Dexmedetomidine protects against sepsis‑associated encephalopathy through Hsp90/AKT signaling

Abstract

Sepsis-associated encephalopathy (Sae) is characterized by neuronal apoptosis and changes in mental status. accumulating evidence has. indicated that dexmedetomidine is capable of protecting the brain against external stimuli and improving cognitive dysfunctions. The aim of the present study was to investigate the possible neuroprotective effects of dexmedetomidine on Sae and the role of heat-shock protein (Hsp)90/aKT signaling in an experimental model of sepsis. The Sae model was established by cecal ligation and perforation (clP) in vivo and lipopolysaccharide (lPS) treated hippocampal neuronal cultures in vitro. it was found that dexmedetomidine inhibited caspase-3, but increased the expression level ofBcl-2 in clP rats. clP rats also exhibited a decreased level of phosphorylated aKT Thr 308 and Hsp90, and their expression could be reversed by treatment with dexmedetomidine. additionally, application of dexmedetomidine increased cell survival and decreased neuronal apoptosis in vitro. Furthermore, the neuroprotective effects of dexmedetomidine could be reversed by 17-aaG (a Hsp90 inhibitor), or wortmannin (a Pi3K inhibitor). analysis of Tunel staining indicated that dexmedetomidine improved lPS-induced neuronal apoptosis, which could be eradicated by aKT short hairpin rna transfection, prazosin or yohimbine. Finally, dexmedetomidine ameliorated both the emotional and spatial cognitive disorders without alteration in locomotor activity. The present findings suggested that dexmedetomidine may protect the brain against Sae, and that the Hsp90/aKT pathway may be involved in this process.

Dexmedetomidine protects against lidocaine-induced neurotoxicity through SIRT1 downregulation-mediated activation of FOXO3a

“…Previous studies have suggested the neuroprotective effects of DEX in various models. [31][32][33][34] In recent years, researchers found that DEX inhibited lidocaine-induced neurotoxicity. 16,17,23 In this study, we also verified the role of SIRT1/FOXO3a signaling in the effect of DEX on lidocaine-induced neurotoxicity.…”

Effect of dexmedetomidine on postoperative systemic inflammation and recovery in patients undergoing digest tract cancer surgery: A meta-analysis of randomized controlled trials

“…Immune cells affect the expression of inflammatory factors, which can trigger the CNS response and amplify neuroinflammation through vagal afferents or BBB ( 61 , 62 ). The inflammatory cells in CNS release more inflammatory cytokines which concentrate in specific brain regions, leading to the occurrence of POCD ( 37 , 63 , 64 ) and resulting in the development of neurodegenerative diseases ( 65 ). The present results indicated that DEX decreased the occurrence of POCD, which could be related to the effect of DEX on perioperative immune function and potential neuroinflammation.…”

The potential role of dexmedetomidine on neuroprotection and its possible mechanisms: Evidence from in vitro and in vivo studies

“…The Hsp90 modulates cell apoptosis and is essential for Akt to regulate cell growth, cell survival, and cell differentiation. Clinically, dexmedetomidine improved emotional and cognitive functions in rodents (Ning et al, 2017;Yeh et al, 2018;Yin et al, 2019).…”

“…Pretreatment with dexmedetomidine reduced microglial activation, which produces proinflammatory cytokines and ROS, resulting in reduced inflammation, apoptosis, and sickness behaviour in mice (Yeh et al, 2018). Posttreatment with dexmedetomidine reduced hippocampal apoptosis in rats by upregulating the Hsp/Akt signalling pathway (Yin et al, 2019). The Hsp90 modulates cell apoptosis and is essential for Akt to regulate cell growth, cell survival, and cell differentiation.…”

“…Although most neurological symptoms can be reversed with supportive care, some evidence suggests that SAE has long-term effects on learning and memory (Weberpals et al, 2009). In both in vitro and in vivo studies, dexmedetomidine protected against neuroinflammation by inhibiting the mitochondrial apoptotic pathway, resulting in less neuronal apoptosis and increased cell viability (Ning et al, 2017;Yeh et al, 2018;Yin et al, 2019). It also protected against pyroptosis in sepsis-induced neuronal injury in astrocytes, PC12 cells and rats (Y.…”