Oklahoma Center for Neuroscience, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA.
Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Pharmacol Res Perspect. 2021 Feb;9(1):e00709. doi: 10.1002/prp2.709.
Few therapeutic options exist for treatment of IC/BPS. A novel high MW GAG biopolymer ("SuperGAG") was synthesized by controlled oligomerization of CS, purified by TFF and characterized by SEC-MALLS and 1H-NMR spectroscopy. The modified GAG biopolymer was tested in an OVX female rat model in which bladder permeability was induced by a 10-minute intravesicular treatment with dilute (1 mg/ml) protamine sulfate and measured by classical Ussing Chamber TEER measurements following treatment with SuperGAG, chondroitin sulfate, or saline. The effect on abrogating the abdominal pain response was assessed using von Frey filaments. The SuperGAG biopolymer was then investigated in a second, genetically modified mouse model (URO-MCP1) that increasingly is accepted as a model for IC/BPS. Permeability was induced with a brief exposure to a sub-noxious dose of LPS and was quantified using contrast-enhanced MRI (CE-MRI). The SuperGAG biopolymer restored impermeability to normal levels in the OVX rat model as measured by TEER in the Ussing chamber and reduced the abdominal pain response arising from induced permeability. Evaluation in the URO-MCP1 mouse model also showed restoration of bladder impermeability and showed the utility of CE-MRI imaging for evaluating the efficacy of agents to restore bladder impermeability. We conclude novel high MW SuperGAG biopolymers are effective in restoring urothelial impermeability and reducing pain produced by loss of the GAG layer on the urothelium. SuperGAG biopolymers could offer a novel and effective new therapy for IC/BPS, particularly if combined with MRI to assess the efficacy of the therapy.
治疗 IC/BPS 的方法有限。一种新型高分子量 GAG 生物聚合物（“SuperGAG”）通过 CS 的受控寡聚合成，通过 TFF 纯化，并通过 SEC-MALLS 和 1H-NMR 光谱学进行表征。在经卵巢雌性大鼠模型中测试了修饰后的 GAG 生物聚合物，该模型通过 10 分钟膀胱内用稀（1mg/ml）鱼精蛋白硫酸盐处理诱导膀胱通透性，并在用 SuperGAG、硫酸软骨素或生理盐水处理后通过经典 Ussing 室 TEER 测量进行测量。使用 von Frey 纤维评估对消除腹痛反应的影响。然后在第二个遗传修饰小鼠模型（URO-MCP1）中研究了 SuperGAG 生物聚合物，该模型越来越被接受为 IC/BPS 的模型。通过短暂暴露于亚毒性剂量的 LPS 诱导通透性，并使用对比增强 MRI（CE-MRI）进行定量。SuperGAG 生物聚合物在经卵巢大鼠模型中恢复正常的 TEER 通透性，如 Ussing 室中的 TEER 测量所示，并减少由诱导的通透性引起的腹痛反应。在 URO-MCP1 小鼠模型中的评估也显示出膀胱通透性的恢复，并显示了 CE-MRI 成像用于评估恢复膀胱通透性的药物的功效的效用。我们得出结论，新型高分子量 SuperGAG 生物聚合物可有效恢复尿路上皮通透性并减少 GAG 层丢失引起的疼痛。SuperGAG 生物聚合物可为 IC/BPS 提供一种新型有效的治疗方法，特别是如果与 MRI 结合以评估治疗的疗效。
