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Treatment of Socially Stressed Mice with Cyclosporine A Prevents Voiding Dysfunction in Spite of CRF mRNA Upregulation in Barrington’s Nucleus.
Stephan Butler, BS, Christopher Long, MD, Joanna Sliwoski, BS, Douglas Canning, MD, Stephan Zderic, MD.
Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: Social Stress induced voiding dysfunction leads to suppression of the voiding reflex, a diminished voiding frequency, and increased voided volumes. Recently, we implicated the calcineurin-NFAT (Nuclear Factor of Activated T cells) pathway in this response when we demonstrated that an NFAT c4 knockout mouse exposed to social stress was able to resist the development of an abnormal voiding phenotype. Based on this finding we were prompted to investigate the effects of Cyclosporine A (CSA), a known inhibitor of the calcineurin pathway, on the voiding phenotype of mice exposed to social stress as well as the stress neuropeptide corticotrophin releasing factor (CRF) mRNA expression in Barrington’s nucleus. The significance of choosing CRF mRNA expression in Barrington’s nucleus is that this is a measure of the stress response and CRF has been shown to suppress the voiding reflex.
Methods: Male Swiss Webster mice (6 weeks of age) were subjected to social stress from mature c57/bl6 retired breeder males in an established resident-intruder model for 1 hour followed by 23 hours of barrier separation to allow for visual and olfactory contact between the aggressor and subordinate mice. Cyclosporine (100 mg/ml) was added to the drinking water for the stressed and non-stress control groups at the start of the trial. An additional group of age-matched Swiss Webster males that did not receive Cyclosporine but was exposed to the same social-stress paradigm was also included. At two weeks voiding patterns were collected followed by sacrifice. CRF mRNA expression in Barrington’s nucleus was determined using in situ hybridization and was recorded as the number of positive cells exhibiting CRF mRNA.
Results:
Control+CSAControlStress+CSAStress Only
Voids/24 hours7.2 ± 0.89.5 ± 2.611 ± 2.93.8±0.4*#
Voided Volume0.11 ± 0.040.08 ± 0.020.09 ± 0.020.36±0.06*#
CRF mRNA Quant7.5 ± 1.78 ± 2.323 ± 2.6*29 ± 5.6*

*P<0.003 vs Control & Control+CSA
#P<0.003 vs Stress+CSA
Conclusion: The addition of cyclosporine to mice exposed to social stress resulting in a voiding pattern identical to non-stressed controls. The addition of CSA to non stressed controls had no effect when compared to untreated controls. However CRF expression in Barrington’s nucleus increased 3 fold over baseline despite CSA treatment and was only slightly lower when compared to the stress only group. These results further suggest that the calcineurin pathway plays a role in mediating the voiding response to social stress. However these results suggest that the effects of calcineurin inhibition may not be occurring within the brain but elsewhere in the brain-bladder axis.


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