Turning the phrase “a little bait catches a large fish” on its head, a research team from the University of Lisbon is hoping to use a little fish to make a big difference in the field of spinal cord injury (SCI). The group has designed a screening approach that determines locomotor rescue properties of small molecules in a zebrafish (Danio rerio) larval spinal cord transection model. The hope is that this simple and efficient drug screening platform will accelerate the discovery of novel therapeutics.

The platform is described in Scientific Reports in a paper titled, “A zebrafish drug screening platform boosts the discovery of novel therapeutics for spinal cord injury in mammals.”

This is a 5-day-old zebrafish larva, in which motor neurons are marked with a green fluorescent protein. [Diana Chapela, iMM]
Spinal cord injuries can have devastating consequences due to the permanent sensory and motor disabilities and lack of treatment options.

“For a significant functional recovery, it is likely that different therapies for multiple targets will be needed, due to the complex nature of the spinal cord lesions,” notes Leonor Saúde, PhD, group leader at the Instituto de Medicina Molecular (iMM) in Lisbon and senior author on the paper. “With this work,” she adds, “we have shown that, using zebrafish, we can accelerate the discovery of new therapeutic targets for spinal cord lesions.”

“We have designed a simple and efficient platform that allows testing a large number of molecules and selecting them based on their ability to accelerate the regeneration of the spinal cord in zebrafish,” explains Diana Chapela, a PhD student and first author of this paper. “Our platform,” she notes, “consists of a model of spinal cord transection in zebrafish larvae where we test different therapeutic protocols and evaluate its efficacy through larvae locomotor function over time.”

The researchers validated the screening platform by testing molecules that are in clinical trials for spinal cord injury. They showed that Riluzole and Minocycline promote rescue of the locomotor function of the transected larvae. Further validation of the platform was obtained through the blind identification of D-Cycloserine, a molecule scheduled to enter Phase IV clinical trials for SCI. The results obtained showed that these drugs can also accelerate the regeneration of the spinal cord in the zebrafish.

“We then tested our zebrafish platform on more than 100 molecules already approved by the FDA for other conditions and identified a molecule with motor recovery properties in zebrafish larvae, the Tranexamic Acid,” says Saúde. Next, the efficacy of this drug was tested in a spinal cord injury model in rodents. “Our results show that this molecule, which is an antifibrinolytic agent, has the ability to improve motor function in mammals with spinal cord injury.”

These results are a proof-of-concept for the use of this zebrafish platform that “has the potential to boost the rapid translation of new therapeutics for the spinal cord lesions in humans” when combined with drug repurposing, notes Saúde. Ultimately, the team hopes that this will accelerate the translation period from discovery to the clinics.

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