The roles of PARP-1 and XPD and their potential interplay in repairing bupivacaine-induced neuron oxidative DNA damage

Zhao, Wei; Liu, Zhongjie; Luo, Jiyuan; Ma, Chang-Qing; Lai, Luhua; Xia, Zhengyuan; Xu, Shiyuan

doi:10.18632/aging.202390

Cited by 4 publications

(7 citation statements)

References 39 publications

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“…In response to oxidative DNA damage, numerous DNA repair enzymes and multiple repair pathways are required to maintain genomic integrity [ 22 ]. Proteomics and other studies have shown that nucleic acid excision repair (NER) plays a key role in bupivacaine-medicated neuronal DNA repair [ 23 ]. PARP-1 is a multidomain and multifunctional nuclear enzyme regulating chromatin structure and transcription.…”

Section: Resultsmentioning

confidence: 99%

Oxidative DNA Damage-induced PARP-1-mediated Autophagic Flux Disruption Contributes to Bupivacaine-induced Neurotoxicity During Pregnancy

Luo

Zeng

et al. 2023

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Objective: Severe neurologic complications after spinal anesthesia are rare but highly distressing, especially in pregnant women. Bupivacaine is widely used in spinal anesthesia, but its neurotoxic effects have gained attention. Methods: Furthermore, the etiology of bupivacaine-mediated neurotoxicity in obstetric patients re- mains unclear. Female C57BL/6 mice were intrathecally injected with 0.75% bupivacaine on the 18th day of pregnancy. We used immunohistochemistry to examine DNA damage after bupivacaine treat- ment in pregnant mice and measured γ-H2AX (Ser139) and 8-OHdG in the spinal cord. A PARP-1 in- hibitor (PJ34) and autophagy inhibitor (3-MA) were administered with bupivacaine in pregnant mice. Parp-1flox/flox mice were crossed with Nes-Cre transgenic mice to obtain neuronal conditional knock- down mice. Then, LC3B and P62 staining were performed to evaluate autophagic flux in the spinal cords of pregnant wild-type (WT) and Parp-1-/- mice. We performed transmission electron microscopy (TEM) to evaluate autophagosomes. Results: The present study showed that oxidative stress-mediated DNA damage and neuronal injury were increased after bupivacaine treatment in the spinal cords of pregnant mice. Moreover, PARP-1 was significantly activated, and autophagic flux was disrupted. Further studies revealed that PARP-1 knockdown and autophagy inhibitors could alleviate bupivacaine-mediated neurotoxicity in pregnant mice. Conclusion: Bupivacaine may cause neuronal DNA damage and PARP-1 activation in pregnant mice. PARP-1 further obstructed autophagic flux and ultimately led to neurotoxicity.

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Section: Resultsmentioning

confidence: 99%

Oxidative DNA Damage-induced PARP-1-mediated Autophagic Flux Disruption Contributes to Bupivacaine-induced Neurotoxicity During Pregnancy

Luo

Zeng

et al. 2023

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“…The expression of the vital repair enzyme XPD was increased, and this enzyme participated in repairing oxidative DNA damage ( Figure 2 ). Our previous study [ 18 ] also suggested that XPD participates in repairing oxidative DNA damage caused by bupivacaine in neurons. Therefore, XPD may be the most critical restriction enzyme in NER, the primary DNA repair pathway in mammalian cells [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 95%

“…The comet assay was used to detect DNA damage in individual cells as previously described [ 18 ]. Briefly, the SH-SY5Y cells were plated in 12-well plates, and the extent of DNA damage was measured by the kit (Trevigen's Comet Assay® Kit) following manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…After being identified by sequencing, hU6-MCS-CMV-EGFP vector and packaging vector were cotransfected into SH-SY5Y cells. Seventy-two hours later, the recombinant lentivirus-mediated gene silencing of XPD was obtained after harvesting and concentrating as previously described [ 18 ]. The fluorescence intensity was obtained 48 h after the cells were transfected with lentivirus.…”

Section: Methodsmentioning

confidence: 99%

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The DNA Repair Enzyme XPD Is Partially Regulated by PI3K/AKT Signaling in the Context of Bupivacaine‐Mediated Neuronal DNA Damage

Zhao

Zeng

Luo

et al. 2021

Oxidative Medicine and Cellular Longevity

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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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“…For experimental conditions, SH-SY5Y cells were maintained in a humidified incubator with 5% CO2 at 37°C. Four different groups were assigned for the experimental protocol: 1. control group, 2. capsaicin group (5,10,20,40,80, and 100 μM), 3. bupivacaine group (0.1, 0.5, 1, 2, 2.5, and 5 mM), 4. capsaicin + bupivacaine group (Cells exposed to capsaicin at concentrations of 2.5, 5, and 10 µM for 24 hours were then treated with bupivacaine (1 mM) for 2 hours. XTT test reagent was added to the groups whose incubation times were completed, and absorbance measurements were made by means of a spectrophotometer (Thermo, Germany) at 450 nm.…”

Section: Xtt Assaymentioning

confidence: 99%

Kapsaisin apoptozu düzenleyerek SH-SY5Y hücrelerinde bupivakain anestezisinin neden olduğu nörotoksisiteyi hafifletmektedir

ALTUN

2022

Acta Med Nicomedia

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Objective: Bupivacaine administered for local anesthesia can cause critical neurotoxicity and neurological dysfunctions. Any substance that can reduce bupivacaine-mediated toxic effects will be of great interest during surgical procedures and in the pain management process. In this context, we evaluated capsaicin, an alkaloid of Capsicum annuum (cayenne pepper), which has been intensively researched for its neuroprotective effect due to its various biological effects such as cardioprotective, antiinflammatory, analgesic, thermogenic, and benefits on the gastrointestinal tract. Methods: In this study, we researched the in vitro effect of capsaicin in SH-SY5Y cells with a model of bupivacaine-mediated neurotoxicity. Cell proliferation assay was handled by XTT, and apoptosis was determined by flow cytometry analysis. Results: We observed a notable increase in apoptosis induction with a significant decrease in the viability of cells exposed to bupivacaine at 1 mM. We found that bupivacaine-mediated cytotoxicity was reduced when increasing concentrations of capsaicin were applied to bupivacaine-treated cells. At the same time, capsaicin also reduced apoptosis in SH-SY5Y cells exposed to bupivacaine. Conclusion: According to our results, it is thought that the administration of capsaicin against bupivacaine-mediated neurotoxicity may be an alternative neuroprotective agent by suppressing the apoptosis response in neurons.

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The roles of PARP-1 and XPD and their potential interplay in repairing bupivacaine-induced neuron oxidative DNA damage

Cited by 4 publications

References 39 publications

Oxidative DNA Damage-induced PARP-1-mediated Autophagic Flux Disruption Contributes to Bupivacaine-induced Neurotoxicity During Pregnancy

Oxidative DNA Damage-induced PARP-1-mediated Autophagic Flux Disruption Contributes to Bupivacaine-induced Neurotoxicity During Pregnancy

The DNA Repair Enzyme XPD Is Partially Regulated by PI3K/AKT Signaling in the Context of Bupivacaine‐Mediated Neuronal DNA Damage

Kapsaisin apoptozu düzenleyerek SH-SY5Y hücrelerinde bupivakain anestezisinin neden olduğu nörotoksisiteyi hafifletmektedir

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