Low oral dose of 4‑methylumbelliferone reduces glial scar but is insufficient to induce functional recovery after spinal cord injury

Scientific Reports, 2023 · DOI: 10.1038/s41598-023-46539-5 · Published: November 14, 2023

Spinal Cord Injury Genetics Neuroplasticity

Simple Explanation

Spinal cord injury leads to the formation of glial scars, which inhibit nerve regeneration. 4-methylumbelliferone (4-MU) is a substance known to inhibit the production of hyaluronan, a component of these scars. This study tested whether 4-MU could reduce glial scarring and promote recovery in rats with spinal cord injuries. Rats were given 4-MU after a spinal contusion injury, combined with treadmill rehabilitation. The treatment reduced glial scarring and increased nerve fiber sprouting, but did not result in significant functional recovery, suggesting the dose of 4-MU used was not high enough to overcome the injury-induced CSPG upregulation.

Study Duration

16 weeks

Participants

55 female Wistar rats

Evidence Level

Not specified

Key Findings

1
A low dose of 4-MU (1.2 g/kg/day) reduced hyaluronan and chondroitin sulfate levels in uninjured spinal cords.
2
In rats with chronic spinal cord injury, 4-MU treatment reduced glial scar formation around the lesion site.
3
4-MU treatment increased sprouting of serotonergic fibers in the ventral horns, but did not enhance overall synaptic density or functional recovery.

Research Summary

This study investigated the effects of 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthesis, on glial scar formation and functional recovery after spinal cord injury (SCI) in rats. Rats with chronic SCI were treated with a low dose of 4-MU (1.2 g/kg/day) combined with treadmill rehabilitation. The treatment reduced glial scar formation and increased serotonergic fiber sprouting. Despite these structural changes, the 4-MU dose was insufficient to induce significant functional recovery, suggesting a higher dose may be needed to overcome CSPG upregulation after SCI.

Practical Implications

Potential Therapeutic Target

4-MU could be a potential therapeutic agent for reducing glial scar formation after SCI, but higher doses or combination therapies may be necessary for functional recovery.

Dosage Adjustment Needed

Further studies should investigate the optimal dosage of 4-MU needed to effectively suppress CSPG upregulation and promote functional recovery after SCI.

Combination Therapy Exploration

Combining 4-MU with other therapeutic strategies, such as ChABC or other CSPG synthesis inhibitors, may enhance its effectiveness in promoting neuroplasticity and functional recovery.

Study Limitations

1
The low dose of 4-MU used in this study may have been insufficient to fully suppress CSPG upregulation after SCI.
2
The study focused on female Wistar rats, and the results may not be generalizable to other species or sexes.
3
Functional recovery was assessed using a limited set of behavioral tests, and other aspects of recovery may not have been captured.

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