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

Current Neuropharmacology, 2023 · DOI: 10.2174/1570159X21666230404102122 · Published: January 1, 2023

Simple Explanation

Spinal anesthesia can lead to neurological complications, especially in pregnant women. This study investigates how bupivacaine, a common anesthetic, can cause neurotoxicity during pregnancy by disrupting the normal cellular process of autophagy. The research shows that bupivacaine increases oxidative stress and DNA damage in the spinal cords of pregnant mice. This damage activates PARP-1, an enzyme involved in DNA repair, which then disrupts the autophagic flux, leading to nerve cell injury. By using PARP-1 inhibitors and autophagy inhibitors, the researchers were able to reduce the neurotoxic effects of bupivacaine in pregnant mice. This suggests that targeting PARP-1 and autophagy could be a potential therapeutic strategy.

Study Duration

Not specified

Participants

Adult female C57BL/6N mice weighing 25-30 g

Evidence Level

Level 3, Animal study

Key Findings

1
Bupivacaine treatment in pregnant mice increases oxidative stress-mediated DNA damage and neuronal injury in the spinal cord.
2
PARP-1 is significantly activated in pregnant mice after bupivacaine treatment, and inhibiting PARP-1 can alleviate the induced neurotoxicity.
3
Bupivacaine disrupts autophagic flux in pregnant mice, and using an autophagy inhibitor can reverse this disruption and reduce neurotoxicity.

Research Summary

This study investigates the neurotoxic effects of bupivacaine, a local anesthetic commonly used in spinal anesthesia, on pregnant mice. The research aims to elucidate the underlying mechanisms, focusing on oxidative stress, PARP-1 activation, and autophagy. The key findings indicate that bupivacaine induces oxidative stress and DNA damage, leading to PARP-1 activation and subsequent disruption of autophagic flux in spinal cord neurons. These events contribute to neurotoxicity in pregnant mice. The study concludes that inhibiting PARP-1 and/or modulating autophagy may serve as a therapeutic strategy to mitigate bupivacaine-induced neurotoxicity during pregnancy, potentially reducing complications like transient neurological symptoms (TNS).

Practical Implications

Therapeutic Target Identification

The study suggests that PARP-1 inhibition and autophagy modulation could be potential therapeutic targets to reduce bupivacaine-induced neurotoxicity during pregnancy.

Clinical Implications for Spinal Anesthesia

The findings may inform clinical practices in spinal anesthesia for pregnant women, encouraging the development of strategies to minimize neurotoxic risks associated with bupivacaine.

Future Research Directions

The research highlights the need for further investigation into the specific mechanisms by which PARP-1 activation fine-tunes autophagic flux initiation and the role of PARP-1-mediated PARylation in regulating spinal cord neuronal injury.

Study Limitations

1
The in vivo studies are limited to the neurotoxic effects of local anesthetics without accounting for the effects of sex hormones.
2
The study acknowledges that hormonal changes intrinsic to pregnancy may alter pain sensitivity, which was not directly assessed.
3
The study defines "autophagic degradation activity” using autophagic flux without detailed variations of autophagy.

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