Gharedaghi Mohammad Hadi, Rahimian Reza, Dehpour Ahmad Reza, Yousefzadeh-Fard Yashar, Mohammadi-Farani Ahmad
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box 13145-784, Tehran, Iran.
Psychopharmacology (Berl). 2015 Aug;232(16):3081-90. doi: 10.1007/s00213-015-3950-x. Epub 2015 May 14.
Many peripheral diseases are associated with a decline in cognitive function. In this regard, there have been reports of patients with inflammatory bowel disease and an otherwise unexplained memory impairment.
We sought to assess the memory performance of mice with colitis. We also investigated the roles of N-methyl D-aspartate (NMDA) receptors and nitric oxide (NO) as possible mediators of colitis-induced amnesia.
To induce colitis, male NMRI mice were intrarectally injected with a solution containing dinitrobenzene sulfonic acid (DNBS; 4 mg in 100 μl) under anesthesia. Three days after intrarectal DNBS instillation, spatial recognition and associative memories were assessed by the Y-maze and passive avoidance tasks, respectively. The NMDA antagonists, MK-801 and memantine, and the inducible NO synthase (iNOS) inhibitor, aminoguanidine, were injected intraperitoneally 45 min before the Y-maze task.
Induction of colitis by DNBS impaired spatial recognition memory in the Y-maze task but had no effect on step through latencies in the passive avoidance test. Colitis-induced amnesia was reversed by administering specific doses of MK-801 and memantine (30 μg/kg and 1 mg/kg, respectively) suggesting dysregulated NMDA receptor activation as an underlying mechanism. No effect was seen with lower and higher doses of these drugs, resulting in a bell-shaped dose response curve. Colitis-induced amnesia was also inhibited by aminoguanidine (50 mg/kg), implicating a role for iNOS activation and neuroinflammation in this phenomenon.
DNBS-induced colitis impairs memory through NMDA receptor overstimulation and NO overproduction.
许多外周疾病都与认知功能下降有关。在这方面，已有炎症性肠病患者出现不明原因记忆障碍的报道。
我们试图评估结肠炎小鼠的记忆表现。我们还研究了N-甲基-D-天冬氨酸（NMDA）受体和一氧化氮（NO）作为结肠炎诱导失忆可能介质的作用。
为诱导结肠炎，在麻醉下给雄性NMRI小鼠经直肠注射含二硝基苯磺酸（DNBS；100μl中含4mg）的溶液。经直肠滴注DNBS三天后，分别通过Y迷宫和被动回避任务评估空间识别和联想记忆。在Y迷宫任务前45分钟腹腔注射NMDA拮抗剂MK-801和美金刚以及诱导型一氧化氮合酶（iNOS）抑制剂氨基胍。
DNBS诱导的结肠炎损害了Y迷宫任务中的空间识别记忆，但对被动回避试验中的步过潜伏期没有影响。给予特定剂量的MK-801和美金刚（分别为30μg/kg和1mg/kg）可逆转结肠炎诱导的失忆，提示NMDA受体激活失调是潜在机制。这些药物的较低和较高剂量均未见效果，导致呈钟形的剂量反应曲线。氨基胍（50mg/kg）也抑制了结肠炎诱导的失忆，提示iNOS激活和神经炎症在这一现象中起作用。
DNBS诱导的结肠炎通过NMDA受体过度刺激和NO过量产生损害记忆。
