Loss of normal motor and sensory bladder function after spinal cord or spinal root injuries has been linked to bladder pathologies and increased susceptibility to urinary tract infections (UTIs). Neurotrophins, including brain-derived neurotrophic factor (BDNF), and associated reactive oxygen species (ROS) modulate neuronal plasticity peripherally and centrally (1). In an established dog model of lower motor neuron-lesioned bladder, somatic nerve transfer was used to promote bladder reinnervation. Levels of BDNF, ROS, and other related markers were evaluated after long-term bladder decentralization, with or without reinnervation procedures.

Three groups of female mongrel hound dogs: 1) Decentralized, after bilateral transection of coccygeal and sacral spinal roots, dorsal roots of lumbar 7, and hypogastric nerves, then 6–21 mo recovery; 2) Reinnervated (ObNT-Reinn), after similar decentralization for 12 mo, then reinnervation by bilateral transfer of obturator to pelvic nerves, then 8–12-mo recovery; and 3) Controls (age-matched sham operated and unoperated animals). Urination postures and frequency of UTIs were monitored. All Decentralized and ObNT-Reinn animals had multiple instances of culture-confirmed bacteriuria that were lowered with antibiotics. At study end, animals were anesthetized, and bladders harvested. Detrusor mucosa and smooth muscle tissues were dissected, homogenized, and used for biochemical assays. Mucosa and smooth muscle levels of total BDNF, the glial cell line-derived neurotrophic factor (GDNF), the sensory nerve marker, calcitonin gene related peptide (CGRP), and the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) were evaluated using enzyme-linked immunosorbent assay. Superoxide production was measured using lucigenin-enhanced chemiluminescence.

ObNT-Reinn bladders contained higher levels of BDNF and ROS in their mucosa, compared to the other two groups, higher muscle levels of BDNF, compared to Decentralized bladders. Both ObNT-Reinn and Decentralized bladders showed lowered ROS levels in the muscle and CGRP and TNF-α in the mucosa and muscle, compared to Controls. The expression levels of GDNF were, overall, lower than that of BDNF in the 3 dog groups, with mucosal levels higher than muscle levels.

The enhanced BDNF and ROS levels in ObNT-Reinn bladders could be perhaps as the result of somatic nerve ingrowth. In both Decentralized and ObNT-Reinn bladders, since CGRP is mostly expressed in sensory nerves, its decrease may occur from long-term bladder deafferentation that the reinnervation strategy did not address in the ObNT-Reinn group. The decreased TNF-ɑ levels in Decentralized and ObNT-Reinn bladders might be the consequence of the prolonged antibiotic treatments needed to control the recurrent UTIs. The variability in the expression of BDNF and GDNF in dog bladders demonstrated that neurotrophins are differentially regulated after peripheral nerve injury, and that different mechanisms are regulating different neurotrophins to promote a proper regeneration of the injured nerves, as was previouly reported (2,3). Further investigation might be necessary to help in understanding those mechanisms.

The enhanced BDNF levels in the bladder after nerve transfer surgery in our preclinical animal model possibly suggests a physiological relevance of this growth factor as a compensatory mechanism to restore bladder function and a potential promising therapeutic target for promoting nerve regeneration and neuroplasticity that would result in functional nerve, and expected to have a significant positive impact on the quality of life of patients with lower motor neuron-lesioned bladders.

Bruna, B., P. Lobos, R. Herrera-Molina, C. Hidalgo, A. Paula-Lima and T. Adasme (2018). "The signaling pathways underlying BDNF-induced Nrf2 hippocampal nuclear translocation involve ROS, RyR-Mediated Ca(2+) signals, ERK and PI3K." Biochem Biophys Res Commun 505(1): 201-207.
Meyer, M., I. Matsuoka, C. Wetmore, L. Olson and H. Thoenen (1992). "Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA." The Journal of cell biology, 1992, Vol.119 (1), p.45-54.
Funakoshi, H., J. Frisén, G. Barbany, T. Timmusk, O. Zachrisson, M. K. V. Valerie and H. Persson (1993). "Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve." The Journal of cell biology, 1993, Vol.123 (2), p.455-465.

Continence 12S (2024) 101373
DOI: 10.1016/j.cont.2024.101373