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  • Bupivacaine is one of the local

    2021-11-20

    Bupivacaine is one of the local anesthetics commonly used in spinal anesthesia. Previous studies had shown that bupivacaine induced neuronal apoptosis and axon degeneration among various neuronal populations in spinal cord, such as sciatic nerves and dorsal root RSL3 synthesis (DRG) neurons [5], [6], [7], [8]. Studies also demonstrated that, various signaling pathways were involved in the bupivacaine-induced neurotoxicity in DRG neurons, such as neurotrophin signaling pathways, phosphatidyl-3-kinase (PI3K) and apoptotic caspase-3 signaling pathways [9], [10], [11]. However, the full scope of molecular pathways associated with bupivacaine-induced DRG neurotoxicity is yet to be elucidated. Glycogen synthase kinase-3 (GSK3) was originally discovered as a glycogen synthase inactivating protein kinase [12]. During past decades, GSK-3 associated signaling pathways had been identified as key regulators and therapeutic targets in neurodegenerative diseases, such as Alzheimer’s disease [13], [14]. It was also demonstrated that GSK-3 played important role in regulating neurodegeneration and neurotoxicity in both central and peripheral nervous systems [15], [16], [17], [18]. In spinal cord, animal trauma model showed that, inhibition of GSK-3 exerted neuroprotective effect on motor neurons by reducing apoptosis and inflammation [19]. It was also demonstrated that, localized GSK-3 inhibition directly promoted axonal outgrowth of spinal cord DRG neurons [20]. Furthermore, after spinal cord sciatic injury, prolonged GSK-3 activity was shown to be key component to promote DRG regeneration [21]. However, little is known of whether GSK-3 is functionally involved in the process of bupivacaine-induced spinal cord DRG neurotoxicity.
    Materials and methods
    Results
    Discussions In this work, we used an in vitro DRG explant model to demonstrate that SB216763, a potent GSK-3 inhibitor, was effective in reducing bupivacaine-induced DRG neurotoxicity by preventing apoptosis and neurite degeneration. These results are in line with previous study showing that GSK-3 inhibition promoted growth cone enrichment in DRG neurons, thus suggesting a pro-neuronal or neuroprotective role of GSK-3 inhibition in DRG neuron regeneration after injury. Interestingly in a recent study, Gobrecht and colleagues showed that, in spinal cord sciatic injury model, constitutive activation of GSK-3 promoted DRG regeneration after sciatic nerve crush [21]. Possible explanation of these two seemingly contrary observations on the role of GSK-3 in DRG regeneration may lie in the animal models used. In most of the studies demonstrating GSK-3-inhibition facilitated axonal regeneration, including our study, pharmacological reagents were the major methods to induce GSK-3 phosphorylation-related inhibition. On the other hand, in Gobrecht’s study, GSK-3 activation was achieved by genetic knock-in of GSK-3 α/β subunits immune to PI3K/AKT phosphorylation [21]. Although it is still controversial and far from concluded regarding the exact mechanisms of GSK-3 contributing to DRG regeneration after injury, one may not ignore the significance of using pharmacological compound, epically small-molecule reagent applied in our study, in clinical settings to provide patients safe and efficient methods to counter neurodegeneration incurred by spinal cord anesthetics. It is interesting to note that, SB216763, while applied on young DRG neurons, had an inhibitory effect on neurite outgrowth [24]. On the other hand, it was reported that SB216763, through the inhibition of GSK-3, promoted axonal growth in cortical hippocampal neurons and induced growth cone enrichment in DRG neurons [25], [26]. It was speculated that the disparity of either pro- or anti- neuronal effect of SB216763 during neural development may be due to the difference in concentration or duration of drug application [27]. However, in adult DRG neuron after injury, it was clearly demonstrated that SB216763-mediated GSK-3 inhibition protected nerve damage and induced regeneration [28]. Thus, along with the results of our work showing SB216763-mediated GSK-3 inhibition rescued apoptosis and neurite loss in bupivacaine-injured adult mouse DRG, it may suggest that GSK-3 inhibition is predominantly acting as a pro-neuronal or neural-rescuing factor in adult spinal cord DRG neurons after injury.