Jangra Ashok, Sriram Chandra Shaker, Lahkar Mangala
Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER), Guwahati, Assam, 781032, India.
Department of Pharmacology, Gauhati Medical College, Guwahati, Assam, 781032, India.
Inflammation. 2016 Aug;39(4):1441-52. doi: 10.1007/s10753-016-0376-5.
Oxido-nitrosative stress, neuroinflammation, and reduced level of neurotrophins are implicated in the pathophysiology of anxiety and depressive illness. A few recent studies have revealed the role of endoplasmic reticulum (ER) stress in the pathophysiology of stress and depression. The aim of the present study is to investigate the neuroprotective potential of sodium phenylbutyrate (SPB), an ER stress inhibitor against lipopolysaccharide (LPS)-induced anxiety and depressive-like behavior in Swiss albino mice. Anxiety and depressive-like behavior was induced by LPS (0.83 mg/kg; i.p.) administration. Various behavioral tests were conducted to evaluate the anxiety and depressive-like behavior in mice. Real-time PCR was employed for the detection and expression of ER stress markers (78-kDa glucose-regulated protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP)). Pretreatment with SPB significantly ameliorated the LPS-induced anxiety and depressive-like behavior as revealed by behavioral paradigm results. LPS-induced oxidative stress was ameliorated by SPB pretreatment in hippocampus (HC) and prefrontal cortex (PFC) region. Neuroinflammation was significantly reduced by SPB pretreatment in LPS-treated mice as evident from reduction in proinflammatory cytokines (IL-1β and TNF-α). Importantly, LPS administration significantly up-regulated the GRP78 mRNA expression level in the HC which suggests the involvement of unfolded protein response (UPR) in LPS-evoked behavioral anomalies. These results highlight the neuroprotective potential of SPB in LPS-induced anxiety and depressive illness model which may be partially due to inhibition of oxidative stress-neuroinflammatory cascade.
氧化亚硝基应激、神经炎症和神经营养因子水平降低与焦虑症和抑郁症的病理生理学有关。最近的一些研究揭示了内质网（ER）应激在应激和抑郁症病理生理学中的作用。本研究的目的是研究苯丁酸钠（SPB）作为一种内质网应激抑制剂对脂多糖（LPS）诱导的瑞士白化小鼠焦虑和抑郁样行为的神经保护潜力。通过腹腔注射LPS（0.83mg/kg）诱导小鼠产生焦虑和抑郁样行为。进行了各种行为测试以评估小鼠的焦虑和抑郁样行为。采用实时定量PCR检测内质网应激标志物（78kDa葡萄糖调节蛋白（GRP78）和CCAAT/增强子结合蛋白同源蛋白（CHOP））的表达。行为范式结果显示，SPB预处理显著改善了LPS诱导的焦虑和抑郁样行为。SPB预处理减轻了海马体（HC）和前额叶皮质（PFC）区域LPS诱导的氧化应激。从促炎细胞因子（IL-1β和TNF-α）的减少可以明显看出，SPB预处理显著降低了LPS处理小鼠的神经炎症。重要的是，LPS给药显著上调了HC中GRP78 mRNA的表达水平，这表明未折叠蛋白反应（UPR）参与了LPS诱发的行为异常。这些结果突出了SPB在LPS诱导的焦虑和抑郁症模型中的神经保护潜力，这可能部分归因于对氧化应激-神经炎症级联反应的抑制。
