Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomti Nagar Extension, Lucknow, 226028, Uttar Pradesh, India.
Centre of Biomedical Research, Sanjay Gandhi Postgraduate Institute of Medical Sciences Campus, Raibareli Road, Lucknow, 226014, Uttar Pradesh, India.
Immunol Res. 2022 Oct;70(5):633-643. doi: 10.1007/s12026-022-09295-8. Epub 2022 Jun 7.
Cognitive dysfunction, sickness-like behavior, for instance, anxiety, and depression are common aspects of neuropsychiatry often associated with neurodegenerative disorders. Growing evidence suggests that high mobility group box 1 (HMGB1) may act as a proinflammatory cytokine that aggravates neurobehavioral dysfunction. However, the detailed underlying mechanism is still elusive. Here we focus on determining the relationship between lipopolysaccharide (LPS)-induced neuroinflammation (in both in vitro and in vivo models), cognitive dysfunction, sickness-like behavior and thus decode the impact of HMGB1 inhibition (using Glycyrrhizin; Gcy as an antagonist). Using a mice model of repeated LPS (1 mg/kg, i.p. for 4 days) injections, we found that LPS induced neurobehavioral deficit and a strong proinflammatory response with increased proinflammatory markers, including tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and iNOS (inducible nitric oxide synthase) at 7 days after the final dose of LPS compared to control animals. Our findings suggest that neurobehavioral dysfunction strongly correlates with the proinflammatory immune response following LPS stimulation. In vitro Gcy pretreatment to LPS-activated BV2 microglia cells significantly reduced nitrite and reactive oxygen species production, along with diminished expression of classical proinflammatory cytokines (TNF-α, IL-1β, IL-6, iNOS). These key proinflammatory changes with LPS and Gcy treatment are also found in vivo mice model and correlate with improved cognitive function and reduced anxiety/depression. Together, these results show that blocking HMGB1 using Gcy abrogated the cognitive dysfunction, sickness-like behavior of anxiety and depression induced by LPS which can be a promising avenue for crucial neurobehavioral dysfunction.
认知功能障碍、类似疾病的行为，如焦虑和抑郁，是神经精神疾病的常见方面，常与神经退行性疾病有关。越来越多的证据表明，高迁移率族蛋白 B1（HMGB1）可能作为一种促炎细胞因子，加重神经行为功能障碍。然而，其详细的潜在机制仍不清楚。在这里，我们专注于确定脂多糖（LPS）诱导的神经炎症（在体外和体内模型中）、认知功能障碍、类似疾病的行为之间的关系，从而解码 HMGB1 抑制（使用甘草酸作为拮抗剂）的影响。使用重复 LPS（1mg/kg，腹腔注射，共 4 天）注射的小鼠模型，我们发现 LPS 诱导了神经行为缺陷和强烈的促炎反应，增加了促炎标志物，包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）和诱导型一氧化氮合酶（iNOS），与对照组相比，在最后一次 LPS 剂量后 7 天达到高峰。我们的研究结果表明，神经行为功能障碍与 LPS 刺激后的促炎免疫反应密切相关。在 LPS 激活的 BV2 小胶质细胞中预先用甘草酸处理，可显著减少亚硝酸盐和活性氧的产生，同时减少经典促炎细胞因子（TNF-α、IL-1β、IL-6、iNOS）的表达。LPS 和甘草酸处理后的这些关键促炎变化也在体内小鼠模型中发现，并与认知功能的改善和焦虑/抑郁的减少相关。总之，这些结果表明，使用甘草酸阻断 HMGB1 可消除 LPS 引起的认知功能障碍、类似疾病的焦虑和抑郁行为，这可能是治疗关键神经行为障碍的有前途的途径。
