Liu Yongqiang, Wu Yunfei, Ren Dewan, Tao Yulong, Mai Fangyi, Zhu Jingyi, Li Xiang, Colla Emanuela, Grimaldi Maria, Giovannini Roberto, Giorgi Fabrizio, Vesci Loredana
Department of Pharmacology, Discovery Services, BioDuro-Sundia, Shanghai, China.
Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open University, Rome, Italy.
Front Pharmacol. 2024 Jul 30;15:1411642. doi: 10.3389/fphar.2024.1411642. eCollection 2024.
Chronic intestinal pseudo-obstruction (CIPO) is a type of intestinal dysfunction with symptoms of intestinal blockage but without the actual mechanical obstruction. Currently, there are no drugs available to treat this disease. Herein, we report the characterization of the PrP-SCA7-92Q transgenic (Tg) line as a valuable CIPO mouse model and investigated the tolerability and efficacy of the 5-hydroxytryptamine type-4 receptor (5HT4R) agonist velusetrag as a promising pharmacological treatment for CIPO.
To test the pharmacodynamics of velusetrag, 8-week-old SCA7 Tg mice, which express human mutated gene containing 92 CAG repeats under the mouse prion protein promoter, were treated for 5 weeks by oral route with velusetrag at 1 and 3 mg/kg doses or vehicle. Body weight was monitored throughout the treatment. After sacrifice, the small intestine and proximal colon were collected for whole-mount immunostaining. Untreated, age-matched, C57BL/6J mice were also used as controls in comparison with the other experimental groups.
Analysis of SCA7 Tg mice showed tissue damage and alterations, mucosal abnormalities, and ulcers in the distal small intestine and proximal colon. Morphological changes were associated with significant neuronal loss, as shown by decreased staining of pan-neuronal markers, and with accumulation of ataxin-7-positive inclusions in cholinergic neurons. Administration of velusetrag reversed intestinal abnormalities, by normalizing tissue damage and re-establishing the normal level of glia/neuron's count in both the small and large intestines.
We demonstrated that the PrP-SCA7-92Q Tg line, a model originally developed to mimic spinocerebellar ataxia, is suitable to study CIPO pathology and can be useful in establishing new therapeutic strategies, such as in the case of velusetrag. Our results suggest that velusetrag is a promising compound to treat patients affected by CIPO or intestinal dysmotility disease.
慢性肠道假性梗阻（CIPO）是一种肠道功能障碍，具有肠道梗阻症状但无实际机械性梗阻。目前，尚无药物可用于治疗该疾病。在此，我们报告了PrP-SCA7-92Q转基因（Tg）品系作为一种有价值的CIPO小鼠模型的特征，并研究了5-羟色胺4型受体（5HT4R）激动剂维芦司琼作为CIPO一种有前景的药物治疗的耐受性和疗效。
为了测试维芦司琼的药效学，8周龄的SCA7转基因小鼠，其在小鼠朊病毒蛋白启动子下表达含有92个CAG重复序列的人类突变基因，通过口服途径用1和3mg/kg剂量的维芦司琼或赋形剂处理5周。在整个治疗过程中监测体重。处死后，收集小肠和近端结肠进行全层免疫染色。未处理的、年龄匹配的C57BL/6J小鼠也用作与其他实验组比较的对照。
对SCA7转基因小鼠的分析显示，远端小肠和近端结肠存在组织损伤和改变、粘膜异常及溃疡。形态学变化与显著的神经元丢失相关，如泛神经元标记物染色减少所示，并且与胆碱能神经元中ataxin-7阳性包涵体的积累相关。维芦司琼的给药通过使组织损伤正常化并重新建立小肠和大肠中神经胶质/神经元计数的正常水平，逆转了肠道异常。
我们证明，最初开发用于模拟脊髓小脑共济失调的PrP-SCA7-92Q转基因品系适用于研究CIPO病理学，并且可用于建立新的治疗策略，如维芦司琼的情况。我们的结果表明，维芦司琼是一种有前景的化合物，可用于治疗受CIPO或肠道动力障碍疾病影响的患者。
