新型 GPR18 选择性激动剂 PSB-KK-1415 在肠道炎症和炎症性疼痛动物模型中具有强大的抗炎和抗痛觉过敏活性。
Novel selective agonist of GPR18, PSB-KK-1415 exerts potent anti-inflammatory and anti-nociceptive activities in animal models of intestinal inflammation and inflammatory pain.
机构信息
Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland.
出版信息
Neurogastroenterol Motil. 2021 Mar;33(3):e14003. doi: 10.1111/nmo.14003. Epub 2020 Oct 14.
BACKGROUND
GPR18 is a recently deorphanized receptor which was reported to act with several endogenous cannabinoid ligands. Here, we aimed to describe the role of GPR18 in intestinal inflammation and inflammatory pain.
METHODS
The anti-inflammatory activity of selective GPR18 agonist, PSB-KK-1415, and antagonist, PSB-CB5, was characterized in semi-chronic and chronic mouse models of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). The extent of inflammation was evaluated based on the macroscopic and microscopic scores, quantification of myeloperoxidase (MPO) activity, and Western blot analyses of tumor necrosis factor-α (TNF-α) and interleukin-6 in colonic tissue. The expression of GPR18 in colonic samples from patients with Crohn's disease (CD) was quantified using real-time PCR. The anti-nociceptive potential of the agonist in intestinal inflammation was evaluated in the mouse model of inflammatory pain.
KEY RESULTS
In semi-chronic colitis, PSB-KK-1415 reduced macroscopic score (1.79 ± 0.22 vs. 2.61 ± 0.48), expression of TNF-α (1.89 ± 0.36 vs. 2.83 ± 0.64), and microscopic score (5.00 ± 0.33 vs. 6.45 ± 0.40), all compared to mice with colitis. In chronic colitis, PSB-KK-1415 decreased macroscopic score (3.33 ± 1.26 vs. 4.00 ± 1.32) and MPO activity (32.23 ± 8.51 vs. 41.33 ± 11.64) compared to inflamed mice. In the mouse model of inflammatory pain, PSB-KK-1415 decreased the number of pain-induced behaviors in both, controls (32.60 ± 2.54 vs. 58.00 ± 6.24) and inflamed mice (60.83 ± 2.85 vs. 85.00 ± 5.77) compared to animals without treatment with PSB-KK-1415 (P < 0.005 for both). Lastly, we showed an increased expression of GPR18 in CD patients compared to healthy controls (3.77 ± 1.46 vs. 2.38 ± 0.66, p = 0.87).
CONCLUSIONS & INFERENCES: We showed that GPR18 is worth considering as a potential treatment target in intestinal inflammation and inflammatory pain.
背景
GPR18 是一种最近被发现的受体，据报道它与几种内源性大麻素配体相互作用。在这里，我们旨在描述 GPR18 在肠道炎症和炎症性疼痛中的作用。
方法
用选择性 GPR18 激动剂 PSB-KK-1415 和拮抗剂 PSB-CB5 对 2,4,6-三硝基苯磺酸（TNBS）诱导的半慢性和慢性小鼠结肠炎模型进行抗炎作用特征描述。根据宏观和微观评分、髓过氧化物酶（MPO）活性的定量以及结肠组织中肿瘤坏死因子-α（TNF-α）和白细胞介素-6 的 Western blot 分析来评估炎症的程度。使用实时 PCR 定量克罗恩病（CD）患者结肠样本中的 GPR18 表达。在炎症性疼痛的小鼠模型中评估激动剂的抗伤害感受潜力。
主要结果
在半慢性结肠炎中，PSB-KK-1415 降低了宏观评分（1.79±0.22 与 2.61±0.48 相比）、TNF-α 的表达（1.89±0.36 与 2.83±0.64 相比）和微观评分（5.00±0.33 与 6.45±0.40 相比），与结肠炎小鼠相比均有统计学意义。在慢性结肠炎中，PSB-KK-1415 降低了宏观评分（3.33±1.26 与 4.00±1.32 相比）和 MPO 活性（32.23±8.51 与 41.33±11.64 相比），与炎症小鼠相比均有统计学意义。在炎症性疼痛的小鼠模型中，与未用 PSB-KK-1415 治疗的动物相比（对照组：32.60±2.54 与 58.00±6.24 相比；炎症组：60.83±2.85 与 85.00±5.77 相比），PSB-KK-1415 减少了对照组和炎症组的疼痛诱导行为次数（P<0.005）。最后，我们发现与健康对照组相比，CD 患者的 GPR18 表达增加（3.77±1.46 与 2.38±0.66，p=0.87）。
结论
我们表明，GPR18 作为一种潜在的肠道炎症和炎症性疼痛治疗靶点值得考虑。
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