Pharmacological Suppression of CNS Scarring by Deferoxamine Reduces Lesion Volume and Increases Regeneration in an In Vitro Model for Astroglial-Fibrotic Scarring and in Rat Spinal Cord Injury In Vivo

PLoS ONE, 2015 · DOI: 10.1371/journal.pone.0134371 · Published: July 29, 2015

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

This study investigates how to reduce scarring in the central nervous system after injuries, which can prevent nerve regeneration. The researchers used a combination of lab experiments with cells and experiments in rats to test a drug called deferoxamine (DFO). They found that DFO can effectively reduce scar formation, promote some nerve regeneration, and improve functional recovery after spinal cord injury in rats. The study also showed that an in vitro model, a lab setup with cells mimicking the scar environment, can be used to quickly screen potential scar-reducing treatments before testing them in animals, saving time and resources.

Study Duration

In vitro: 10-16 days. In vivo: 19 weeks

Participants

In vitro: Rat astrocytes, fibroblasts, cortical neurons. In vivo: Adult female Wistar rats

Evidence Level

Level II: In vitro and in vivo experimental study

Key Findings

1
DFO treatment led to a significant reduction of scarring and slightly increased regeneration of corticospinal tract as well as ascending CGRP-positive axons.
2
DFO was the only treatment resulting in increased growth of neurites on the clusters. Corrected for the cluster diameter, DFO showed an increase in the maximal length and the sum length of the neurites
3
The in vitro model for CNS scarring is suitable for efficient pre-screening and identification of putative scar-suppressing agents prior to in vivo application and validation.

Research Summary

The study modified an in vitro scarring model to study mechanisms of scar formation and reduction, and to investigate new scar-reducing treatments. The model uses a co-culture system of cerebral astrocytes and meningeal fibroblasts stimulated with TGF-β to form scar-like clusters. The iron chelator deferoxamine (DFO) proved to be the most effective treatment to suppress scar-like cluster formation, reduce both the scar area and its inhibitory properties, and increase neurite length of cortical neurons on the remaining clusters. In vivo experiments in rats with spinal cord injury showed that DFO treatment led to a reduction of scar size, preservation of spinal cord tissue, a slight increase in axon regeneration, and a moderate improvement of locomotor behavior.

Practical Implications

Drug Development

Deferoxamine (DFO) shows promise as a potential therapeutic agent for reducing scarring and promoting regeneration after spinal cord injury.

Pre-clinical Screening

The in vitro model provides a cost-effective and efficient method for pre-screening potential scar-reducing agents before in vivo studies.

Treatment Strategies

The study supports the use of pharmacological interventions targeting scar formation to improve functional outcomes after CNS injuries.

Study Limitations

1
The effects of the treatments on the ECM proteins seem at first sight quite weak.
2
A 2 week DFO infusion is probably not sufficient to promote long-term functional recovery in general, since reportedly DFO has a short half-life
3
BPY-DCA may show false-negative results in this in vitro assay.

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