EphA4 Blockers Promote Axonal Regeneration and Functional Recovery Following Spinal Cord Injury in Mice

PLoS ONE, 2011 · DOI: 10.1371/journal.pone.0024636 · Published: September 13, 2011

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Following spinal cord injury, molecules that guide axon growth during development are reactivated and can inhibit regeneration. This study investigated whether blocking one of these molecules, EphA4, could promote recovery in mice with spinal cord injuries. Two different EphA4 blockers were tested: unclustered ephrin-A5-Fc and EphA4-Fc. These blockers were administered for two weeks after injury and their effect on axon regeneration and functional recovery was assessed. The study found that both blockers promoted substantial axonal regeneration and functional recovery. This suggests that blocking EphA4 interactions is a viable therapeutic option for spinal cord injury treatment.

Study Duration

5 weeks

Participants

Adult (8–12 week old) male C57BL/6 mice

Evidence Level

Level 2: Experimental study in mice

Key Findings

1
Administration of either ephrin-A5-Fc or EphA4-Fc for 2 weeks following spinal cord injury resulted in substantial axonal regeneration, with many axons entering and crossing the lesion site.
2
Treatment with EphA4-Fc or ephrin-A5-Fc showed a significant decrease in GFAP positive astrocyte numbers, indicating reduced astrocytic gliosis.
3
Both ephrin-A5-Fc and EphA4-Fc treatments resulted in significant improvement in the ability to walk or climb on a grid, with animals making far fewer foot falls and showing weight support with the affected left hind limb.

Research Summary

This study provides evidence that soluble inhibitors of EphA4 function can be used therapeutically to promote recovery from spinal cord injury in mice. Two EphA4 blockers, ephrin-A5-Fc and EphA4-Fc, were administered to wildtype mice after spinal cord hemisection. Both treatments resulted in significant axonal regeneration and functional improvement. The mechanism by which the Eph-blocking treatments promoted regeneration appears to be primarily at the level of the axonal growth cone, blocking EphA4:ephrin interactions that would normally result in growth cone collapse.

Practical Implications

Therapeutic Potential

Soluble inhibitors of EphA4 function offer considerable therapeutic potential for the treatment of spinal cord injury.

Broader Applications

EphA4 inhibitors may have broader potential for the treatment of other central nervous system injuries, such as brain trauma or stroke.

Combination Therapies

A combined therapy that includes blocking of semaphorins, for example, may be even more effective at promoting axonal regeneration and further functional recovery.

Study Limitations

1
The study was conducted on mice, and the results may not be directly applicable to humans.
2
The exact mechanisms by which EphA4 blockers promote regeneration require further elucidation.
3
The long-term effects of EphA4 blockade on spinal cord repair and function were not fully explored.

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