Highlights d Senescent cells are induced at the lesion periphery upon spinal cord injury d Administration of senolytic drugs promotes locomotor and sensory recovery d ABT-263 treatment suppresses pro-inflammatory and profibrotic SASP responses d Targeting senescent cells favors a pro-repair microenvironment after injury

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.

No abstract

Persistent senescent cells (SCs) are known to underlie ageing-related chronic disorders, but it is now recognized that SCs may be at the center of tissue remodeling events, namely during development or organ repair. Here we show that two distinct senescence profiles are induced in the context of a spinal cord injury between the regenerating zebrafish and the non-regenerating mouse. While induced-SCs in the zebrafish are progressively cleared out, they accumulate over time in mice. Depletion of SCs in spinal cord injured mice, with different senolytic drugs, improved locomotor, sensory and bladder functions. This functional recovery is associated with improved myelin sparing, reduced fibrotic scar, attenuated inflammation and increased axonal growth. Targeting SCs is a promising therapeutic strategy not only for spinal cord injuries but potentially for other organs that lack regenerative competence.