Acute ampakines increase voiding function and coordination in a rat model of SCI.
Acute ampakines increase voiding function and coordination in a rat model of SCI.
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急性安帕金可增强 SCI 大鼠模型的排尿功能和协调性。
DOI：
10.1101/2023.05.26.542339
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Mickle,AaronD
中科院分区：
文献类型：
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作者：
Rana,Sabhya;Alom,Firoj;Martinez,RobertC;Fuller,DavidD;Mickle,AaronD
神经源性膀胱功能障碍会导致泌尿系统并发症，并降低脊髓损伤 (SCI) 患者的生活质量。通过 AMPA 受体发出的谷氨酸信号对于控制膀胱排尿的神经回路至关重要。 Ampakins 是 AMPA 受体的正变构调节剂，可以增强 SCI 后谷氨酸能神经回路的功能。我们假设安帕金可以急性刺激因胸部挫伤 SCI 而受损的膀胱排尿。成年雌性 Sprague-Dawley 大鼠 T9 脊髓单侧挫伤（n = 10）。 SCI 后 5 天，在乌拉坦麻醉下评估膀胱功能（膀胱测压）和与尿道外括约肌 (EUS) 的协调性。将数据与脊柱完整的大鼠（n=8）的反应进行比较。 “低影响”ampakine CX1739（5、10 或 15 mg/kg）或载体（2-羟丙基-β-环糊精 [HPCD]）通过静脉注射给药。 HPCD 车辆对排尿没有明显影响。相反，CX1739后，诱导膀胱收缩的压力阈值、排尿量和膀胱收缩之间的间隔显着降低。这些反应以剂量依赖性方式发生。我们得出的结论是，使用 ampakines 调节 AMPA 受体功能可以快速改善挫伤 SCI 后亚急性时间点的膀胱排尿能力。这些结果可能为 SCI 后急性膀胱功能障碍的治疗靶向提供一种新的可转化方法。
Neurogenic bladder dysfunction causes urological complications and reduces the quality of life in persons with spinal cord injury (SCI). Glutamatergic signaling via AMPA receptors is fundamentally important to the neural circuits controlling bladder voiding. Ampakines are positive allosteric modulators of AMPA receptors that can enhance the function of glutamatergic neural circuits after SCI. We hypothesized that ampakines can acutely stimulate bladder voiding that has been impaired due to thoracic contusion SCI. Adult female Sprague–Dawley rats received a unilateral contusion of the T9 spinal cord (n= 10). Bladder function (cystometry) and coordination with the external urethral sphincter (EUS) were assessed 5 d post-SCI under urethane anesthesia. Data were compared to responses in spinal-intact rats (n= 8). The ‘low-impact’ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (2-hydroxypropyl-beta-cyclodextrin [HPCD]) was administered intravenously. The HPCD vehicle had no discernible impact on voiding. In contrast, following CX1739, the pressure threshold for inducing bladder contraction, voided volume, and the interval between bladder contractions were significantly reduced. These responses occurred in a dose-dependent manner. We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder-voiding capability at subacute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI.