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Bupivacaine, a common local anesthetic, causes serious nerve injury, especially in diabetic patients, as high glucose has been reported to enhance bupivacaine-induced neurotoxicity. However, the key regulator for synergism remains unknown. To our surprise, the expression of repair protein Ku70 is suppressed, while the high-glucose environment induces DNA oxidative damage in neurons. Here, we aim to investigate whether the inhibition of Ku70 by high-glucose conditions aggrandized bupivacaine-induced DNA damage. Consistent with previous results, bupivacaine induced reactive oxygen species production and upregulated Ku70 and cleaved caspase-3 expressions at both transcript and protein levels and ultimately caused nucleic acid damage and apoptosis in human neuroblastoma (SH-SY5Y) cells. High-glucose treatment inhibited the expression of Ku70 and enhanced bupivacaine-induced neurotoxicity. In contrast, the overexpression of Ku70 mitigated DNA damage and apoptosis triggered by bupivacaine and high glucose. In conclusion, our data indicated that local anesthetics may aggravate nerve toxicity in a high-glucose environment. [ABSTRACT FROM AUTHOR]