Dexmedetomidine Alleviates Lipopolysaccharide-Induced hippocampal neuronal apoptosis via inhibiting the p38 MAPK/c-Myc/CLIC4 Signaling Pathway in Rats

Abstract

\n Dexmedetomidine (DEX) reportedly possessed multiple bioactivities. Here, we mainly investigated the neuroprotective role and detailed molecular mechanism of DEX against lipopolysaccharide (LPS)-induced hippocampal neurons apoptosis. In vivo, Sprague Dawley rats were administered with LPS (10 mg/kg) and/or DEX (30 µg/kg). We found that DEX improved LPS-induced hippocampal microstructure (necrosis and number reduction of neurons in the CA1 and CA3 regions) and ultrastructure (mitochondrial damage) lesions. DEX also attenuated LPS-induced hippocampal apoptosis by down-regulating the expression of mitochondrial apoptosis pathway-related proteins. Moreover, DEX prevented the activation of c-Myc/chloride intracellular channel 4 (CLIC4) pathway induced by LPS. Notably, DEX inhibited p38 MAPK pathway, not JNK and ERK. To further clarify whether DEX alleviated LPS-induced neuronal apoptosis through the p38 MAPK/c-Myc/CLIC4 pathway, PC12 cells were treated with p38 MAPK inhibitor SB203582 (10µM). As expected, 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, showing decreased Bax and Tom20 fluorescent double-stained positive cells, reduced Annexin V-FITC/PI apoptosis rate, and lessened protein expression levels of Bax, cytochrome C, cleaved caspase-9 and cleaved caspase-3. Taken together, DEX attenuates LPS-induced hippocampal neuronal apoptosis by regulating the p38 MAPK/c-Myc/CLIC4 signaling pathway, which will provide new insights into the mechanism research and drug development of Alzheimer s disease and depression.