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Toxicol Lett. 2020 Jan;318:104-113. doi: 10.1016/j.toxlet.2019.10.020. Epub 2019 Oct 28.

Inhibition of Ku70 in a high-glucose environment aggravates bupivacaine-induced dorsal root ganglion neurotoxicity.

Author information

1
Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, No. 253 Middle Gongye Street, Guangzhou, Guangdong Province, 510282, China.
2
Department of Rehabilitation, Zhujiang Hospital, Southern Medical University, No. 253 Middle Gongye Street, Guangzhou, Guangdong Province, 510282, China.
3
Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, No. 1333, Xinhu Road, Baoan District, Shenzhen, Guangdong Province, 518110, China.
4
Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, No. 253 Middle Gongye Street, Guangzhou, Guangdong Province, 510282, China. Electronic address: zw618812@smu.edu.cn.
5
Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, No. 253 Middle Gongye Street, Guangzhou, Guangdong Province, 510282, China. Electronic address: xsy998@smu.edu.cn.

Abstract

BACKGROUND:

Bupivacaine (BP) is commonly used as a local anaesthetic(LA) in the clinic, but it can also cause neurotoxicity, especially in patients with diabetes. Previous studies have found that high-glucose environments can aggravate BP-induced DNA damage in nerve cells. Ku70 is subunit of the DNA damage repair enzyme DNA-PK. This study was designed to determine whether high-glucose conditions enhance BP neurotoxicity and DNA damage by inhibiting Ku70 expression.

METHODS:

We examined the effect of BP on apoptosis and DNA damage in murine dorsal root ganglion (DRG) neurons under hyperglycaemic conditions. Untreated DRG cells and DRG cells pretreated with NU7441, a DNA-PK inhibitor, were cultured for 3 days under normal culture conditions or with 50 mM glucose, and the cells were then treated with BP for 3 h. DNA damage was investigated via comet assays, the ratio of early to late apoptotic cells was assessed by Annexin V-FITC/PI staining, and cell viability was measured by CCK-8 assays. The protein expression levels of DNA-PK, Ku70, Bax, Bcl-2 and γH2ax were measured by immunofluorescence or Western blotting.

RESULTS:

Compared to its effect under normal culture conditions, BP treatment led to decreased cell viability and increased DNA damage in DRG cells grown under high-glucose conditions. The rate of DRG cell apoptosis and the expression of γH2ax, the ratio of Bax to Bcl-2 also increased under the high-glucose conditions. Furthermore, Ku70 expression was inhibited. The DNA-PK inhibitor, NU7441, could significantly inhibit DNA-PK and Ku70 expression, simultaneously further aggravating BP-induced apoptosis and DNA damage under high-glucose conditions.

CONCLUSION:

These data indicate that hyperglycaemia may enhance BP-induced neurotoxicity and DNA damage by inhibiting the DNA repair protein Ku70.

KEYWORDS:

Bupivacaine; DNA damage; DNA repair; DRG; Ku70; Neurotoxicity

PMID:
31672611
DOI:
10.1016/j.toxlet.2019.10.020
[Indexed for MEDLINE]

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