Li X, Sung P, Zhang D, Yan L
Department of Neurology, Tangshan Gongren Hospital, Tangshan, Hebei Province, China.
Physiol Res. 2023 Aug 31;72(4):497-510. doi: 10.33549/physiolres.935054.
Oxidative stress and autophagy are potential mechanisms associated with cerebral ischemia/reperfusion injury (IRI) and is usually linked to inflammatory responses and apoptosis. Curcumin has recently been demonstrated to exhibit anti-inflammatory, anti-oxidant, anti-apoptotic and autophagy regulation properties. However, mechanism of curcumin on IRI-induced oxidative stress and autophagy remains not well understood. We evaluated the protective effects and potential mechanisms of curcumin on cerebral microvascular endothelial cells (bEnd.3) and neuronal cells (HT22) against oxygen glucose deprivation/reoxygenation (OGD/R) in vitro models that mimic in vivo cerebral IRI. The cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) activity assays revealed that curcumin attenuated the OGD/R-induced injury in a dose-specific manner. OGD/R induced elevated levels of inflammatory cytokines TNF-alpha, IL-6 as well as IL-1beta, and these effects were notably reduced by curcumin. OGD/R-mediated apoptosis was suppressed by curcumin via upregulating B-cell lymphoma-2 (Bcl-2) and downregulating Bcl-associated X (Bax), cleaved-caspase3 and TUNEL apoptosis marker. Additionally, curcumin increased superoxide dismutase (SOD) and glutathione (GSH), but suppressed malondialdehyde (MDA) and reactive oxygen species (ROS) content. Curcumin inhibited the levels of autophagic biomarkers such as LC3 II/LC3 I and Beclin1. Particularly, curcumin induced p62 accumulation and its interactions with keap1 and promoted NF-E2-related factor 2 (Nrf2) translocation to nucleus, accompanied by increased NADPH quinone dehydrogenase (Nqo1) and heme oxygenase 1 (HO-1). Treatment of curcumin increased phosphorylation-phosphatidylinositol 3 kinase (p-PI3K) and p-protein kinase B (p-AKT). The autophagy inhibitor 3-methyladenine (3-MA) activated the keap-1/Nrf2 and PI3K/AKT pathways. This study highlights the neuroprotective effects of curcumin on cerebral IRI.
氧化应激和自噬是与脑缺血/再灌注损伤（IRI）相关的潜在机制，通常与炎症反应和细胞凋亡有关。姜黄素最近被证明具有抗炎、抗氧化、抗凋亡和自噬调节特性。然而，姜黄素对IRI诱导的氧化应激和自噬的机制仍未完全了解。我们在模拟体内脑IRI的体外模型中，评估了姜黄素对脑微血管内皮细胞（bEnd.3）和神经元细胞（HT22）抗氧糖剥夺/复氧（OGD/R）的保护作用及潜在机制。细胞计数试剂盒-8（CCK-8）和乳酸脱氢酶（LDH）活性测定显示，姜黄素以剂量特异性方式减轻了OGD/R诱导的损伤。OGD/R诱导炎性细胞因子肿瘤坏死因子-α、白细胞介素-6以及白细胞介素-1β水平升高，而姜黄素显著降低了这些作用。姜黄素通过上调B细胞淋巴瘤-2（Bcl-2）和下调Bcl相关X蛋白（Bax）、裂解的半胱天冬酶-3和TUNEL凋亡标记物来抑制OGD/R介导的细胞凋亡。此外，姜黄素增加了超氧化物歧化酶（SOD）和谷胱甘肽（GSH），但抑制了丙二醛（MDA）和活性氧（ROS）含量。姜黄素抑制了自噬生物标志物如LC3 II/LC3 I和Beclin1的水平。特别是，姜黄素诱导p62积累及其与Keap1的相互作用，并促进核因子E2相关因子2（Nrf2）转位至细胞核，同时伴有NADPH醌脱氢酶（Nqo1）和血红素加氧酶1（HO-1）增加。姜黄素处理增加了磷酸化磷脂酰肌醇3激酶（p-PI3K）和磷酸化蛋白激酶B（p-AKT）。自噬抑制剂3-甲基腺嘌呤（3-MA）激活了Keap-1/Nrf2和PI3K/AKT途径。本研究突出了姜黄素对脑IRI的神经保护作用。
