Bupivacaine-induced apoptosis independently of WDR35 expression in mouse neuroblastoma Neuro2a cells

Abstract

BackgroundBupivacaine-induced neurotoxicity has been shown to occur through apoptosis. Recently, bupivacaine was shown to elicit reactive oxygen species (ROS) production and induce apoptosis accompanied by activation of p38 mitogen-activated protein kinase (MAPK) in a human neuroblastoma cell line. We have reported that WDR35, a WD40-repeat protein, may mediate apoptosis through caspase-3 activation. The present study was undertaken to test whether bupivacaine induces apoptosis in mouse neuroblastoma Neuro2a cells and to determine whether ROS, p38 MAPK, and WDR35 are involved.ResultsOur results showed that bupivacaine induced ROS generation and p38 MAPK activation in Neuro2a cells, resulting in apoptosis. Bupivacaine also increased WDR35 expression in a dose- and time-dependent manner. Hydrogen peroxide (H2O2) also increased WDR35 expression in Neuro2a cells. Antioxidant (EUK-8) and p38 MAPK inhibitor (SB202190) treatment attenuated the increase in caspase-3 activity, cell death and WDR35 expression induced by bupivacaine or H2O2. Although transfection of Neuro2a cells with WDR35 siRNA attenuated the bupivacaine- or H2O2-induced increase in expression of WDR35 mRNA and protein, in contrast to our previous studies, it did not inhibit the increase in caspase-3 activity in bupivacaine- or H2O2-treated cells.ConclusionsIn summary, our results indicated that bupivacaine induced apoptosis in Neuro2a cells. Bupivacaine induced ROS generation and p38 MAPK activation, resulting in an increase in WDR35 expression, in these cells. However, the increase in WDR35 expression may not be essential for the bupivacaine-induced apoptosis in Neuro2a cells. These results may suggest the existence of another mechanism of bupivacaine-induced apoptosis independent from WDR35 expression in Neuro2a cells.

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“…suggested that the p38 mitogen‐activated protein kinase (MAPK) and AMP‐activated protein kinase (AMPK) pathways were involved in bupivacaine induced apoptosis in neuroblastoma SH‐SY5Y cells. These findings were corroborated by another study in mouse neuroblastoma cells by Harato et al . More recently, Zheng et al .…”

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“…The authors noted that axonal degeneration induced by lidocaine is prevented by p38 MAPK inhibitor but not by caspase inhibition [36]. Harato et al also demonstrated that p38 MAPK inhibitor treatment attenuated the caspase 3 activity and cell death induced by bupivacaine [37]. In another study, p38 MAPK pathway is implicated in bupivacaine-induced apoptosis in human neuroblastoma SH-SY5Y cells [17].…”

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“…However, laboratory studies have shown that intrathecal application of bupivacaine causes severe injuries in the sensory and motor system [6][7][8]. Although the mechanism lying behind is not known, bupivacaine-induced neurotoxicity has been proposed to be associated with neuronal apoptosis [9,10]. Caspase-3 is a crucial protease involved in the process of apoptosis [11].…”