Lamarre Neil S, Braverman Alan S, Malykhina Anna P, Barbe Mary F, Ruggieri Michael R
Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
Division of Urology, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Glenolden, Pennsylvania, United States of America.
PLoS One. 2014 Oct 13;9(10):e109314. doi: 10.1371/journal.pone.0109314. eCollection 2014.
Patients with neurodegenerative diseases such as multiple sclerosis, Parkinson's, and Alzheimer's often present with lower urinary tract symptoms (LUTS, urinary frequency, urgency, nocturia and retention) resulting from damage to the peripheral and central nervous systems. These studies were designed to examine the changes in the function of the bladder that may underlie neurogenic bladder dysfunction using a mouse model of demyelination in the CNS.
Bladders from 12 week old male C57BL/6J mice with coronavirus-induced encephalomyelitis (CIE, a chronic, progressive demyelinating disease model of human MS), and age-matched controls, were cut into 5-7 strips and suspended in physiological muscle baths for tension measurement in response to agonists and electric field stimulation (EFS). Experiments were performed on intact and denuded (with mucosa removed) bladder strips.
The maximum effect of EFS was not significantly different between CIE and control bladders. Nerve-evoked EFS contractions (tetrodotoxin-sensitive) were blocked by a combination of atropine (cholinergic antagonist) and α,β-methylene ATP (an ATP analog that desensitizes purinergic receptors). In response to EFS, the α,β-methylene ATP-resistant (cholinergic) component of contraction was significantly reduced, while the atropine-resistant (purinergic) component was significantly increased in CIE bladders. Removal of the mucosa in CIE bladders restored the cholinergic component. Bethanechol (muscarinic receptor agonist) potency was significantly increased in CIE bladders.
Our data demonstrate a deficit in the nerve-evoked cholinergic component of contraction that is not due to the ability of the smooth muscle to respond to acetylcholine. We conclude that neurodegenerative bladder dysfunction in this model of multiple sclerosis may be due, in part, to pathologic changes in the mucosa that causes suppression of muscarinic receptor-mediated contractile response and augmentation of purinergic response of the underlying muscle. Further studies utilizing CIE mice should help elucidate the pathological changes in the mucosa resulting from demyelination in the CNS.
患有神经退行性疾病（如多发性硬化症、帕金森病和阿尔茨海默病）的患者，常因外周和中枢神经系统受损而出现下尿路症状（LUTS，包括尿频、尿急、夜尿和尿潴留）。这些研究旨在利用中枢神经系统脱髓鞘小鼠模型，研究可能是神经源性膀胱功能障碍基础的膀胱功能变化。
将12周龄雄性C57BL/6J小鼠（患有冠状病毒诱导的脑脊髓炎，CIE，一种人类多发性硬化症的慢性、进行性脱髓鞘疾病模型）和年龄匹配的对照小鼠的膀胱切成5 - 7条，悬挂于生理肌肉浴槽中，以测量对激动剂和电场刺激（EFS）的张力反应。实验在完整和去黏膜（去除黏膜）的膀胱条上进行。
CIE小鼠和对照小鼠膀胱对EFS的最大反应无显著差异。神经诱发的EFS收缩（对河豚毒素敏感）被阿托品（胆碱能拮抗剂）和α,β - 亚甲基ATP（一种使嘌呤能受体脱敏的ATP类似物）联合阻断。对EFS反应时，CIE小鼠膀胱收缩的α,β - 亚甲基ATP抗性（胆碱能）成分显著降低，而阿托品抗性（嘌呤能）成分显著增加。CIE小鼠膀胱去除黏膜后，胆碱能成分恢复。在CIE小鼠膀胱中，氨甲酰甲胆碱（毒蕈碱受体激动剂）的效力显著增加。
我们的数据表明，神经诱发的收缩胆碱能成分存在缺陷，这并非由于平滑肌对乙酰胆碱的反应能力所致。我们得出结论，在这个多发性硬化症模型中，神经退行性膀胱功能障碍可能部分归因于黏膜的病理变化，这种变化导致毒蕈碱受体介导的收缩反应受到抑制，以及基础肌肉的嘌呤能反应增强。利用CIE小鼠进行的进一步研究应有助于阐明中枢神经系统脱髓鞘导致的黏膜病理变化。
