A zebrafish drug screening platform boosts the discovery of novel therapeutics for spinal cord injury in mammals

Abstract

Spinal cord injury (SCI) is a complex condition, with limited therapeutic options, that results in sensory and motor disabilities. To boost discovery of novel therapeutics, we designed a simple and efficient drug screening platform. This innovative approach allows to determine locomotor rescue properties of small molecules in a zebrafish ( Danio rerio ) larval spinal cord transection model. We validated our screening platform by showing that Riluzole and Minocycline, two molecules that are in clinical trials for SCI, 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. Importantly, we identified Tranexamic acid and further showed that this molecule maintains its locomotor recovery properties in a rodent female contusion model. Our screening platform, combined with drug repurposing, promises to propel the rapid translation of novel therapeutics to improve SCI recovery in humans.

Epitranscriptomic m6A regulation following spinal cord injury

“…Compared with the control group, significant locomotion deficits were observed in the SCI group at 2 dpi and 4 dpi, as shown by a reduction in total moving distance and alteration in turn angle (a measure of the change in head direction, an important indicator for the fitness of the movement), but these differences were negligible at 6 dpi (Figure 1f‐g). These are consistent with previous study that larval zebrafish have a rapid morphological and functional recovery from SCI, which can be achieved in 5–6 dpi (Chapela et al., 2019).…”

“…(f-g) Behavioral analysis of larval zebrafish at 2, 4, and 6 day post injury (f: 2 dpi, t17 = 10.87, p < 0.0001; 4 dpi, t21 = 8.217, p < 0.0001; 6 dpi, t22 = 1.494, p = 0.1494 g: 2 dpi, t18 = 3.295, p = 0.0040; 4 dpi, t34 = 2.240, p = 0.0318; 6dpi, t26 = 1.146, p = 0.2621) [Color figure can be viewed at wileyonlinelibrary.com] the change in head direction, an important indicator for the fitness of the movement), but these differences were negligible at 6 dpi (Figure 1f-g). These are consistent with previous study that larval zebrafish have a rapid morphological and functional recovery from SCI, which can be achieved in 5-6 dpi (Chapela et al, 2019).…”

“…Larval zebrafish at 5 dpf have similar spinal cord structures as their adults and are easy for genetic manipulation and imaging analysis, which has become a widely used model in SCI study (Briona & Dorsky, 2014a; Chapela et al., 2019; Tsarouchas et al., 2018). To generate a SCI model, a complete transection was made in the spinal cord at the level of anal pore as previously reported (Figure 1a, Briona & Dorsky, 2014b).…”

“…To generate a SCI model, a complete transection was made in the spinal cord at the level of anal pore as previously reported (Figure 1a, Briona & Dorsky, 2014b). A successful surgery was confirmed by a complete gap between the rostral and caudal spinal cord stumps but leaving the muscles and vessels intact (Chapela et al., 2019). A lack of sensory response was also observed when the caudal to the injury sites was poked.…”

Shock waves promote spinal cord repair via TLR3

“…TLR3 is neuroprotective in a model of SCI in zebrafish. Zebrafish are characterized by a remarkable regenerative capacity, with robust axonal growth and, as a consequence, extensive restoration of locomotor function; therefore, they represent a well-established model to investigate spinal cord regeneration (13)(14)(15). As regeneration involves signaling processes conserved between mammals and fish (16), we aimed to further substantiate the importance of TLR3 signaling for spinal cord protection in zebrafish.…”