Abstract
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.
Highlights
Diabetic nerves are more susceptible to the toxicity of local anesthetics [1]
reactive oxygen species (ROS) overproduction causes DNA degradation and induces neuronal apoptosis [8]. e accumulating studies have suggested that damaged nucleic acids were found in the certain tissues of diabetic rats [9, 10]. e current study aims to address whether ROSmediated DNA damage aggrandized bupivacaine-induced neurotoxicity under high-glucose conditions
Our results have shown that Ku70 protein levels were significantly elevated by bupivacaine treatment in SH-SY5Y cells, which were remarkably decreased by pretreatment with high glucose for 7 days (Figure 4(a))
Summary
Clinical and experimental evidence has suggested that local anesthetics induced oxidative damage, which leads to neurotoxicity and apoptosis [2,3,4]. The mechanism of enhanced local anesthetic neurotoxicity under high-glucose conditions has not yet been fully understood. Redox imbalances caused by upregulated aldose reductase activity, altered activity of protein kinase C, elevated advanced glycation end products, and prostanoid imbalances may lead to ROS overproduction under hyperglycemia conditions [6, 7]. ROS overproduction causes DNA degradation and induces neuronal apoptosis [8]. E accumulating studies have suggested that damaged nucleic acids were found in the certain tissues of diabetic rats [9, 10]. E current study aims to address whether ROSmediated DNA damage aggrandized bupivacaine-induced neurotoxicity under high-glucose conditions
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