Maternal sciatic nerve administered bupivacaine induces hippocampal cell apoptosis in offspring

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Abstract

Background

Bupivacaine, an amid-type local anesthetic, is widely used for clinical patients especially in pregnant women. In addition to neurotoxicity effect of bupivacaine, it can cross the placenta, accumulates in this tissue and retained in fetal tissues. Nevertheless, whether bupivacaine can cause neurotoxicity in fetus remains unclear. Hence, this study was design to investigate the effects of maternal bupivacaine use on fetus hippocampal cell apoptosis and the possible related mechanism.

Methods

On day 15 of pregnancy, sciatic nerve of pregnant wistar rat (180–200 g) were exposed by lateral incision of the right thigh and 0.2 ml of bupivacaine was injected. After their delivery, we randomly selected one male offspring of every mother. On day 30 after of their birth, the rat’s hippocampi were isolated for molecular studies. Western blotting was used to examine the expression of cleaved caspase-3, caspase-8 and p-Akt in fetal hippocampus.

Results

Our results showed that maternal bupivacaine use caused a significant increment of cleaved caspase-3 and caspase-8 expression in fetal hippocampus compared with the sham group. In addition, maternally administered bupivacaine could significantly decrease hippocampal P.Akt/T.Akt ratio which was concurrent with an increment of cleaved caspase-3 and caspase-8 expression.

Conclusion

Our data suggest that maternal bupivacaine use increases fetal hippocampal cell apoptosis markers such as caspase 8 and cleaved caspase 3, at least in part, via inhibiting the Akt activation.

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Most cited references 39

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Neurological complications after regional anesthesia: contemporary estimates of risk.

Gavin Chan, Richard Brull, Hossam El-Rewaidy … (2007)

Regional anesthesia (RA) provides excellent anesthesia and analgesia for many surgical procedures. Anesthesiologists and patients must understand the risks in addition to the benefits of RA to make an informed choice of anesthetic technique. Many studies that have investigated neurological complications after RA are dated, and do not reflect the increasing indications and applications of RA nor the advances in training and techniques. In this brief narrative review we collate the contemporary investigations of neurological complications after the most common RA techniques. We reviewed all 32 studies published between January 1, 1995 and December 31, 2005 where the primary intent was to investigate neurological complications of RA. The sample size of the studies that investigated neurological complications after central and peripheral (PNB) nerve blockade ranged from 4185 to 1,260,000 and 20 to 10,309 blocks, respectively. The rate of neuropathy after spinal and epidural anesthesia was 3.78:10,000 (95% CI: 1.06-13.50:10,000) and 2.19:10,000 (95% CI: 0.88-5.44:10,000), respectively. For common PNB techniques, the rate of neuropathy after interscalene brachial plexus block, axillary brachial plexus block, and femoral nerve block was 2.84:100 (95% CI 1.33-5.98:100), 1.48:100 (95% CI: 0.52-4.11:100), and 0.34:100 (95% CI: 0.04-2.81:100), respectively. The rate of permanent neurological injury after spinal and epidural anesthesia ranged from 0-4.2:10,000 and 0-7.6:10,000, respectively. Only one case of permanent neuropathy was reported among 16 studies of neurological complications after PNB. Our review suggests that the rate of neurological complications after central nerve blockade is <4:10,000, or 0.04%. The rate of neuropathy after PNB is <3:100, or 3%. However, permanent neurological injury after RA is rare in contemporary anesthetic practice.

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Placental transfer of drugs administered to the mother.

M Pacifici, R Nottoli (1995)

Drugs administered to mothers have the potential to cross the placenta and reach the fetus. Under particular circumstances, the comparison of the drug concentration in the maternal and fetal plasma may give an idea of the exposure of the fetus to the maternally administered drugs. In this review drugs are classified according to their type of transfer across the placenta. Several drugs rapidly cross the placenta and pharmacologically significant concentrations equilibrate in maternal and fetal plasma. Their transfer is termed 'complete'. Other drugs cross the placenta incompletely, and their concentrations are lower in the fetal than in maternal plasma. The majority of drugs fit into 1 of these 2 groups. A limited number of drugs reach greater concentrations in fetal than maternal plasma. It is said that these drugs have an 'exceeding' transfer. The impression prevails that suxamethonium chloride (succinylcholine chloride) and doxorubicin do not cross the placenta. However, a careful analysis of the literature suggests that this impression is wrong and that all drugs cross the placenta, although the extent transfer varies considerably. The following parameters were considered as possible factors determining the extent of placental transfer: (i) the molecular weight of the drug; (ii) the pKa (pH at which the drug is 50% ionised); and (iii) the extent of drug binding to the plasma protein. Drugs with molecular weights greater than 500D have an incomplete transfer across the human placenta. Strongly dissociated acid drug molecules should have an incomplete transfer, but this does not seem to be an absolute rule. For example, ampicillin and methicillin transfer completely and they are strongly dissociated at physiological pH. The extent of drug binding to plasma protein does not influence the type of drug transfer across the human placenta.

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Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells.

K-S Seo, Minho Moon, Seungjoon Park … (2008)

Only acylated ghrelin (AG) binds GH secretagog receptor 1a (GHS-R1a) and has central endocrine activities. An anti-apoptotic effect of AG in neuronal cells has recently been reported. However, whether there is a neuroprotective effect of unacylated ghrelin (UAG), the most abundant form of ghrelin in plasma, is still unknown. Therefore, we investigated whether UAG was neuroprotective against ischemic neuronal injury using primary cultured rat cortical neurons exposed to oxygen and glucose deprivation (OGD). Both AG and UAG inhibited OGD-induced apoptosis. Exposure of cells to the receptor-specific antagonist D-Lys-3-GHRH-6 abolished the protective effects of AG against OGD, whereas those of UAG were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. Chemical inhibition of MAPK and phosphatidylinositol-3-kinase (PI3K) blocked the anti-apoptotic effects of AG and UAG. Ghrelin siRNA enhanced apoptosis either during OGD or even in normoxic conditions. The protective effects of AG and UAG were accompanied by an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and glycogen synthase kinase-3beta (GSK-3beta). Furthermore, treatment of cells with AG or UAG resulted in nuclear translocation of beta-catenin. In addition, both AG and UAG increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. The data indicate that, independent of acylation, ghrelin can function as a neuroprotective agent that inhibits apoptotic pathways. These effects may be mediated via activation of the MAPK and PI3K/Akt pathways. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3beta and stabilization of beta-catenin contribute to the anti-apoptotic effects of ghrelin.

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Author and article information

Contributors

Jalal Zaringhalam: jzaringhalam@yahoo.com

Journal

Journal ID (nlm-ta): BMC Anesthesiol

Journal ID (iso-abbrev): BMC Anesthesiol

Title: BMC Anesthesiology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2253

Publication date (Electronic): 7 September 2020

Publication date PMC-release: 7 September 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 228

Affiliations

[1 ]GRID grid.411600.2, Department of Anesthesiology, , Shahid Beheshti University of Medical Sciences, ; Tehran, 1985717443 Iran

[2 ]GRID grid.411600.2, Department of Physiology, School of Medicine, , Shahid Beheshti University of Medical Sciences, ; Tehran, Iran

[3 ]GRID grid.411463.5, ISNI 0000 0001 0706 2472, Department of Gynecology, , Tehran Azad University, ; Tehran, Iran

[4 ]GRID grid.411600.2, Department of Gastroenterology, , Shahid Beheshti University of Medical Sciences, ; Tehran, Iran

Article

Publisher ID: 1143

DOI: 10.1186/s12871-020-01143-2

PMC ID: 7487602

PubMed ID: 32894054

SO-VID: bb52bc72-49ca-4b7b-923a-9c5ba656a83f

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 25 March 2020

Date accepted : 1 September 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100005851, Shahid Beheshti University of Medical Sciences;

Award ID: 15193

Award Recipient : Alireza Shakeri

Custom metadata

ScienceOpen disciplines: Anesthesiology & Pain management

Keywords: bupivacaine,apoptosis,akt,pregnancy

Data availability:

ScienceOpen disciplines: Anesthesiology & Pain management

Keywords: bupivacaine, apoptosis, akt, pregnancy

Maternal sciatic nerve administered bupivacaine induces hippocampal cell apoptosis in offspring

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Irish Journal of Paramedicine

Most cited references 39

Neurological complications after regional anesthesia: contemporary estimates of risk.

Placental transfer of drugs administered to the mother.

Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells.

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