Inosine Improves Neurogenic Detrusor Overactivity following Spinal Cord Injury.
Inosine Improves Neurogenic Detrusor Overactivity following Spinal Cord Injury.
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DOI：
10.1371/journal.pone.0141492
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Adam RM
中科院分区：
文献类型：
--
作者：
Chung YG;Seth A;Doyle C;Franck D;Kim D;Cristofaro V;Benowitz LI;Tu DD;Estrada CR;Mauney JR;Sullivan MP;Adam RM
神经源性逼尿肌过度活动和相关的膀胱控制能力丧失是脊髓损伤（SCI）最具挑战性的并发症之一。抗胆碱能药物是医学治疗逼尿肌过度活跃的主要药物。然而，它们的使用受到严重副作用的限制，因此有必要寻找新的治疗方法。肌苷是一种天然存在的嘌呤核苷，具有神经保护、神经营养和抗氧化作用，已知可改善脊髓损伤临床前模型的运动功能。然而，其对下尿路功能的影响尚未确定。本研究的目的是确定全身肌苷给药对脊髓损伤后排尿功能的影响，并描述其潜在的作用机制。Sprague - Dawley大鼠接受完全脊髓横断，或在T8时应用动脉瘤夹压迫脊髓30秒。肌苷（225 mg/kg）或对照物在损伤后立即或延迟8周后每天通过腹腔注射。在治疗结束时，通过膀胱术评估排尿行为。免疫荧光成像检测膀胱组织突触素（SYP）、神经丝200 （NF200）、TRPV1水平。肌苷给药降低了两种脊髓损伤模型的过度活动，与载药处理的脊髓损伤大鼠相比，充血过程中自发非排尿收缩的频率显著降低（p<0.05），包括延迟治疗的情况。免疫荧光染色显示，肌苷处理的大鼠膀胱组织中泛神经元标记物SYP和Adelta纤维标记物NF200的水平升高，但c纤维标记物TRPV1的染色降低，与药物处理的动物相比，包括延迟治疗后。这些发现表明肌苷可以阻止脊髓损伤后逼尿肌过度活动的发展，并减轻现有的过度活动，并可能通过调节感觉神经传递来实现其作用。
Neurogenic detrusor overactivity and the associated loss of bladder control are among the most challenging complications of spinal cord injury (SCI). Anticholinergic agents are the mainstay for medical treatment of detrusor overactivity. However, their use is limited by significant side effects such that a search for new treatments is warranted. Inosine is a naturally occurring purine nucleoside with neuroprotective, neurotrophic and antioxidant effects that is known to improve motor function in preclinical models of SCI. However, its effect on lower urinary tract function has not been determined. The objectives of this study were to determine the effect of systemic administration of inosine on voiding function following SCI and to delineate potential mechanisms of action. Sprague−Dawley rats underwent complete spinal cord transection, or cord compression by application of an aneurysm clip at T8 for 30 sec. Inosine (225 mg/kg) or vehicle was administered daily via intraperitoneal injection either immediately after injury or after a delay of 8 wk. At the end of treatment, voiding behavior was assessed by cystometry. Levels of synaptophysin (SYP), neurofilament 200 (NF200) and TRPV1 in bladder tissues were measured by immunofluorescence imaging. Inosine administration decreased overactivity in both SCI models, with a significant decrease in the frequency of spontaneous non−voiding contractions during filling, compared to vehicle−treated SCI rats (p<0.05), including under conditions of delayed treatment. Immunofluorescence staining demonstrated increased levels of the pan-neuronal marker SYP and the Adelta fiber marker NF200, but decreased staining for the C-fiber marker, TRPV1 in bladder tissues from inosine-treated rats compared to those from vehicle-treated animals, including after delayed treatment. These findings demonstrate that inosine prevents the development of detrusor overactivity and attenuates existing overactivity following SCI, and may achieve its effects through modulation of sensory neurotransmission.