Spinal cord injury (SCI) above the lumbosacral level results in lower urinary tract dysfunction, including (1) detrusor hyperreflexia, wherein bladder compliance is low, and (2) a lack of external urethral sphincter (EUS) control, leading to detrusor-sphincter dyssynergia (DSD) with poor voiding efficiency. Experimental studies in animals have shown a dense innervation of serotonergic (5-HT) fibers and multiple 5-HT receptors in the spinal reflex circuits that control voiding function. Here, we investigated the efficacy of NLX-112 (a.k.a. befiradol or F13640), in regulating lower urinary tract function after T8 contusive SCI in rats. NLX-112 is a very potent, highly-selective, and fully efficacious 5-HT1A receptor agonist, which has been developed for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease patients. We performed urodynamics tests and external urethral sphincter electromyogram recordings to assess lower urinary tract function while NLX-112 was infused through the femoral vein in rats with chronic complete SCI or contusive SCI. The dose response studies indicated that NLX-112 was able to improve voiding behavior by regulating both detrusor and EUS activity. These included improvements in voiding efficiency, reduction of detrusor hyperactivity, and phasic activity of EUS during the micturition period. In addition, the application of a selective 5-HT1A receptor antagonist, WAY100635, reversed the improved detrusor and EUS activity elicited by NLX-112. In summary, the current data suggest that pharmacological activation of 5-HT1A receptors by NLX-112 may constitute a novel therapeutic strategy to treat neurogenic bladder after SCI.
Experimental neurology. 2020 Jun 30 [Epub]
Ching-Yi Lin, Alexander Sparks, Yu-Shang Lee
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA., Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: .