Abstract
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 (10mg/kg) and/or DEX (30µg/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-1β, interleukin-6, interleukin-18, and tumor necrosis factor-α 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 (10µM). 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.
Highlights
Alzheimer's disease (AD) and depression pose a huge threat to human health and are major causes of increasing morbidity and mortality worldwide
In vivo, we focused on investigating the effects of DEX on mitogen-activated protein kinase (MAPK) family and c-Myc/chloride intracellular channel 4 (CLIC4) pathway in LPS-induced hippocampal apoptosis
The current results revealed that DEX attenuated the apoptosis of hippocampal neurons induced by LPS, which may be a potential neuroprotective mechanism of DEX against AD and depression
Summary
Alzheimer's disease (AD) and depression pose a huge threat to human health and are major causes of increasing morbidity and mortality worldwide. 5.4 million people in the United States alone have AD [1]. More than 350 million victims in the world are currently affected by depression [2], which is predicted to be the world's second largest disability-inducing factor by 2030 [3]. Hippocampal injury (loss of neuronal populations [4], reduced hippocampal volume [5], and massive neuronal death [6]) is regarded as an important pathological hallmark of AD and depression. It is necessary to find safe, side-effect-free antiapoptotic drugs to prevent and treat AD and depression
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