Dexmedetomidine Alleviates Lipopolysaccharide-Induced Hippocampal Neuronal Apoptosis via Inhibiting the p38 MAPK/c-Myc/CLIC4 Signaling Pathway in Rats

Abstract

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 uorescent 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.

Integrated transcriptomics and metabolomics analysis of the hippocampus reveals altered neuroinflammation, downregulated metabolism and synapse in sepsis-associated encephalopathy

“…In this study, we examined the enriched expressed genes and metabolites of the hippocampus to decipher the possible mechanisms of SAE in the early phase with an LPS-induced experimental sepsis model. The results showed that acute sepsis mice developed inflammation (dramatic upregulation of proinflammatory cytokines), hippocampal neuron injury, and behavior changes, which indicated that a reproducible SAE-like-symptom occurred in hippocampal tissues as in previous findings ( Wang et al, 2013 ; Chen et al, 2021 ).…”

“…Sepsis initiates a series of systemic inflammatory responses leading to deregulated peripheral inflammation, neuroinflammation, ischemic damage, oxidative stress, and metabolic disorders, disrupting the integrity of the brain–blood barrier (BBB) and, thus, causing the progression of SAE ( Gofton and Young, 2012 ). Furthermore, the histological studies on animal models have shown enlarged ventricles, reduced hippocampus volume, and increased apoptosis of hippocampal neurons in lipopolysaccharide (LPS)-exposure rodents ( Wang et al, 2013 ; Chen et al, 2021 ). Therefore, the hippocampus is an overly sensitive brain region in LPS-triggered animals.…”

[Retracted] Helicid Improves Lipopolysaccharide‐Induced Apoptosis of C6 Cells by Regulating SH2D5 DNA Methylation via the CytC/Caspase9/Caspase3 Signaling Pathway

“…Clinical and animal studies have confirmed associations of decreased hippocampal volume and weight and apoptosis with depression. Hippocampal injury (hippocampal volume reduction and excessive neuronal death) is considered an important marker of the pathogenesis of depression [ 5 , 6 ]. Numerous studies have linked apoptosis to hippocampus damage.…”

Dexmedetomidine Can Enhance PINK1/Parkin-Mediated Mitophagy in MPTP-Induced PD Mice Model by Activating AMPK

“…As shown in Figure 1 , mice were injected with MPTP 30 mg/kg intraperitoneally for 5 consecutive days to establish a PD subacute model. Dex was injected intraperitoneally 30 minutes before MPTP injection [ 12 , 33 ]. CC (10 μ g/kg) was injected intraperitoneally 30 minutes before Dex.…”