Song Hai, Ding Zhongyun, Chen Jilin, Chen Tingbao, Wang Tinghua, Huang Jin
Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming, China.
Animal Zoology Department, Kunming Medical University, Kunming, China.
Immunopharmacol Immunotoxicol. 2022 Dec;44(6):970-983. doi: 10.1080/08923973.2022.2096464. Epub 2022 Aug 8.
Traumatic brain injury (TBI) induces inflammations that lead to secondary damage. Hesperetin (Hes) exerts anti-inflammatory activities against central nervous system (CNS) diseases. This article probes the possible neuroprotective effect and mechanism of Hes on TBI-induced acute cerebral damage.
Male C57BL/6J mice were subjected to controlled cortical impingement (CCI) and Hes (50 mg/kg) treatment after the surgery. Short-term neurological deficits were assessed with the modified neurological severity score (mNSS) and the Rota-rod test. The brain edema was tested by the wet/dry method. Neuron apoptosis was evaluated by Nissl staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. The blood-brain barrier (BBB) integrity was measured by Evans' blue staining, and immunohistochemistry (IHC) was conducted to study BV2 microglial activation. BV2 microglia and HT22 neuronal cells were stimulated by oxygen-glucose deprivation followed by recovery (OGD/R) and processed with Hes. Quantitative real-time-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were implemented to gauge the expression of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-β (IL-1-β) and interleukin-6 (IL-6). Western blot (WB) was performed to check AMPK-SIRT1-FoxO1 both and .
Hes eased neurological deficits, cerebral edema, and neuronal apoptosis in mice following TBI. Hes hampered microglial activation and pro-inflammatory cytokines production. Hes promoted AMPK and SIRT1 expression, whereas repressed the phosphorylation of FoxO1-NF-κB, and inhibited NLRP3 expression. The AMPK inhibitor Compound C markedly reversed Hes-mediated anti-inflammatory and neuron-protective effects.
Hes curbs microglial activation-mediated inflammation the AMPK-SIRT1-FoxO1-NF-κB axis, thereby improving neurobehavioral function after TBI.
创伤性脑损伤（TBI）会引发炎症，进而导致继发性损伤。橙皮素（Hes）对中枢神经系统（CNS）疾病具有抗炎活性。本文探讨了橙皮素对TBI诱导的急性脑损伤可能的神经保护作用及机制。
雄性C57BL/6J小鼠接受控制性皮质撞击（CCI）手术，术后给予橙皮素（50 mg/kg）治疗。采用改良神经功能缺损评分（mNSS）和转棒试验评估短期神经功能缺损。通过干湿法检测脑水肿情况。采用尼氏染色和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色评估神经元凋亡。通过伊文思蓝染色测量血脑屏障（BBB）完整性，并进行免疫组织化学（IHC）研究BV2小胶质细胞活化情况。BV2小胶质细胞和HT22神经元细胞经氧糖剥夺再复氧（OGD/R）刺激后用橙皮素处理。采用定量实时聚合酶链反应（qRT-PCR）和酶联免疫吸附测定（ELISA）检测包括肿瘤坏死因子-α（TNF-α）、白细胞介素-β（IL-1-β）和白细胞介素-6（IL-6）在内的炎性细胞因子的表达。进行蛋白质免疫印迹（WB）检测AMPK-SIRT1-FoxO1信号通路相关蛋白。
橙皮素减轻了TBI小鼠的神经功能缺损、脑水肿和神经元凋亡。橙皮素抑制小胶质细胞活化和促炎细胞因子的产生。橙皮素促进AMPK和SIRT1表达，同时抑制FoxO1-NF-κB的磷酸化，并抑制NLRP3表达。AMPK抑制剂化合物C显著逆转了橙皮素介导的抗炎和神经保护作用。
橙皮素通过AMPK-SIRT1-FoxO1-NF-κB轴抑制小胶质细胞活化介导的炎症，从而改善TBI后的神经行为功能。
