Nerve transfer for restoration of lower motor neuron-lesioned bladder function. Part 1: attenuation of purinergic bladder smooth muscle contractions.

This study determined the effect of pelvic organ decentralization and reinnervation 1 yr later on the contribution of muscarinic and purinergic receptors to ex vivo, nerve-evoked, bladder smooth muscle contractions. Nineteen canines underwent decentralization by bilateral transection of all coccygeal and sacral (S) spinal roots, dorsal roots of lumbar (L)7, and hypogastric nerves. After exclusions, 8 were reinnervated 12 mo postdecentralization with obturator-to-pelvic and sciatic-to-pudendal nerve transfers then euthanized 8-12 mo later. Four served as long-term decentralized only animals. Controls included six sham-operated and three unoperated animals. Detrusor muscle was assessed for contractile responses to potassium chloride (KCl) and electric field stimulation (EFS) before and after purinergic receptor desensitization with α, ß-methylene adenosine triphosphate (α,ß-mATP), muscarinic receptor antagonism with atropine, or sodium channel blockade with tetrodotoxin. Atropine inhibition of EFS-induced contractions increased in decentralized and reinnervated animals compared with controls. Maximal contractile responses to α,ß-mATP did not differ between groups. In strips from decentralized and reinnervated animals, the contractile response to EFS was enhanced at lower frequencies compared with normal controls. The observation of increased blockade of nerve-evoked contractions by muscarinic antagonist with no change in responsiveness to purinergic agonist suggests either decreased ATP release or increased ecto-ATPase activity in detrusor muscle as a consequence of the long-term decentralization. The reduction in the frequency required to produce maximum contraction following decentralization may be due to enhanced nerve sensitivity to EFS or a change in the effectiveness of the neurotransmission.

Blocking CTGF/CCN2 reverses neural fibrosis and sensorimotor declines in a rat model of overuse-induced median mononeuropathy.

Encapsulation of median nerves is a hallmark of overuse-induced median mononeuropathy and contributes to functional declines. We tested if an antibody against CTGF/CCN2 (termed FG-3019 or Pamrevlumab) reduces established neural fibrosis and sensorimotor declines in a clinically relevant rodent model of overuse in which median mononeuropathy develops. Young adult female rats performed a high repetition high force (HRHF) lever-pulling task for 18 weeks. Rats were then euthanised at 18 weeks (HRHF untreated), or rested and systemically treated for 6 weeks with either an anti-CCN2 monoclonal antibody (HRHF-Rest/FG-3019) or IgG (HRHF-Rest/IgG), with results compared with nontask control rats. Neuropathology was evident in HRHF-untreated and HRHF-Rest/IgG rats as increased perineural collagen deposition and degraded myelin basic protein (dMBP) in median nerves, and increased substance P in lower cervical dorsal root ganglia (DRG), compared with controls. Both groups showed functional declines, specifically, decreased sensory conduction velocity in median nerves, noxious cold temperature hypersensitivity, and grip strength declines, compared with controls. There were also increases of ATF3-immunopositive nuclei in ventral horn neurons in HRHF-untreated rats, compared with controls (which showed none). FG-3019-treated rats showed no increase above control levels of perineural collagen or dMBP in median nerves, Substance P in lower cervical DRGs, or ATF3-immunopositive nuclei in ventral horns, and similar median nerve conduction velocities and thermal sensitivity, compared with controls. We hypothesize that neural fibrotic processes underpin the sensorimotor declines by compressing or impeding median nerves during movement, and that inhibiting fibrosis using an anti-CCN2 treatment reverses these effects.

Nerve transfer for restoration of lower motor neuron-lesioned bladder and urethra function: establishment of a canine model and interim pilot study results.

OBJECTIVE: Previous patient surveys have shown that patients with spinal cord or cauda equina injuries prioritize recovery of bladder function. The authors sought to determine if nerve transfer after long-term decentralization restores bladder and sphincter function in canines. METHODS: Twenty-four female canines were included in this study. Transection of sacral roots and hypogastric nerves (S Dec) was performed in 6 animals, and 7 animals underwent this procedure with additional transection of the L7 dorsal roots (L7d+S Dec). Twelve months later, 3 L7d+S Dec animals underwent obturator-to-pelvic nerve and sciatic-to-pudendal nerve transfers (L7d+S Dec+Reinn). Eleven animals served as controls. Squat-and-void behaviors were tracked before and after decentralization, after reinnervation, and following awake bladder-filling procedures. Bladders were cystoscopically injected with Fluoro-Gold 3 weeks before euthanasia. Immediately before euthanasia, transferred nerves were stimulated to evaluate motor function. Dorsal root ganglia were assessed for retrogradely labeled neurons. RESULTS: Transection of only sacral roots failed to reduce squat-and-void postures; L7 dorsal root transection was necessary for significant reduction. Three L7d+S Dec animals showing loss of squat-and-void postures post-decentralization were chosen for reinnervation and recovered these postures 4-6 months after reinnervation. Each showed obturator nerve stimulation-induced bladder contractions and sciatic nerve stimulation-induced anal sphincter contractions immediately prior to euthanasia. One showed sciatic nerve stimulation-induced external urethral sphincter contractions and voluntarily voided twice following nonanesthetized bladder filling. Reinnervation was confirmed by increased labeled cells in L2 and the L4-6 dorsal root ganglia (source of obturator nerve in canines) of L7d+S Dec+Reinn animals, compared with controls. CONCLUSIONS: New neuronal pathways created by nerve transfer can restore bladder sensation and motor function in lower motor neuron-lesioned canines even 12 months after decentralization.