutic Potential

Soluble NgR protein may offer a therapeutic approach for promoting recovery after spinal cord injury by enhancing axonal growth and improving locomotor function.

Targeted Drug Development

The Nogo-66 receptor is a potential target for the development of drugs aimed at promoting axonal regeneration and functional recovery after CNS injuries.

Combination Therapies

Combining NgR blockade with interventions targeting glial scar inhibition may offer a more effective therapeutic strategy for SCI.

Study Limitations

1
The density of CST fibers in the lumbar cord is a small fraction of the pre-injury density.
2
The study focuses on a specific injury model (dorsal over-hemisection) and may not be generalizable to other types of spinal cord injuries.
3
The long-term effects of transgenic NgR(310)ecto expression on spinal cord function and potential side effects were not fully explored.

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