Sevoflurane induces inflammation in primary hippocampal neurons by regulating Hoxa5/Gm5106/miR-27b-3p positive feedback loop

Abstract

Postoperative cognitive dysfunction (POCD) is a normal condition that develops after surgery with anesthesia, leading to deterioration of cognitive functions. However, the mechanism of POCD still remains unknown. To elucidate the POCD molecular mechanism, sevoflurane was employed in the present study to generate neuroinflammation mice model. Sevoflurane treatment caused inflammatory markers IL6, IL-10 and TNF-α high expression in primary hippocampal neurons and blood samples. Long non-coding RNA Gm5106 was found to be increased after being stimulated with sevoflurane. Silencing Gm5106 inhibited neuron inflammation. In the meanwhile, Gm5106 was identified as a direct target of miR-27b-3p that was inhibited by sevoflurane and related to inflammation suppression. In addition, transcription factor (TF) Hoxa5 was validated to activate Gm5106 through two binding motifs in the promoter region after sevoflurane exposure. Furthermore, miR-27b-3p also directly targeted Hoxa5 3ʹUTR, which affected nuclear Hoxa5 protein served as TF. Hoxa5 protein instead of 3ʹUTR reduced miR-27b-3p, in which Gm5106 knocking down abrogated this effect. In conclusion, sevoflurane induces neuroinflammation through increasing long non-coding RNA Gm5106, which is transcriptionally activated by Hoxa5 and directly targeted by miR-27-3p. Apart from that, Hoxa5, Gm5106, and miR-27b-3p form a positive feedback loop in sevoflurane stimulation.

Dexmedetomidine alleviates propofol-induced pyroptosis of hippocampal neurons through NLRP3 inflammasome pathway

“…HOXA5 has been previously proven to participate in the successive phases of central nervous system formation in embryonic and fetal stages [35]. Furthermore, HOXA5 suppression is potent to repress sevoflurane-induced inflammation in hippocampal neurons [15]. In our study, we disclosed that HOXA5 expression was elevated in propofol-induced neurons and declined in neurons with dexmedetomidine pretreatment.…”

“…1d), and dexmedetomidine of 1 μM was chosen for follow-up experiments. HOXA5 was previously reported to be implicated with hippocampal neuronal inflammation [15]. HOXA5 expression levels in primary hippocampal neurons with different treatments were examined, and the results disclosed that HOXA5 expression was highly expressed in propofol-induced hippocampal neurons and under-expressed in dexmedetomidine-pretreated hippocampal neurons (P < 0.05, Fig.…”

“…Homeobox A5 ( HOXA5 ) imparts a predominant effect on organogenesis and governs organs of the respiratory and digestive systems [13] and participates in proliferation, inflammation, angiogenesis, and cytoskeletal remodeling [14]. Interestingly, a current study concluded that HOXA5 is associated with anesthesia-induced neuroinflammation [15]. Nonetheless, whether HOXA5 can influence neuronal damage associated with propofol remains undiscovered.…”

Recent progress on the role of non-coding RNA in postoperative cognitive dysfunction

“…However, in rodent models of encephalopathy, miR-21 and miR-34a negatively affected the permeability of the BBB, enhancing ischemia-induced leakage, by regulating tight junction proteins ( Ma et al, 2020 ). While the association between ncRNAs and POCD has been documented ( Twaroski et al, 2014 ; Li et al, 2018 ; Zhu and Ma, 2021 ), direct experimental evidence is lacking for the relationship between these ncRNA molecules and surgery/anesthesia-induced BBB disruption.…”

Tongue−Brain‐Transported ZnO Nanoparticles Induce Abnormal Taste Perception

“…[ 31,32 ] However, it was reported that neurons also participate in neuroinflammation, which directly affecting the excitability of neurons, resulting in cognitive dysfunction and behavioral changes. [ 33,34 ] Importantly, we found that ZnO NPs‐induced neuroinflammation could originate from neurons. When we treated PC12 cells, we found that ZnO NPs entered the cells and induced apparent neuroinflammation in a dose‐ and time‐dependent manner (Figure S5, Supporting Information).…”