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POST-STRESS CYCLOSPORINE REDUCES SOCIAL STRESS INDUCED VOIDING DYSFUNCTION
Dana A. Weiss, MD, Christopher J. Long, MD, Stephan J. Butler, BS, Joanna Fesi, BS, Douglas A. Canning, MD, Stephen A. Zderic, MD.
The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

BACKGROUND
Social stress induced voiding dysfunction in male mice is characterized by diminished voiding frequency and increased volume. We have previously shown that cyclosporine (CSA) given during stress helps to prevent the onset of voiding dysfunction, however we have not yet been able to reverse the voiding phenotype once it develops. We now sought to determine whether cyclosporine administered after stress would help to reverse the impact on voiding.
METHODS
Retired c57 male breeder mice were utilized as aggressors to stress 8-week old wild type Swiss-Webster mice. One hour of aggressor exposure was followed by 23 hours of barrier separation. Voiding patterns were assessed after 1 month, and mice were randomized into 2 groups with an even distribution of abnormal voiding patterns allocated to two groups. One group received cyclosporine in the drinking water for 1 month while living in single cage housing, while the other group did not. One month later, voiding patterns were assessed prior to sacrifice. The bladders were evaluated with muscle physiology studies, and the brains were tested for CRH expression in Barrington’s nucleus with in situ hybridization.
RESULTS
Voiding patterns for mice that received CSA during their reversal period improved to levels close to pre-stress conditions, while those who underwent reversal alone had persistent abnormal voiding. In the brain, we found no significant difference between the amount of CRH expressed in Barrington’s nucleus between reversal groups (p=0.42), but both were elevated from control (P<0.05). There were no differences in response to direct depolarization with KCL, administration of atropine, electrical field stimulation, or maximal velocity of contraction between stressed mouse bladders treated with CSA, stressed mouse bladders treated with reversal alone, or non-stressed controls.
CONCLUSIONS
CSA treatment reverses the dysfunctional voiding phenotype to normal values. CSA administration does not change the stress induced CRH increase in Barrington’s nucleus, suggesting that the groups of mice were equally stressed. Despite the improved voiding phenotype, the smooth muscle physiology is unchanged by CSA treatment. We suspect that additional CSA responsive neural changes play a pivotal role in the abnormal voiding phenotype following social stress.
After StressReversal - no CSAAfter StressReversal - CSAControl
Bladder mass/body ratio0.810.790.73
Voids in 24 hours5.757.62
(p=0.0852)
5.4210.42
(p=0.0035)
Barrington's nucleus: Number CRH + cells30.8
(p=0.42)
27.8
(p=0.42)
0


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