Department of Clinical Pharmacology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54124, Thessaloníki, Greece.
Department of Clinical Pharmacology, School of Health Sciences, Aristotle University of Thessaloniki, PO Box 1532, 54006, Thessaloníki, Greece.
Pharmacol Rep. 2022 Feb;74(1):84-95. doi: 10.1007/s43440-021-00328-x. Epub 2021 Sep 27.
Circulating cytokines have been proposed to be implicated in the development of mood disorders and cognitive impairment. This study aims to examine the effect of chronic treatment with infliximab, a tumor necrosis factor-alpha (TNF-alpha) inhibitor, and tocilizumab, an antibody against interleukin-6 (IL-6) receptor on anxiety-like behavior and cognitive function.
Twenty-eight male, Wistar rats were randomly allocated into negative control, vehicle, infliximab and tocilizumab groups. After 8 weeks of intraperitoneal drug administration, rats performed the elevated-plus maze, the elevated-zero maze, the olfactory social memory and the passive avoidance tests. Brain sections at the level of the hippocampus, the amygdala and the prefrontal cortex were histologically examined. Finally, hippocampal and amygdaloid brain-derived neurotrophic factor (BDNF) expression was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).
Infliximab group exhibited a significantly higher number of entries and time spent into the open arms of the mazes, showing a lower level of anxiety. In the olfactory social memory test, tocilizumab significantly increased the ratio of interaction. Both infliximab- and tocilizumab-treated animals had a significantly lower latency time in the passive avoidance test that suggests an improved memory. Histological examination revealed similar morphology and neuronal density between groups. BDNF expression levels were significantly increased in the groups receiving anti-cytokine treatment.
Our findings suggest that long-term peripheral TNF-alpha and IL-6 inhibition improves anxiety and cognitive function in rats and leads to an increased BDNF expression in the brain.
循环细胞因子被认为与心境障碍和认知障碍的发展有关。本研究旨在研究肿瘤坏死因子-α（TNF-α）抑制剂英夫利昔单抗和白细胞介素-6（IL-6）受体拮抗剂托珠单抗的慢性治疗对焦虑样行为和认知功能的影响。
28 只雄性 Wistar 大鼠随机分为阴性对照组、载体组、英夫利昔单抗组和托珠单抗组。腹腔给药 8 周后，大鼠进行高架十字迷宫、高架零迷宫、嗅觉社交记忆和被动回避测试。在海马、杏仁核和前额叶皮层水平对脑切片进行组织学检查。最后，通过逆转录定量聚合酶链反应（RT-qPCR）测定海马和杏仁核脑源性神经营养因子（BDNF）的表达。
英夫利昔单抗组进入和停留在迷宫开放臂的次数和时间明显增加，焦虑水平较低。在嗅觉社交记忆测试中，托珠单抗显著增加了相互作用的比例。接受英夫利昔单抗和托珠单抗治疗的动物在被动回避测试中的潜伏期明显缩短，表明记忆力提高。组织学检查显示各组之间的形态和神经元密度相似。接受抗细胞因子治疗的组中 BDNF 表达水平显著增加。
我们的研究结果表明，长期外周 TNF-α和 IL-6 抑制可改善大鼠的焦虑和认知功能，并导致大脑中 BDNF 表达增加。
