Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, 260-8670, Japan; Department of Respirology, Chiba University Graduate School of Medicine, Chiba, 260-8670, Japan.
Eur J Pharmacol. 2021 Apr 15;897:173954. doi: 10.1016/j.ejphar.2021.173954. Epub 2021 Feb 19.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that causes long-lasting inflammation and colitis in the gastrointestinal tract. Depression is a common symptom in patients with UC. (R)-ketamine is a new safer antidepressant than (R,S)-ketamine and (S)-ketamine. Here, we examined the effects of two ketamine enantiomers on the dextran sulfate sodium (DSS)-induced colitis model of UC. Ingestion of 3% DSS in drinking water for 14 days increased the scores of Disease Activity Index (DAI) in mice. Repeated administration of (R)-ketamine (10 mg/kg/day, 14 days or last 7 days), but not (S)-ketamine (10 mg/kg/day, 14 days or last 7 days), significantly ameliorated the increased DAI score and increased blood levels of interleukin-6 (IL-6) in DSS-treated mice. In addition, (R)-ketamine, but not (S)-ketamine, attenuated the reduced colonic length in DSS-treated mice. Furthermore, DSS-induced increased DAI score and blood IL-6 levels were significantly ameliorated after subsequent repeated administration of (R)-ketamine (10 mg/kg/day for last 7 days), but not 5-aminosalicyclic acid (50 mg/kg/day for last 7 days). Moreover, the pretreatment with a tropomyosin-receptor-kinase B (TrkB) antagonist ANA-12 (0.5 mg/kg) significantly blocked the beneficial effects of (R)-ketamine in DSS-induced UC model. The study shows that (R)-ketamine can produce beneficial effects in DSS-induced colitis model through TrkB stimulation. Therefore, (R)-ketamine may be a novel therapeutic drug for inflammatory bowel diseases such as UC.
溃疡性结肠炎（UC）是一种慢性炎症性肠病，会导致胃肠道长期炎症和结肠炎。抑郁是 UC 患者的常见症状。（R）-氯胺酮是一种比（R，S）-氯胺酮和（S）-氯胺酮更安全的新型抗抑郁药。在这里，我们研究了两种氯胺酮对葡聚糖硫酸钠（DSS）诱导的 UC 结肠炎模型的影响。在饮用水中摄入 3%的 DSS 14 天会增加小鼠疾病活动指数（DAI）的评分。重复给予（R）-氯胺酮（10mg/kg/天，14 天或最后 7 天），但不是（S）-氯胺酮（10mg/kg/天，14 天或最后 7 天），可显著改善 DSS 处理小鼠增加的 DAI 评分和增加的白细胞介素-6（IL-6）血水平。此外，（R）-氯胺酮，而不是（S）-氯胺酮，可减轻 DSS 处理小鼠的结肠长度缩短。此外，在随后重复给予（R）-氯胺酮（最后 7 天每天 10mg/kg）后，DSS 诱导的增加的 DAI 评分和血液 IL-6 水平显著改善，但 5-氨基水杨酸（50mg/kg/天，最后 7 天）则不然。此外，使用原肌球蛋白受体激酶 B（TrkB）拮抗剂 ANA-12（0.5mg/kg）预处理可显著阻断（R）-氯胺酮在 DSS 诱导的 UC 模型中的有益作用。该研究表明，（R）-氯胺酮可通过刺激 TrkB 产生有益的作用，在 DSS 诱导的结肠炎模型中发挥作用。因此，（R）-氯胺酮可能是治疗溃疡性结肠炎等炎症性肠病的新型治疗药物。
