Long-Term 5-HT1A Receptor Agonist NLX-112 Treatment Improves Functional Recovery After Spinal Cord Injury

Spinal cord injury (SCI) results in functional deficits below the injured spinal level. The descending serotonergic system in the spinal cord is critically involved in the control of motor and autonomic functions. Specifically, SCI damages the projections of serotonergic fibers, which leads to reduced serotonin inputs and increased amounts of spinal serotonergic receptors. Our previous pharmacological study demonstrated that brief administration of a highly selective 5-HT_1A receptor agonist, NLX-112, improves lower urinary tract (LUT) function at the termination stage of thoracic 8 (T8) contusive SCI in rats. However, whether chronic activation of serotonin 5-HT_1A receptors by NLX-112 after SCI is beneficial remains an unanswered question. Here, we evaluated the efficacy of long-term NLX-112 intervention starting from two weeks post-T8 contusive SCI for an additional six weeks. We evaluated locomotion, LUT function, bladder morphology, and the number of spinal 5-HT_1A receptors in both L4 and L6/S1 spinal cord segments. Our results indicate that NLX-112 treatment significantly improves locomotion in a dose-dependent fashion, improves LUT function, reduces bladder weight and bladder wall thickness, and reduces the SCI-upregulated spinal 5-HT_1A receptors compared to vehicle-treated SCI animals. These data suggest promising therapeutic potential for long-term NLX-112 activation of 5-HT_1A receptors to treat SCI.