Elsevier

Urology

Volume 88, February 2016, Pages 57-65
Urology

Female Urology
Spontaneous Recovery of Reflex Voiding Following Spinal Cord Injury Mediated by Anti-inflammatory and Neuroprotective Factors

https://doi.org/10.1016/j.urology.2015.10.017Get rights and content

Objective

To investigate the time-dependent changes in expression of cytokines that characterizes the spontaneous recovery of reflex voiding after spinal cord injury (SCI). SCI is known to reorganize the neural circuitry of micturition reflex after injury.

Methods

Under isoflurane anesthesia, spinal cord of 18 adult female Sprague-Dawley rats was completely transected at the Th9-10 level. Awake cystometry was performed at each time point on controls and 6 SCI animals, and bladder was then harvested for analysis of 29 proteins Millipore kit or enzyme-linked immunosorbent assay. Prophylactic dose of ampicillin 100 mg/kg was administered periodically to all SCI animals.

Results

Spontaneous recovery of voiding after SCI at 12 weeks was evident from increased intercontractile interval and voiding efficiency during cystometry. Expression of proinflammatory interleukins ([IL] IL-1α and IL-1β, IL-2, IL-5, IL-6, IL-18, tumor necrosis factor alpha [TNF-α]) and CXC chemokines (CXCL1, CXCL2, CXCL10), CX3CL1, and CCL2 showed significant elevation at 4 and at 8 weeks with slight decrease at 12 weeks. In contrast, expression of anti-inflammatory IL-10 and neuroprotective factors, CXCL-5, and leptin, was elevated at 8 and at 12 weeks (P < .05). In contrast, expression of CCL3, CCL5, and growth factors (vascular endothelial growth factor, nerve growth factor, epidermal growth factor, granulocyte colony-stimulating factor, and granulocyte macrophage colony-stimulating factor) did not show any significant temporal change after SCI.

Conclusion

Spontaneous recovery of reflex voiding at 12 weeks was marked by increased endogenous expression of anti-inflammatory cytokine IL-10 and neuroprotective factors, CXCL-5, and leptin, which suggests that pharmacological suppression of inflammation, can hasten the emergence of reflex voiding after SCI.

Section snippets

Methods

Experiments were performed on 24 adult female Sprague-Dawley rats (Hilltop, Pittsburgh, PA). All animal experiments were in accordance with institutional guidelines approved by the Institutional Animal Care and Use Committee at the University of Pittsburgh. Six animals were left spinal intact to serve as controls and the rest of the 18 animals received complete spinal cord transection at the level of Th9-10 vertebrae under isoflurane anesthesia. After Th9-10 laminectomy, the dura and spinal

Effect of SCI on Cystometry

Awake CMG of spinal-intact and SCI animals at various time points revealed time-dependent changes in the voiding function induced by SCI. Representative CMG tracings from controls and SCI animals at each time point are shown in Figure 1A. Relative to spinal-intact control animals, the ICI between 2 voiding events in SCI animals progressively increased from 4 to 12 weeks, with maximum at the time point of 12 weeks. Significantly increased ICI of SCI animals was recorded at 12 weeks relative to

Discussion

Inflammatory mediators have been shown to play an important role in the pathological consequences secondary to SCI.15, 16, 17 The main findings from this study are that inflammation plays a key role in the time-dependent changes in voiding function after SCI. Upregulation of anti-inflammatory mediators and neuroprotective molecules is likely to play an important role in the plasticity of bladder afferent pathways and the reorganization of synaptic connections in the spinal cord. Poor voiding

Conclusion

SCI-induced voiding dysfunction and the spontaneous recovery at 12 weeks is associated with time-dependent changes in expression of proinflammatory and anti-inflammatory mediators. Investigations at the molecular level are crucial to advance the understanding of SCI-induced voiding dysfunction and develop new treatments.

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    Financial Disclosure: The authors declare that they have no relevant financial interests.

    Funding Support: This work was partly supported by funding from National Institutes of Health (DK088836 and DK093424) and U.S. Department of Defense (W81XWH-11-1-0763).

    Pradeep Tyagi and Katsumi Kadekawa contributed equally.

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