Eriocalyxin B 对实验性自身免疫性前列腺炎小鼠模型中前列腺炎症和盆腔疼痛的影响。

Effect of Eriocalyxin B on prostatic inflammation and pelvic pain in a mouse model of experimental autoimmune prostatitis.

机构信息

Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.

Institute of Urology, Anhui Medical University, Hefei, Anhui, China.

出版信息

Prostate. 2020 Dec;80(16):1394-1404. doi: 10.1002/pros.24065. Epub 2020 Sep 23.

DOI:10.1002/pros.24065

PMID:32965686

Abstract

BACKGROUND

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disease in males. Eriocalyxin B (EriB), a natural diterpenoid purified from Isodon eriocalyx var. laxiflora, was previously reported to have antitumor effects via multiple immune-related pathways. In this study, we investigated the effect of EriB on CP/CPPS using a mouse model of experimental autoimmune prostatitis (EAP) and explored its potential mechanisms.

METHODS

The EAP model was established in nonobese diabetic mice by intradermal injecting a mixture of prostate antigens and Complete Freund's Adjuvant on days 0 and 28. Then, EAP mice received daily intraperitoneal injections of EriB (5 or 10 mg/kg/d) for 14 days, from days 28 to 42 (EAP+EriB5 or EAP+EriB10 groups). The histopathological appearance of the prostate tissues was evaluated. Chronic pelvic pain development was assessed by cutaneous allodynia. Inflammatory cytokines were measured by enzyme-linked immunosorbent assay tests. We then explored anti-inflammatory potential mechanisms of EriB by studying the effects of PI3K inhibitor wortmannin (EAP+EriB10+Wort group) and NF-κB inhibitor SC75741 (EAP+EriB10+SC group) on prostate inflammation and pelvic pain using this model.

RESULTS

Histological analyses revealed significant prostate inflammation in EAP mice compared with control mice. Significantly increased pelvic pain was detected in EAP mice (P < .05). Compared with the EAP+Veh group, chronic pain development, histological appearance, and cytokine levels demonstrated that EriB could alleviate the severity of EAP in a dose-dependent manner though upregulation of the PI3K/Akt/mTOR pathway and downregulation of the NF-κB pathway. Further mechanism research demonstrated that the PI3K/AKT/mTOR pathway could be blocked by wortmannin, but was not affected by SC75741. In addition, the NF-κB pathway could be further inhibited by SC75741 compared with the EAP+EriB10+Veh group. However, wortmannin could reactivate the NF-κB pathway, indicating that the PI3K/AKT/mTOR pathway negatively regulates the NF-κB pathway during EriB treatment.

CONCLUSIONS

The results of the present study suggested that EriB could alleviate the severity of prostatic inflammation and pelvic pain in an EAP mouse model. These findings may broaden the value of EriB as a promising candidate for the treatment of CP/CPPS.

摘要

背景

慢性前列腺炎/慢性骨盆疼痛综合征（CP/CPPS）是男性的一种常见疾病。Eriocalyxin B（EriB）是从三叶香茶菜中分离得到的一种天然二萜类化合物，先前的研究表明，它通过多种免疫相关途径具有抗肿瘤作用。在这项研究中，我们使用实验性自身免疫性前列腺炎（EAP）的小鼠模型研究了 EriB 对 CP/CPPS 的影响，并探讨了其潜在的机制。

方法

通过在第 0 天和第 28 天给非肥胖型糖尿病（NOD）小鼠皮内注射前列腺抗原和完全弗氏佐剂混合物，建立 EAP 模型。然后，EAP 小鼠在第 28 天至第 42 天（EAP+EriB5 或 EAP+EriB10 组）期间每天接受腹腔内注射 EriB（5 或 10mg/kg/d）。评估前列腺组织的组织病理学表现。通过皮肤感觉过敏评估慢性骨盆疼痛的发展。通过酶联免疫吸附试验（ELISA）测定炎性细胞因子。然后，我们通过研究 PI3K 抑制剂wortmannin（EAP+EriB10+Wort 组）和 NF-κB 抑制剂 SC75741（EAP+EriB10+SC 组）对该模型中前列腺炎症和骨盆疼痛的影响，探讨 EriB 的抗炎潜力机制。

结果

与对照组小鼠相比，EAP 小鼠的前列腺组织有明显的炎症。EAP 小鼠的骨盆疼痛明显增加（P<.05）。与 EAP+Veh 组相比，EriB 以剂量依赖性方式减轻 EAP 的严重程度，表现为慢性疼痛发展、组织学表现和细胞因子水平的降低，这表明 EriB 可能通过上调 PI3K/Akt/mTOR 通路和下调 NF-κB 通路来缓解 EAP。进一步的机制研究表明，PI3K/AKT/mTOR 通路可被 wortmannin 阻断，但不受 SC75741 的影响。此外，与 EAP+EriB10+Veh 组相比，SC75741 可进一步抑制 NF-κB 通路。然而，wortmannin 可以重新激活 NF-κB 通路，表明在 EriB 治疗过程中，PI3K/AKT/mTOR 通路负调节 NF-κB 通路。