Combined RhoA morpholino and ChABC treatment protects identiﬁed lamprey neurons from retrograde apoptosis after spinal cord injury

Front. Cell. Neurosci., 2023 · DOI: 10.3389/fncel.2023.1292012 · Published: December 21, 2023

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

This study investigates the combined effects of RhoA knockdown and ChABC treatment on neuronal survival and axon regeneration after spinal cord injury in lampreys. Researchers used morpholinos (MOs) to reduce RhoA levels and ChABC to digest CSPGs, evaluating the impact on nerve regeneration and apoptotic signaling. The study found that combining RhoA knockdown with ChABC treatment had a better protective effect on reticulospinal (RS) neurons than either treatment alone. This combination also enhanced Akt phosphorylation, a key signaling molecule involved in cell survival and regeneration. These results suggest that RhoA and CSPGs have both overlapping and independent mechanisms in inhibiting nerve regeneration. Therefore, therapies targeting both pathways simultaneously may be more effective in treating spinal cord injuries.

Study Duration

2, 4, and 10 weeks

Participants

Wild-type larval lampreys, Petromyzon marinus, 10–14 cm in length (4–5 years old)

Evidence Level

Not specified

Key Findings

1
The combination of RhoA MO plus ChABC had the best protective effect on identiﬁed reticulospinal (RS) neurons compared to control, ChABC alone, or RhoA MO alone at 4 weeks post-transection.
2
The percent regenerated axons in the RhoA MO plus ChABC group was greater than that in any of the other groups at 10 weeks post-transection.
3
The RhoA MO plus ChABC treatment enhanced pAkt-308 phosphorylation more than any of the other treatment groups, indicating a synergistic effect on Akt activation.

Research Summary

This study examines the additive effects of RhoA knockdown via morpholinos (MOs) and ChABC treatment on promoting axon regeneration and inhibiting apoptotic signaling in lampreys after spinal cord injury (SCI). The research demonstrates that the combination of RhoA MO and ChABC provides a greater benefit than either treatment alone in reducing retrograde neuronal apoptosis and enhancing axon regeneration post-SCI. The study also reveals that combinatorial treatment significantly enhances Akt phosphorylation, suggesting a critical intracellular mechanism underlying the observed neuroprotective and regenerative effects.

Practical Implications

Therapeutic potential for SCI

Combined therapies targeting both RhoA and CSPGs may offer a more effective approach for promoting neuronal survival and axon regeneration after spinal cord injury.

Understanding SCI mechanisms

The study provides insights into the overlapping and independent roles of RhoA and CSPGs in inhibiting nerve regeneration, which can inform the development of more targeted treatments.

Enhancing Akt activation

Strategies to enhance Akt phosphorylation, possibly through combinatorial approaches, could be beneficial in promoting neuronal survival and axon regeneration in SCI and other neurological conditions.

Study Limitations

1
The method of measuring axon regeneration by retrograde transport of tracer may underestimate the total amount of axon regeneration.
2
The diﬀerence between the RhoA MO plus ChABC combined treatment and either treatment alone might not have reached statistical signiﬁcance.
3
Limitations of the retrograde labeling method make detection of diﬀerences less accurate.

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