A novel cannabidiol-derived small molecule ameliorates lower urinary tract dysfunction in mice with spinal cord injury via suppressing neuroinflammation.

Abstract

AIMS: Neurogenic lower urinary tract dysfunction (NLUTD) is a major secondary complication following spinal cord injury (SCI). CIAC001, a cannabidiol-derived small molecule, has been reported to exhibit anti-neuroinflammatory efficacy. This study aimed to investigate whether CIAC001 ameliorates SCI-induced bladder dysfunction by suppressing local neuroinflammation. MATERIALS AND METHODS: Female C57BL/6 mice were subjected to severe compression SCI at the T9 level and randomized into Sham, SCI + Vehicle, and SCI + CIAC001 groups. The treatment group received daily intraperitoneal CIAC001 (8 mg/kg) for 28 days. Assessments included urography, measurement of renal function markers, bladder weight and histology (Masson's trichrome), voiding behavior analysis, cystometry, immunofluorescence staining for neuroinflammation markers (GFAP, C3, β3-Tubulin) in the spinal cord, and retrograde neural tracing from the bladder to the periaqueductal gray and pontine micturition center using pseudorabies virus. KEY FINDINGS: SCI led to significant bladder dilation, increased bladder weight, detrusor muscle thinning, voiding dysfunction (increased spot number), and impaired urodynamics (elevated non-voiding contractions, micturition pressure, and bladder capacity; reduced voiding efficiency). These changes were associated with marked neuroinflammation (astrogliosis, A1 phenotype induction) and reduced supraspinal neural connectivity. CIAC001 treatment significantly attenuated these pathological alterations: it reduced bladder weight and improved urodynamic parameters, suppressed spinal cord neuroinflammation (reduced C3+ A1 astrocytes, enhanced axonal regeneration), and promoted the re-establishment of bladder-related neural pathways. SIGNIFICANCE: CIAC001 effectively ameliorates key symptoms of SCI-induced NLUTD in mice, primarily through suppressing neuroinflammation and facilitating neural repair. These findings highlight CIAC001 as a promising therapeutic candidate for neurogenic bladder dysfunction after SCI, warranting further mechanistic and translational investigation.