Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Department of Urology, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Neurourol Urodyn. 2024 Jun;43(5):1207-1216. doi: 10.1002/nau.25458. Epub 2024 Mar 27.
Activation of the endocannabinoid system by monoacylglycerol lipase (MAGL) blockade may affect the lower urinary tract function. We investigated the effect of an MAGL inhibitor, MJN110, on neurogenic lower urinary tract dysfunction (LUTD) in the mouse model of spinal cord injury (SCI).
Female C57BL/6 mice that underwent spinal cord transection at T8-10 level were divided into three groups consisting of (1) vehicle-treated SCI mice, (2) 5 mg/kg, or (3) 10 mg/kg of MJN110-treated SCI mice. MJN110 and vehicle were administered intraperitoneally for 7 days from 4 weeks after spinal cord transection. We then conducted awake cystometrograms and compared urodynamic parameters between three groups. The expression of cannabinoid (CB) receptors, TRP receptors, and inflammatory cytokines in L6-S1 dorsal root ganglia (DRG) or the bladder mucosa were evaluated and compared among three groups. Changes in the level of serum 2-arachidonoylglycerol (2-AG) and bladder MAGL were also evaluated.
In the cystometrogram, detrusor overactivity (DO) parameters, such as the number of nonvoiding contraction (NVC), a ratio of time to the 1st NVC to intercontraction interval (ICI), and NVC integrals were improved by MJN110 treatment, and some effects were dose dependent. Although MJN110 did not improve voiding efficiency, it decreased bladder capacity, ICI, and residual urine volume compared to vehicle injection. MJN110 treatment groups had lower CB2, TRPV1, TRPA1, and inflammatory cytokines mRNA levels in DRG and bladder mucosa. Serum 2-AG was increased, and bladder MAGL was decreased after MAGL inhibitor treatment.
MAGL inhibition improved LUTD including attenuation of DO after SCI. Thus, MAGL can be a therapeutic target for neurogenic LUTD after SCI.
通过单酰基甘油脂肪酶 (MAGL) 阻断激活内源性大麻素系统可能会影响下尿路功能。我们研究了 MAGL 抑制剂 MJN110 对脊髓损伤 (SCI) 小鼠模型神经原性下尿路功能障碍 (LUTD) 的影响。
将 T8-10 水平脊髓横断的雌性 C57BL/6 小鼠分为三组：（1） vehicle 处理的 SCI 组；（2）5mg/kg 或（3）10mg/kg 的 MJN110 处理的 SCI 组。在脊髓横断后 4 周开始，MJN110 和载体通过腹腔内给药，连续给药 7 天。然后，我们进行了清醒的膀胱测压，并比较了三组之间的尿动力学参数。比较了三组 L6-S1 背根神经节 (DRG) 或膀胱黏膜中大麻素 (CB) 受体、TRP 受体和炎症细胞因子的表达。还评估了血清 2-花生四烯酸甘油 (2-AG) 和膀胱 MAGL 水平的变化。
在膀胱测压中，通过 MJN110 处理改善了逼尿肌过度活动 (DO) 参数，如无排尿收缩 (NVC) 次数、首次 NVC 至 ICI 时间与 ICI 比值和 NVC 积分，并且某些作用呈剂量依赖性。尽管 MJN110 没有改善排尿效率，但与载体注射相比，它降低了膀胱容量、ICI 和残余尿量。与 vehicle 注射相比，MJN110 处理组的 DRG 和膀胱黏膜中 CB2、TRPV1、TRPA1 和炎症细胞因子的 mRNA 水平较低。血清 2-AG 增加，膀胱 MAGL 减少。
MAGL 抑制改善了 SCI 后的 LUTD，包括 DO 减弱。因此，MAGL 可能是 SCI 后神经原性 LUTD 的治疗靶点。
