Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Kamrup, Assam, 781101, India.
Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Kamrup, Assam, 781101, India.
J Psychiatr Res. 2021 Dec;144:462-482. doi: 10.1016/j.jpsychires.2021.10.021. Epub 2021 Oct 21.
Major depressive disorder (MDD) is the foremost leading psychiatric illness prevailing around the globe. It usually exists along with anxiety and other clinical conditions (cardiovascular, cancer, neurodegenerative diseases, and infectious diseases). Chronic restraint stress (RS) and LPS-induce neurobehavioral alterations in rodent models however their interaction studies in association with the pathogenesis of MDD are still unclear. Therefore, the current study was aimed to investigate the LPS influence on chronic RS mediated redox imbalance, apoptosis, and autophagic dysregulation in the hippocampus (HIP) and frontal cortex (FC) of mice brain. Male Balb/c mice were exposed to 28 days consecutive stress (6h/day) with a single-dose LPS challenge (0.83 mg/kg, i.p.) on the last day (Day 28). In addition, we also carried out separate study to understand physiological relevance, where we used the DSS (dextran sulfate sodium), a water soluble polysaccharide (negatively charged) and studied its influence on RS induced neurobehavioral and certain neurochemical anomalies. The obtained results in RS and RS + LPS animal groups showed significant immune dysfunction, depleted monoamines, lowered ATP & NAD level, elevated serum CORT level, serum and brain tissues IL-1β/TNF-α/IL-6, SOD activity but reduced CAT activity. Furthermore, the redox perturbation was found where significantly upregulated P-NFκB p65, Keap-1, Prx-SO3 and downregulated Nrf2, Srx1, Prx2 protein expression was seen in RS + LPS mice. The apoptosis signaling (P-ASK1, P-p38 MAPK, P-SAPK/JNK, cleaved PARP, cleaved Caspase-3, Cyto-C), autophagic impairment (p62, LC3II/I) were noticed in HIP and FC of RS and RS + LPS grouped animals. Our new findings provide a complex interplay of chemical (LPS) and physical (RS) stressors where both single dose LPS challenge and 3% DSS in drinking water (for 7 days) exaggerated chronic RS-induced inflammation, lowered redox status, increased apoptosis and dysregulated autophagy leading drastic neurobehavioral alterations in the mice.
重度抑郁症（MDD）是全球范围内首要的精神疾病。它通常伴随着焦虑和其他临床病症（心血管疾病、癌症、神经退行性疾病和传染病）。慢性束缚应激（RS）和 LPS 诱导啮齿动物模型的神经行为改变，但它们与 MDD 发病机制的相互作用研究仍不清楚。因此，本研究旨在探讨 LPS 对慢性 RS 介导的氧化还原失衡、凋亡和自噬失调的影响，以及 LPS 在小鼠大脑海马（HIP）和前额叶皮层（FC）中的作用。雄性 Balb/c 小鼠连续 28 天接受应激（每天 6 小时），最后一天（第 28 天）给予单次 LPS 挑战（0.83mg/kg，腹腔注射）。此外，我们还进行了单独的研究以了解生理相关性，其中我们使用了 DSS（葡聚糖硫酸钠），一种水溶性多糖（带负电荷），并研究了它对 RS 诱导的神经行为和某些神经化学异常的影响。在 RS 和 RS+LPS 动物组中，获得的结果显示出明显的免疫功能障碍、单胺类物质耗竭、ATP 和 NAD 水平降低、血清 CORT 水平升高、血清和脑组织中 IL-1β/TNF-α/IL-6、SOD 活性升高，但 CAT 活性降低。此外，还发现氧化还原失调，RS+LPS 小鼠中 P-NFκB p65、Keap-1、Prx-SO3 显著上调，Nrf2、Srx1、Prx2 蛋白表达下调。在 RS 和 RS+LPS 分组动物的 HIP 和 FC 中，观察到凋亡信号（P-ASK1、P-p38 MAPK、P-SAPK/JNK、cleaved PARP、cleaved Caspase-3、Cyto-C）和自噬损伤（p62、LC3II/I）。我们的新发现提供了化学（LPS）和物理（RS）应激源的复杂相互作用，其中单次 LPS 挑战和 3% DSS 饮用水（7 天）都加剧了慢性 RS 诱导的炎症、降低了氧化还原状态、增加了凋亡并扰乱了自噬，导致小鼠的神经行为发生剧烈改变。
