Dignify Therapeutics LLC, Research Triangle Park, North Carolina.
J Neurotrauma. 2020 Mar 15;37(6):868-876. doi: 10.1089/neu.2019.6676. Epub 2019 Nov 13.
Acute administration of [Lys5,Me,Leu9,Nle10]-NKA(4-10) (LMN-NKA) produces contractions of the detrusor and rectum with voiding in intact and acutely spinal cord injured (SCI) rats. In the current study, the ability of LMN-NKA (10 μg/kg or 100 μg/kg, subcutaneous [SC], twice a day [bid]) or vehicle to induce voiding and defecation in chronic SCI rats was examined across 30 days. After the last day of administration, voiding response rates and bladder pressure (BP) responses to LMN-NKA (intravenous [IV] and SC) were evaluated under anesthesia. In conscious rats, LMN-NKA (100 μg/kg) produced dose-dependent micturition within 5 min, with response rates >90%, and voiding efficiency >80% in males and >60% in females, which remained stable across the 1-month test period. Similarly, LMN-NKA administration rapidly induced defecation, which also remained stable. Under anesthesia, LMN-NKA increased BP, voiding efficiency, and voiding response rates, which reached 100% at 3 and 10 μg/kg IV in males and females, respectively. SC administration produced 100% response rates in males (30 μg/kg) but only 71% in females (100 μg/kg). Efficacy in rats chronically treated with LMN-NKA was similar to naïve and vehicle-treated rats, except for reduced voiding efficiency in chronically dosed female rats (100 μg/kg). No differences in bladder weights or collagen-to-smooth muscle ratios in histological sections were seen between the groups. Thus neither tolerance, nor sensitization, to LMN-NKA-induced micturition and defecation occurs with chronic administration in rats with chronic SCI. Efficacy was higher in male than in female rats.
急性给予 [Lys5,Me,Leu9,Nle10]-NKA(4-10)（LMN-NKA）可引起完整和急性脊髓损伤（SCI）大鼠逼尿肌和直肠收缩伴排尿。在目前的研究中，在慢性 SCI 大鼠中，每天两次皮下（SC）给予 LMN-NKA（10μg/kg 或 100μg/kg）或载体，检查其诱导排尿和排便的能力，持续 30 天。在最后一天给药后，在麻醉下评估 LMN-NKA（静脉内 [IV] 和 SC）对排尿的反应率和膀胱压（BP）的反应。在清醒大鼠中，LMN-NKA（100μg/kg）在 5 分钟内产生剂量依赖性的排尿，雄性的反应率>90%，排尿效率>80%，雌性的反应率>60%，在 1 个月的测试期间保持稳定。同样，LMN-NKA 给药迅速诱导排便，也保持稳定。在麻醉下，LMN-NKA 增加 BP、排尿效率和排尿反应率，在雄性和雌性中分别在 3 和 10μg/kg IV 时达到 100%。SC 给药在雄性中产生 100%的反应率（30μg/kg），但在雌性中仅产生 71%（100μg/kg）。在慢性给予 LMN-NKA 的大鼠中，疗效与未处理和载体处理的大鼠相似，除了慢性剂量雌性大鼠的排尿效率降低（100μg/kg）。各组之间在膀胱重量或组织学切片中的胶原与平滑肌比无差异。因此，在慢性 SCI 大鼠中，慢性给予 LMN-NKA 不会导致对 LMN-NKA 诱导的排尿和排便产生耐受性或敏感性。雄性大鼠的疗效高于雌性大鼠。
