title: Impairment of sensory afferents by intrathecal administration of botulinum toxin A improves neurogenic detrusor overactivity in chronic spinal cord injured rats.
abstract: Spinal cord injury (SCI) often leads to neurogenic detrusor overactivity (NDO) due to sprouting of sensory afferents on the lumbosacral spinal cord. NDO is characterized by high frequency of voiding contractions and increased intravesical pressure that may lead to urinary incontinence. The latter has been described as one of the consequences of SCI that mostly decreases quality of life. Bladder wall injections of botulinum toxin A (Onabot/A) are an effective option to manage NDO. The toxin strongly impairs parasympathetic and sensory fibres coursing the bladder wall. However the robust parasympathetic inhibition may inhibit voiding contractions and cause urinary retention in patients that retain voluntary voiding. Here, we hypothesised that by restricting the toxin activity to sensory fibres we can improve NDO without impairing voiding contractions. In the present work, we assessed the effect of Onabot/A on sensory neurons in chronic (4weeks) SCI rats by injecting the toxin intrathecally (IT), at lumbosacral spinal cord level. This route of administration was shown before to have an effect on bladder pain and contractility in an animal model of bladder inflammation. We found that IT Onabot/A led to a significant reduction in the frequency of expulsive contractions and a normalization of bladder basal pressure while maintaining voiding contractions of normal amplitude. Cleavage of SNAP-25 protein occurred mainly at the dorsal horn regions where most of the bladder afferents end. Cleaved SNAP-25 was not detected in motor or preganglionic parasympathetic neurons. A significant decrease in CGRP expression, a peptide exclusively present in sensory fibres in the spinal cord, occurred at the L5/L6 segments and associated dorsal root ganglia (DRG) after Onabot/A injection in SCI animals. Onabot/A strongly increased the expression of ATF3, a marker of neuronal stress, in L5/L6 DRG neurons. Taken together, our results suggest that IT Onabot/A has a predominant effect on bladder sensory fibres, and that such effect is enough to control NDO following chronic SCI. The mechanism of action of Onabot/A includes not only the cleavage of SNAP-25 in sensory terminals but also impairment of basic cellular machinery in the cell body of sensory neurons.
authors.affiliation: Department of Experimental Biology, Faculty of Medicine of Porto, University of Porto, Portugal; Translational NeuroUrology, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal; Instituto de Investigação e Inovação em Saúde - i3S, Universidade do Porto, Portugal. Electronic address: anacoelho@med.up.pt.
authors.forename: Ana
authors.initials: A
authors.lastname: Coelho
authors.affiliation: Department of Experimental Biology, Faculty of Medicine of Porto, University of Porto, Portugal; Translational NeuroUrology, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal; Instituto de Investigação e Inovação em Saúde - i3S, Universidade do Porto, Portugal. Electronic address: raquellmmoliveira@gmail.com.
authors.forename: Raquel
authors.initials: R
authors.lastname: Oliveira
authors.affiliation: Translational NeuroUrology, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal; Instituto de Investigação e Inovação em Saúde - i3S, Universidade do Porto, Portugal; Department of Urology, Hospital de S. João, Porto, Portugal. Electronic address: cruzfjmr@med.up.pt.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cruz
authors.affiliation: Department of Experimental Biology, Faculty of Medicine of Porto, University of Porto, Portugal; Translational NeuroUrology, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal; Instituto de Investigação e Inovação em Saúde - i3S, Universidade do Porto, Portugal. Electronic address: ccruz@med.up.pt.
authors.forename: Célia Duarte
authors.initials: CD
authors.lastname: Cruz
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007278:Injections, Spinal; D009465:Neuromuscular Agents / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013119:Spinal Cord Injuries / Q000150:complications* / Q000473:pathology; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000209:etiology*
chemical_list: D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D009465:Neuromuscular Agents; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D019274:Botulinum Toxins, Type A; D015740:Calcitonin Gene-Related Peptide
keywords: Botulinum toxin; Neurogenic detrusor overactivity; Spinal cord injury; Urinary bladder