Department of Physiology and Biophysics, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794-8661, United States of America.
Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY 11794, United States of America.
Exp Neurol. 2023 Jan;359:114242. doi: 10.1016/j.expneurol.2022.114242. Epub 2022 Oct 12.
Spinal cord injury (SCI) above the level of the lumbosacral spinal cord produces lower urinary tract (LUT) dysfunction, resulting in impairment of urine storage and elimination (voiding). While spontaneous functional recovery occurs due to remodeling of spinal reflex micturition pathways, it is incomplete, indicating that additional strategies to further augment neural plasticity following SCI are essential. To this end, acute intermittent hypoxia (AIH) exposure has been proposed as a therapeutic strategy for improving recovery of respiratory and other somatic motor function following SCI; however, the impact of AIH as a therapeutic intervention to improve LUT dysfunction remains to be determined. Therefore, we examined the effects of daily AIH (dAIH) on both spontaneous micturition patterns and reflex micturition event (rME) behaviors in adult female Sprague-Dawley rats with mid-thoracic moderate contusion SCI. For these experiments, dAIH gas exposures (five alternating 3 min 12% O and 21% O episodes) were delivered for 7 consecutive days beginning at 1-week after SCI, with awake micturition patterns being evaluated weekly for 2-3 sessions before and for 4 weeks after SCI and rME behaviors elicited by continuous infusion of saline into the bladder being evaluated under urethane anesthesia at 4-weeks after SCI; daily normoxia (dNx; 21% O episodes) served as a control. At 1-week post-SCI, both an areflexic phenotype (i.e., no effective voiding events) and a functional voiding phenotype (i.e., infrequent voiding events with large volumes) were observed in spontaneous micturition patterns (as expected), and subsequent dAIH, but not dNx, treatment led to recovery of spontaneous void frequency pattern to pre-SCI levels; both dAIH- and dNx-treated rats exhibited slightly increased void volumes. At 4-weeks post-SCI, rME behaviors showed increased effectiveness in voiding in dAIH-treated (compared to dNx-treated) rats that included an increase in both bladder contraction pressure (delta BP; P = 0.014) and dynamic voiding efficiency (P = 0.018). Based on the voiding and non-voiding bladder contraction behaviors (VC and NVC, respectively) observed in the BP records, bladder dysfunction severity was classified into mild, moderate, and severe phenotypes, and while rats in both treatment groups included each severity phenotype, the primary phenotype observed in dAIH-treated rats was mild and that in dNx-treated rats was moderate (P = 0.044). Taken together, these findings suggest that 7-day dAIH treatment produces beneficial improvements in LUT function that include recovery of micturition pattern, more efficient voiding, and decreased NVCs, and extend support to the use of dAIH therapy to treat SCI-induced LUT dysfunction.
脊髓损伤（SCI）位于腰骶脊髓以上部位会导致下尿路（LUT）功能障碍，从而导致尿液储存和排出（排尿）受损。虽然脊髓反射排尿途径的重塑会导致自发的功能恢复，但恢复并不完全，这表明 SCI 后进一步增强神经可塑性的额外策略是必要的。为此，人们提出急性间歇性低氧（AIH）暴露作为一种治疗策略，以改善 SCI 后呼吸和其他躯体运动功能的恢复；然而，AIH 作为改善 LUT 功能障碍的治疗干预措施的影响仍有待确定。因此，我们研究了每日 AIH（dAIH）对成年雌性 Sprague-Dawley 大鼠中胸段中度挫伤 SCI 后自发排尿模式和反射性排尿事件（rME）行为的影响。在这些实验中，从 SCI 后 1 周开始，连续 7 天进行 dAIH 气体暴露（5 次交替的 3 分钟 12% O 和 21% O 期），在 SCI 前 2-3 次和 SCI 后 4 周每周评估一次清醒排尿模式，并在 SCI 后 4 周在 urethane 麻醉下评估持续输注盐水引起的 rME 行为；每日常氧（dNx；21% O 期）作为对照。在 SCI 后 1 周，自发排尿模式既表现出无反射表型（即无有效排尿事件），也表现出功能性排尿表型（即排尿次数较少，但每次排尿量较大）（如预期），随后的 dAIH 治疗，但不是 dNx 治疗，导致自发排尿频率模式恢复到 SCI 前水平；dAIH 和 dNx 治疗的大鼠均表现出排尿量略有增加。在 SCI 后 4 周，rME 行为显示出在 dAIH 治疗（与 dNx 治疗相比）大鼠中的有效性增加，包括膀胱收缩压（BP）的增加（delta BP；P=0.014）和动态排尿效率的增加（P=0.018）。根据 BP 记录中观察到的排尿和非排尿膀胱收缩行为（VC 和 NVC，分别），将膀胱功能障碍严重程度分为轻度、中度和重度表型，虽然两组治疗大鼠均包含每个严重程度表型，但 dAIH 治疗大鼠的主要表型为轻度，dNx 治疗大鼠的主要表型为中度（P=0.044）。综上所述，这些发现表明，7 天 dAIH 治疗可改善 LUT 功能，包括排尿模式恢复、更有效的排尿和减少 NVC，并为使用 dAIH 治疗治疗 SCI 引起的 LUT 功能障碍提供支持。
