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  • HO acted as an intracellular defender

    2022-08-04

    HO-1 acted as an intracellular defender against oxidative stress-induced cell damage. To elucidate the effects of HO-1 in ropivacaine-induced cytotoxicity in neuronal cells, HO-1 activity was inhibited using a specific HO-1 inhibitor zinc protoporphyrin, ZnPP. Our results indicate that ZnPP treatment significantly exacerbated ropivacaine-induced production of ROS (Fig. 6A). Also, we found that ZnPP treatment significantly exacerbated ropivacaine-induced depletion of reduced GSH (Fig. 6B). Release of LDH has been used to index cytotoxicity. Here, our results indicate that ZnPP treatment significantly exacerbated ropivacaine-induced release of LDH (Fig. 7).
    Discussion Increasing evidence has shown that high-dosage intake and long-term exposure to LAs could provoke diverse biological activities in neuronal and non-neuronal pak1 inhibitor [17]. Previous studies have reported that administration of LAs resulted in toxic effects in diverse cell types [18]. As a long-acting, enantiomerically pure amide LA, ropivacaine is widely used for nerve blocks, interventional spinal procedures, and labor analgesia in clinical settings [19]. However, clinical studies have reported that central nervous system (CNS) toxicity was found in several cases after inadvertent intravascular administration of ropivacaine [20]. In addition, the safety of spinal neurotoxicity of ropivacaine has come to be of great concern [21, 22]. Ropivacaine has been reported to activate intracellular signaling cascades and interact with functional proteins. However, the underlying mechanisms remain unclear. In the current study, we found that ropivacaine could increase the expression and activity of HO-1 in human SHSY5Y neuroblastoma cells. Additionally, our results indicated that ropivacaine increased phosphorylation of p38, while blockage of p38 activation attenuated ropivacaine-induced expression of HO-1. Mechanistically, we found that the stimulatory effects of ropivacaine on HO-1 expression were mediated by the Nrf2/ARE transcriptional factor system. Also, inhibition of HO-1 exacerbated ropivacaine-induced oxidative stress and cell death. These findings implicated that HO-1 might exert a protective effect against ropivacaine-induced neurotoxicity in neuronal cells. HO-1 has been reported as a well-characterized cytoprotective enzyme in diverse tissues and cells, which could initiate powerful endogenous antioxidant signals [23]. Induction of HO-1 expression is considered as an essential therapeutic strategy for various diseases in which oxidative stress is symptomatic [24]. In the present study, we reported that ropivacaine induced expression of HO-1 in SHSY5Y cells. Notably, our findings demonstrated that inhibition of HO-1 exacerbated ropivacaine-induced production of ROS and depletion of reduced GSH. The majority of intracellular ROS was produced in mitochondria, which can directly cause mitochondrial dysfunction. Previous studies have shown that mitochondrial energy metabolism is an important underlying mechanism whereby LAs induce cytotoxicity [25]. Indeed, previous in vivo and in vitro studies have reported that ropivacaine affected mitochondrial function pak1 inhibitor and energy metabolism in Ehrlich ascites tumor cells [26] and in rat liver mitochondria [27]. Importantly, our results indicated that inhibition of HO-1 exacerbated ropivacaine-induced release of LDH, suggesting that HO-1 could protect SHSY5Y cells against ropivacaine-induced cell death. Consistently, induction of HO-1 expression is considered to be neuroprotective due to its numerous beneficial intracellular effects in response to toxic insults [28]. Generation of ROS caused by different stimuli results in translocation of the transcription factor Nrf2 from cytosol to the nucleus, which then binds to the ARE-promoter region and initiates the transcription of HO-1 [29]. In the current study, we explored a novel mechanism by showing that ropivacaine treatment induced nuclear translocation of Nrf2 and mediated induction of HO-1.