Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People's Republic of China.
Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, People's Republic of China.
Int J Nanomedicine. 2023 May 30;18:2839-2853. doi: 10.2147/IJN.S402871. eCollection 2023.
Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR.
The microemulsions loaded with BR and decorated with cannabidiol (CBD/BR-MEs) were developed through a one-step emulsion method. The pharmaceutical behaviors of the CBD/BR-MEs were measured using dynamic light scattering and high-performance liquid chromatography. The efficacy of the anti-IBS-D therapy was evaluated by assessing fecal water content, Bristol score, and AWR score. The intestinal permeability were assessed through immunofluorescent staining of CB1 and ZO-1, respectively. The signaling of CREB/BDNF/c-Fos was also studied along with immunofluorescent and immunohistochemical examination of brain sections.
The CBD/BR-MEs, which had a particle size of approximately 30 nm and a surface density of 2% (wt%) CBD, achieved greater than 80% (wt%) encapsulation efficiency of BR. The pharmacokinetics performance of CBD/BR-MEs was significantly improved in the KD-fed IBS-D rats than the standard diet-fed ones, which is highly related to intestinal expression of CB1 receptors. The treatment with CBD/BR-MEs and KD exhibited evident comprehensive advantages over the other groups in terms of anti-IBS-D efficacy. CBD/BR-MEs and KD synergistically decreased intestinal permeability. Moreover, the treatment with CBD/BR-MEs and KD not only blocked the CREB/BDNF/c-Fos signaling in the brain but also decreased the levels of neurotrophic factors, neurotransmitters, and inflammatory cytokines in the serum of IBS-D model rats.
Such a design represents the first attempt at IBS-D-targeted drug delivery for improved oral absorption and efficacy through KD-induced target exposure, which holds promising potential for the treatment of IBS-D.
小檗碱（BR）作为治疗腹泻型肠易激综合征（IBS-D）的候选药物具有广阔的前景。然而，其不理想的理化性质和较差的口服吸收限制了其临床转化。生酮饮食（KD）可以诱导肠道大麻素 CB1 受体过表达，这可能为 IBS-D 特异性 BR 递药提供一个潜在的靶点。
采用一步乳化法制备小檗碱载药微乳（CBD/BR-MEs）。采用动态光散射和高效液相色谱法测定 CBD/BR-MEs 的制剂行为。通过评估粪便含水量、Bristol 评分和 AWR 评分来评估抗 IBS-D 治疗的疗效。通过 CB1 和 ZO-1 的免疫荧光染色分别评估肠道通透性。还通过脑切片的免疫荧光和免疫组织化学研究了 CREB/BDNF/c-Fos 信号。
CBD/BR-MEs 的粒径约为 30nm，表面 CBD 密度为 2%（wt%），实现了 BR 超过 80%（wt%）的包封效率。在 KD 喂养的 IBS-D 大鼠中，CBD/BR-MEs 的药代动力学性能明显优于标准饮食喂养的大鼠，这与肠道 CB1 受体的表达高度相关。与其他组相比，CBD/BR-MEs 和 KD 的联合治疗在抗 IBS-D 疗效方面具有明显的综合优势。CBD/BR-MEs 和 KD 协同降低了肠道通透性。此外，CBD/BR-MEs 和 KD 的治疗不仅阻断了脑内的 CREB/BDNF/c-Fos 信号，还降低了 IBS-D 模型大鼠血清中神经营养因子、神经递质和炎症细胞因子的水平。
这种设计代表了首次尝试通过 KD 诱导的靶点暴露进行 IBS-D 靶向药物递送，以提高口服吸收和疗效，为治疗 IBS-D 提供了有前景的方法。
