Abstract
Bupivacaine, a local anesthetic widely used for regional anesthesia and pain management, has been reported to induce neuronal injury, especially DNA damage. Neurons employ different pathways to repair DNA damage. However, the mechanism underlying bupivacaine-mediated DNA damage repair is unclear. A rat neuronal injury model was established by intrathecal injection of (3%) bupivacaine. An in vitro neuronal injury model was generated by exposing SH-SY5Y cells to bupivacaine (1.5 mmol/L). Then, a cDNA plate array was used to identify the DNA repair genes after bupivacaine exposure. The results showed that xeroderma pigmentosum complementary group D (XPD) of the nuclear excision repair (NER) pathway was closely associated with the repair of DNA damage induced by bupivacaine. Subsequently, Western blot assay and immunohistochemistry indicated that the expression of the repair enzyme XPD was upregulated after DNA damage. Downregulation of XPD expression by a lentivirus aggravated the DNA damage induced by bupivacaine. In addition, phosphatidyl-3-kinase (PI3K)/AKT signaling in neurons was inhibited after exposure to bupivacaine. After PI3K/AKT signaling was inhibited, bupivacaine-mediated DNA damage was further aggravated, and the expression of XPD was further upregulated. However, knockdown of XPD aggravated bupivacaine-mediated neuronal injury but did not affect PI3K/AKT signaling. In conclusion, the repair enzyme XPD, which was partially regulated by PI3K/AKT signaling, responded to bupivacaine-mediated neuronal DNA damage. These results can be used as a reference for the treatment of bupivacaine-induced neurotoxicity.
Highlights
Local anesthesia (LA) has been widely used for surgical anesthesia and short- and long-term pain management since 1884 [1]
Accumulating evidence has shown that the local anesthetics are potentially neurotoxic and that neurologic impairment after spinal anesthesia may result from the direct neurotoxic effect of bupivacaine [19]
The paw withdrawal mechanical threshold (PWMT) (Figure 1(c); ∗∗∗∗p = 0:0001) and paw withdrawal threshold latency (PWTL) (Figure 1(d); ∗∗∗∗p = 0:0001) were significantly increased in the bupivacaine group compared with the control group
Summary
Local anesthesia (LA) has been widely used for surgical anesthesia and short- and long-term pain management since 1884 [1]. An amide-type local anesthetic, bupivacaine, is one of the most widely used local anesthetics for during labor and postoperative pain management. Our previous studies revealed that oxidative stress is essential for neurotoxicity induced by bupivacaine [6, 7]. Oxidative stress is a crucial factor in DNA damage. DNA damage repair mechanisms are known to play an essential role in bupivacaine-mediated neurotoxicity. It is not clear which repair pathways are primarily involved in the pathological process of bupivacaine
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