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

Abstract

Lidocaine, a typical local anesthetic, has been shown to directly induce neurotoxicity in clinical settings. Dexmedetomidine (DEX) is an alpha-2-adrenoreceptor agonist that has been used as anxiolytic, sedative, and analgesic agent which has recently found to protect against lidocaine-induced neurotoxicity. Nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 (SIRT1)/forkhead box O3 (FOXO3a) signaling is critical for maintaining neuronal function and regulation of the apoptotic pathway. In the present study, we designed in vitro and in vivo models to investigate the potential effects of lidocaine and DEX on SIRT1 and FOXO3a and to verify whether SIRT1/FOXO3a-mediated regulation of apoptosis is involved in DEX-induced neuroprotective effects against lidocaine. We found that in both PC12 cells and brains of mice, lidocaine decreased SIRT1 level through promoting the degradation of SIRT1 protein. Lidocaine also increased FOXO3a protein level and increased the acetylation of SIRT1 through inhibiting SIRT1. Upregulation of SIRT1 or downregulation of FOXO3a significantly inhibited lidocaine-induced changes in both cell viability and apoptosis. DEX significantly inhibited the lidocaine-induced decrease of SIRT1 protein level and increase of FOXO3a protein level and acetylation of FOXO3a. Downregulation of SIRT1 or upregulation of FOXO3a suppressed DEX-induced neuroprotective effects against lidocaine. The data suggest that SIRT1/FOXO3a is a potential novel target for alleviating lidocaine-induced neurotoxicity and provide more theoretical support for the use of DEX as an effective adjunct to alleviate chronic neurotoxicity induced by lidocaine.

RETRACTED ARTICLE: Dexmedetomidine attenuates ischemia and reperfusion-induced cardiomyocyte injury through p53 and forkhead box O3a (FOXO3a)/p53-upregulated modulator of apoptosis (PUMA) signaling signaling

“…Zhong et al [ 26 ] reported that DEX could ameliorate I/R and hypoxia/reoxygenation (H/R) injury in rat cardiomyocyte by activating the FOXO3a, and reduce renal dysfunction in cardiac surgery by inhibiting FOXO3a signaling [ 27 ]. Zheng et al [ 28 ] reported that DEX could effectively regulate the sirtuin 1/FOXO3a pathway and inhibit cell apoptosis. DEX was also found to decrease Bax expression and reduce p53 and caspase-3 activation, and reduce cisplatin-induced tubular damage score [ 29 ].…”

[Retracted] Resveratrol Suppresses Bupivacaine‐Induced Spinal Neurotoxicity in Rats by Inhibiting Endoplasmic Reticulum Stress via SIRT1 Modulation

“…He et al reported that RSV attenuates morphine antinociceptive tolerance by regulating spinal cord SIRT1 activity in rats [ 25 ]. Furthermore, Zheng et al found that lidocaine downregulates SIRT1 expression and that increasing SIRT1 protein levels significantly reversed lidocaine-induced neuronal apoptosis [ 28 ]. Here, we examined the effect of bupivacaine on spinal cord SIRT1 levels in rats and confirmed that it downregulates SIRT1 levels.…”

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

“…The NAD + -dependent deacetylase SIRT1/FOXO3a signalling is essential for maintaining neuronal function and apoptotic regulation. Dexmedetomidine upregulated SIRT1 protein level and inhibited FOXO3a protein level, preventing lidocaineinduced neuro-apoptosis in PC12 cells (L. N. Zheng et al, 2020). In HT22 cells, dexmedetomidine prevented bupivacaine-induced neuronal apoptosis and increased cell proliferation by preserving PI3K-AKT activity and suppressing the HIF-α/PKM2 pathway (F. Bao et al, 2019).…”