Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Department of Natural Products Chemistry, Medical University of Lublin, Lublin, Poland.
Int Immunopharmacol. 2023 Jun;119:110239. doi: 10.1016/j.intimp.2023.110239. Epub 2023 May 1.
Neuroinflammation mediated by microglia activation is a critical contributor to Alzheimer's disease (AD) pathogenesis. Dysregulated microglia polarization in terms of M1 overactivation with M2 inhibition is involved in AD pathological damage. Scoparone (SCO), a coumarin derivative, displays several beneficial pharmacological effects including anti-inflammatory and anti-apoptotic properties, however, its neurological effect in AD is still elusive. This study investigated the neuroprotective potential of SCO in AD animal model focusing on determining its effect on M1/M2 microglia polarization and exploring the plausible mechanism involved via investigating its modulatory role on TLR4/MyD88/NF-κB and NLRP3 inflammasome. Sixty female Wistar rats were randomly allocated into four groups. Two groups were sham-operated and treated or untreated with SCO, and the other two groups were subjected to bilateral ovariectomy (OVX) and received D-galactose (D-Gal; 150 mg/kg/day, i.p) alone or with SCO (12.5 mg/kg/day, i.p) for 6 weeks. SCO improved memory functions of OVX/D-Gal rats in the Morris water maze and novel object recognition tests. It also reduced the hippocampal burden of amyloid-β and p-Tau, additionally, the hippocampal histopathological architecture was prominently preserved. SCO inhibited the gene expression of TLR4, MyD88, TRAF-6, and TAK-1, additionally, p-JNK and NF-κBp65 levels were significantly curbed. This was associated with repression of NLRP3 inflammasome along with M1-to-M2 microglia polarization shifting as exemplified by mitigating pro-inflammatory M1 marker (CD86) and elevating M2 neuroprotective marker (CD163). Therefore, SCO could promote microglia transition towards M2 through switching off TLR4/MyD88/TRAF-6/TAK-1/NF-κB axis and inhibiting NLRP3 pathway, with consequent mitigation of neuroinflammation and neurodegeneration in OVX/D-Gal AD model.
小胶质细胞激活介导的神经炎症是阿尔茨海默病（AD）发病机制的关键因素。M1 过度激活而 M2 抑制失调的小胶质细胞极化参与 AD 病理损伤。香豆素衍生物 7-甲氧基香豆素（SCO）具有多种有益的药理作用，包括抗炎和抗凋亡作用，但它在 AD 中的神经作用仍不清楚。本研究通过研究其对 TLR4/MyD88/NF-κB 和 NLRP3 炎性小体的调节作用，探讨 SCO 在 AD 动物模型中的神经保护潜力，重点确定其对 M1/M2 小胶质细胞极化的影响，并探讨其可能的作用机制。
将 60 只雌性 Wistar 大鼠随机分为 4 组。两组假手术并给予 SCO 治疗或未治疗，另外两组行双侧卵巢切除术（OVX），并给予 D-半乳糖（D-Gal；150mg/kg/天，腹腔注射）单独或与 SCO（12.5mg/kg/天，腹腔注射）共 6 周。SCO 改善了 OVX/D-Gal 大鼠在 Morris 水迷宫和新物体识别测试中的记忆功能。它还减少了海马体中淀粉样β和 p-Tau 的负担，此外，海马体的组织病理学结构也得到了明显的保存。SCO 抑制了 TLR4、MyD88、TRAF-6 和 TAK-1 的基因表达，此外，p-JNK 和 NF-κBp65 水平也显著受到抑制。这与 NLRP3 炎性小体的抑制以及 M1 向 M2 小胶质细胞极化的转变有关，表现为减轻促炎 M1 标志物（CD86）和提高 M2 神经保护标志物（CD163）。因此，SCO 可能通过关闭 TLR4/MyD88/TRAF-6/TAK-1/NF-κB 轴和抑制 NLRP3 途径，促进小胶质细胞向 M2 转化，从而减轻 OVX/D-Gal AD 模型中的神经炎症和神经退行性变。
