Dexmedetomidine Alleviates Lipopolysaccharide-Induced Hippocampal Neuronal Apoptosis via Inhibiting the p38 MAPK/c-Myc/CLIC4 Signaling Pathway in Rats
Dexmedetomidine Alleviates Lipopolysaccharide-Induced Hippocampal Neuronal Apoptosis via Inhibiting the p38 MAPK/c-Myc/CLIC4 Signaling Pathway in Rats
复制标题
右美托咪定通过抑制 p38 MAPK/c-Myc/CLIC4 信号通路减轻脂多糖诱导的大鼠海马神经元凋亡
DOI：
10.1007/s12035-021-02512-9
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发表时间：
2021-08-07
影响因子：
5.1
通讯作者：
Fan, Honggang
中科院分区：
文献类型：
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作者：
Chen, Yongping;Li, Lin;Fan, Honggang
右美托咪定（DEX）具有多种生物学效应。本研究旨在探讨DEX对脂多糖（LPS）诱导的海马神经元凋亡的保护作用及其分子机制。Sprague道利大鼠腹腔内注射LPS（10 mg/kg）和/或DEX（30 μ g/kg）。我们发现DEX改善LPS诱导的海马微结构（CA 1和CA 3区域的坏死和神经元丢失）和超微结构（线粒体损伤）的改变。DEX还通过抑制白细胞介素-1 β、白细胞介素-6、白细胞介素-18和肿瘤坏死因子-α水平的增加以及下调线粒体凋亡途径相关蛋白的表达来减轻LPS诱导的炎症和海马凋亡。此外，DEX阻止LPS诱导的c-Myc/氯细胞内通道4（CLIC 4）途径的激活。DEX抑制p38 MAPK通路，但不抑制JNK和ERK。为了进一步阐明DEX是否通过p38 MAPK/c-Myc/CLIC 4途径减轻LPS诱导的神经元凋亡，我们用p38 MAPK抑制剂SB 203582（10 μ M）处理PC 12细胞。DEX在降低c-Myc和CLIC 4的蛋白和mRNA表达方面具有与SB 203582相同的作用。此外，DEX和SB 203582减少LPS诱导的细胞凋亡，表现为Bax和Tom 20荧光双染细胞减少，膜联蛋白V-FITC/PI凋亡率降低，Bax、细胞色素C、裂解的caspase-9和裂解的caspase-3蛋白表达水平降低。综上所述，研究结果表明DEX通过调节p38 MAPK/c-Myc/CLIC 4信号通路来减弱LPS诱导的海马神经元凋亡。这些发现为阿尔茨海默病和抑郁症的机制提供了新的见解，并可能有助于这些疾病的药物开发。
Dexmedetomidine (DEX) has multiple biological effects. Here, we investigated the neuroprotective role and molecular mechanism of DEX against lipopolysaccharide (LPS)-induced hippocampal neuronal apoptosis. Sprague Dawley rats were intraperitoneally injected with LPS (10 mg/kg) and/or DEX (30 mu g/kg). We found that DEX improved LPS-induced alterations of hippocampal microstructure (necrosis and neuronal loss in the CA1 and CA3 regions) and ultrastructure (mitochondrial damage). DEX also attenuated LPS-induced inflammation and hippocampal apoptosis by inhibiting the increase of interleukin-1 beta, interleukin-6, interleukin-18, and tumor necrosis factor-alpha levels and downregulating the expression of mitochondrial apoptosis pathway-related proteins. Moreover, DEX prevented the LPS-induced activation of the c-Myc/chloride intracellular channel 4 (CLIC4) pathway. DEX inhibited the p38 MAPK pathway, but not JNK and ERK. To further clarify whether DEX alleviated LPS-induced neuronal apoptosis through the p38 MAPK/c-Myc/CLIC4 pathway, we treated PC12 cells with p38 MAPK inhibitor SB203582 (10 mu M). DEX had the same effect as SB203582 in reducing the protein and mRNA expression of c-Myc and CLIC4. Furthermore, DEX and SB203582 diminished LPS-induced apoptosis, indicated by decreased Bax and Tom20 fluorescent double-stained cells, reduced annexin V-FITC/PI apoptosis rate, and reduced protein expression levels of Bax, cytochrome C, cleaved caspase-9, and cleaved caspase-3. Taken together, the findings indicate that DEX attenuates LPS-induced hippocampal neuronal apoptosis by regulating the p38 MAPK/c-Myc/CLIC4 signaling pathway. These findings provide new insights into the mechanism of Alzheimer's disease and depression and may help aid in drug development for these diseases.