Effect Of Nerve Growth Factor And 5-HT₇ Receptor In Lower Urinary Tract Dysfunction After Spinal Cord Injury

Aims:Lower urinary tract dysfunction?LUTD?is a common complication of spinal cord injury?SCI?and a major cause of death.This study aimed to demonstrate the effect of nerve growth factor?NGF?and 5-HT₇ receptor in LUTD after SCI,and explore the possible underlying mechanisms.Materials and methods:In Part?,the bladder function and morphology were compared between normal and SCI mice by urodynamic and histology experiments.The cystometrograms?CMGs?of all group were recorded to evaluate the effect of NGF on bladder function.The whole-cell patch clamp study was performed to compare the electrophysiological properties of bladder afferent neurons and demonstrate the NGF-induced Na⁺channel plasticity.Finally,combing the laser capture microdissection technique with molecular expriments,the expression of Na⁺channel subtypes were examined in all groups.In Part?,CMG and EUS-EMG tests were performed to compare the urodynamic variables between normal and SCI rats.Then,the effect of intrathecal 5-HT₇ receptor agonist was examined in both normal and SCI rats.Last,the expression of 5-HT₇ receptor in spinal cord of normal and SCI rats was examined by retrograde tracing and molecular studies.Results:In Part?,the CMG data showed the bladder overactivity,performed as increased non-voiding contractions,in SCI mice.And NGF neutralizing treatment could significantly improve the bladder overactivity.The electrophysiology study demonstrated that the excitability of bladder afferent DRG neurons was significantly increased,accompanied by increased total Na+current,TTX-S Na+current and decreased TTX-R Na+current.All these changes of electrophysiological properties could be reversed by NGF neutralizing treatment.Molecular studies showed that Nav1.7 was significantly increased and Nav1.8 was significantly decreased in bladder afferent neurons.In Part?,CMG and EMG data showed that high frequency ocilliations?HFOs?were existed in the micturition period in normal rat,whereas they disappeared in SCI rats and resulted in voiding dysfunction.Then,we found that intrathecal administration of 5-HT₇receptor agonist could significantly improve EUS function,increase the number of HFOs,and enhance the voiding efficiency in SCI rats.Finally,molecular experiments demonstrated that 5-HT₇ receptor was significantly up-regulated in Onuf's nucleus after SCI.Conclusions:NGF can induce Na⁺channel plasticity after SCI,which could be a mechanism for bladder overactivity after SCI.The up-regulation of 5-HT₇receptor in the lumbosacral cord Onuf's nucleus might be related to the DSD after SCI.NGF and 5-HT₇ receptor could be novel therapeutic targets for LUTD after SCI.