Yadav Vipul, Mai Yang, McCoubrey Laura E, Wada Yasufumi, Tomioka Motoyasu, Kawata Satofumi, Charde Shrikant, Basit Abdul W
Intract Pharma Limited, London Bioscience Innovation Centre, London NW1 0NH, UK.
School of Pharmaceutical Sciences (Shenzen), Sun Yat-sen University, Guangzhou 510275, China.
Biomedicines. 2021 May 20;9(5):578. doi: 10.3390/biomedicines9050578.
5-Aminolevulinic acid (5-ALA) is a naturally occurring nonprotein amino acid licensed as an optical imaging agent for the treatment of gliomas. In recent years, 5-ALA has been shown to possess anti-inflammatory and immunoregulatory properties through upregulation of heme oxygenase-1 via enhancement of porphyrin, indicating that it may be beneficial for the treatment of inflammatory conditions. This study systematically examines 5-ALA for use in inflammatory bowel disease (IBD). Firstly, the ex vivo colonic stability and permeability of 5-ALA was assessed using human and mouse fluid and tissue. Secondly, the in vivo efficacy of 5-ALA, in the presence of sodium ferrous citrate, was investigated via the oral and intracolonic route in an acute DSS colitis mouse model of IBD. Results showed that 5-ALA was stable in mouse and human colon fluid, as well as in colon tissue. 5-ALA showed more tissue restricted pharmacokinetics when exposed to human colonic tissue. In vivo dosing demonstrated significantly improved colonic inflammation, increased local heme oxygenase-1 levels, and decreased concentrations of proinflammatory cytokines TNF-α, IL-6, and IL-1β in both plasma and colonic tissue. These effects were superior to that measured concurrently with established anti-inflammatory treatments, ciclosporin and 5-aminosalicylic acid (mesalazine). As such, 5-ALA represents a promising addition to the IBD armamentarium, with potential for targeted colonic delivery.
5-氨基乙酰丙酸（5-ALA）是一种天然存在的非蛋白质氨基酸，被许可用作治疗神经胶质瘤的光学成像剂。近年来，5-ALA已被证明通过增强卟啉上调血红素加氧酶-1而具有抗炎和免疫调节特性，这表明它可能对治疗炎症性疾病有益。本研究系统地研究了5-ALA在炎症性肠病（IBD）中的应用。首先，使用人和小鼠的体液及组织评估5-ALA在体外结肠中的稳定性和渗透性。其次，在IBD的急性葡聚糖硫酸钠（DSS）结肠炎小鼠模型中，通过口服和结肠内途径研究了5-ALA在柠檬酸亚铁存在下的体内疗效。结果表明，5-ALA在小鼠和人结肠液以及结肠组织中均稳定。当暴露于人结肠组织时，5-ALA表现出更多的组织限制性药代动力学。体内给药显示结肠炎症明显改善，局部血红素加氧酶-1水平升高，血浆和结肠组织中促炎细胞因子TNF-α、IL-6和IL-1β的浓度降低。这些效果优于与既定抗炎治疗环孢素和5-氨基水杨酸（美沙拉嗪）同时测量的效果。因此，5-ALA是IBD治疗药物库中有前景的补充药物，具有靶向结肠递送的潜力。
