<p>Dexmedetomidine protects PC12 cells from lidocaine-induced cytotoxicity via downregulation of Stathmin 1</p>

Abstract

Background: Understanding of lidocaine-induced neurotoxicity is not complete, resulting in the unsuccessful treatment in some clinical settings. Dexmedetomidine (DEX) has been shown to alleviate lidocaine-induced neurotoxicity in our previous cell model. However, the rationale for DEX combined with lidocaine to reduce lidocaine-induced neurotoxicity in the clinical setting remains to be further clarified in the detailed molecular mechanism. Methods: In this study, we established a cellular injury model by lidocaine preconditioning. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2ʹ-deoxyuridine (EdU) proliferation assay kit were used to analyze cell proliferation. Cell apoptosis was measured by flow cytometry and Hoechst 33342 staining. Cell cycle progression was detected by flow cytometry. The protein expression levels were detected by Western blotting and immunofluorescence staining. Results: Our results showed that DEX dose-dependently restored impaired proliferation of PC12 cells induced by lidocaine，as reflected by the increased cell viability and EdU positive cells, which were consistent with the decreased expression of tumor suppressor protein p21 and increased expression of cell cycle-related cyclin D1 and CDK1. In addition, DEX dose-dependently reduced apoptotic PC12 cells induced by lidocaine，as reflected by the decreased expression of apoptosis-related Bax, caspase-3 and caspase-9 and increased expression of anti-apoptotic Bcl-2 compared to the cells only treated with lidocaine. Mechanistically, with gain-or-loss-of-function of STMN1, we showed that DEX-mediated neuroprotection by lidocaine-induced damage is associated with downregulation of STMN1 which might be an upstream molecule involved in regulation of mitochondria death pathway. Conclusion: Our results reveal that DEX is likely to be an effective adjunct to alleviate chronic neurotoxicity induced by lidocaine.

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

“…[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. We found that DEX concentration-dependently inhibited lidocaine-induced decrease in SIRT1 and increase in FOXO3a and suppressed the increase in acetylation of FOXO3a mediated by reducing SIRT1.…”

“…20,21 Several studies have found that DEX exhibits a neuroprotective effect in the lidocaine-induced model of neurotoxicity. 16,[21][22][23] However, the mechanism of DEX-related protective effects in lidocaineinduced neurotoxicity is still not completely understood.…”

“…13 In particular, it has been reported that DEX could inhibit lidocaine-induced cytotoxicity. Downregulation of stathmin 1 16 and miR-let-7b-mediated downregulation of COL3A1 17 are involved in the protective effects of DEX against lidocaine-induced cytotoxicity. However, the molecular mechanism underlying the neuroprotective effects of DEX is not completely understood.…”

<p>Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12.6/RyR2 signaling</p>

“…27 In a recent study, 150 μM was the maximum safe concentration for DEX in PC12 cells, and 50 μM was eventually selected for the subsequent experiments. 51 Other studies used DEX 50 ng/mL (equivalent to 250 nM) on pacemaker cells in sinoatrial nodes of rabbits and DEX 200 ng/mL (equivalent to 1 µM) on rat ventricular myocytes. 48,52 Therefore, it is possible that the safe concentration of DEX varies in different species and cell types.…”

Dexmedetomidine: another arrow in the quiver to fight COVID-19 in intensive care units

“…Finally, by upregulating SIRT/FOXO3a signaling 24 as well as by inhibiting Stathmin-1/Bcl-2/Caspase-9/Caspase-3 mediated lidocaine-induced neurotoxicity, 25 dexmedetomidine used in conjunction with lidocaine may provide additional anti-inflammatory benefits, while improving the safety profile of lidocaine.…”