The DNA Repair Enzyme XPD Is Partially Regulated by PI3K/AKT Signaling in the Context of Bupivacaine-Mediated Neuronal DNA Damage.
The DNA Repair Enzyme XPD Is Partially Regulated by PI3K/AKT Signaling in the Context of Bupivacaine-Mediated Neuronal DNA Damage.
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在布比卡因介导的神经元 DNA 损伤中，DNA 修复酶 XPD 部分受到 PI3K/AKT 信号传导的调节。
DOI：
10.1155/2021/9925647
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发表时间：
2021
影响因子：
--
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Zhao W;Zeng L;Luo J;Li J;Lai L;Xu S;Liu Z
布比卡因是一种广泛应用于区域麻醉和疼痛控制的局部麻醉药，有报道称其可引起神经元损伤，尤其是DNA损伤。神经元采用不同的途径来修复DNA损伤。然而，布比卡因介导的DNA损伤修复的机制尚不清楚。鞘内注射3%布比卡因建立大鼠神经元损伤模型。采用布比卡因（1.5mmol/L）诱导SH-SY 5 Y细胞损伤模型。然后，使用cDNA平板阵列来鉴定布比卡因暴露后的DNA修复基因。结果表明，着色性干皮病的核切除修复（NER）途径中的互补D组（XPD）与布比卡因诱导的DNA损伤修复密切相关。随后，Western印迹分析和免疫组织化学表明，DNA损伤后修复酶XPD的表达上调。通过慢病毒下调XPD表达加重了布比卡因诱导的DNA损伤。此外，暴露于布比卡因后，神经元中的磷脂酰-3-激酶（PI 3 K）/AKT信号被抑制。抑制PI 3 K/AKT信号通路后，布比卡因介导的DNA损伤进一步加重，XPD表达进一步上调。然而，敲低XPD加重布比卡因介导的神经元损伤，但不影响PI 3 K/AKT信号转导。总之，修复酶XPD，这是部分调节PI 3 K/AKT信号，响应布比卡因介导的神经元DNA损伤。这些结果可作为布比卡因神经毒性治疗的参考。
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.
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