Skip to main content
Top
Published in: BMC Anesthesiology 1/2020

Open Access 01-12-2020 | Anesthetics | Research article

Maternal sciatic nerve administered bupivacaine induces hippocampal cell apoptosis in offspring

Authors: Alireza Mirkheshti, Alireza Shakeri, Elham Memary, Mansoureh Baniasadi, Jalal Zaringhalam, Ardeshir Tajbakhsh, Marzieh Mirzaei, Elena Lak

Published in: BMC Anesthesiology | Issue 1/2020

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
go back to reference Fan Y-L, Li H-C, Zhao W, Peng H-H, Huang F, Jiang W-H, Xu S-Y. Curcumin attenuated bupivacaine-induced neurotoxicity in SH-SY5Y cells via activation of the Akt signaling pathway. Neurochem Res. 2016;41(9):2425–32.PubMed Fan Y-L, Li H-C, Zhao W, Peng H-H, Huang F, Jiang W-H, Xu S-Y. Curcumin attenuated bupivacaine-induced neurotoxicity in SH-SY5Y cells via activation of the Akt signaling pathway. Neurochem Res. 2016;41(9):2425–32.PubMed
2.
go back to reference Rudolph AM. Pharmacodynamics in the maternal-fetal-placental unit. NIDA Res Monogr. 1995;154:163–74.PubMed Rudolph AM. Pharmacodynamics in the maternal-fetal-placental unit. NIDA Res Monogr. 1995;154:163–74.PubMed
3.
go back to reference Liu Y, Sun L, Ma Y, Wei B, Gao M, Shang L. High glucose and bupivacaine-induced cytotoxicity is mediated by enhanced apoptosis and impaired autophagy via the PERK-ATF4-CHOP and IRE1-TRAF2 signaling pathways. Mol Med Rep. 2019;20(3):2832–42.PubMedPubMedCentral Liu Y, Sun L, Ma Y, Wei B, Gao M, Shang L. High glucose and bupivacaine-induced cytotoxicity is mediated by enhanced apoptosis and impaired autophagy via the PERK-ATF4-CHOP and IRE1-TRAF2 signaling pathways. Mol Med Rep. 2019;20(3):2832–42.PubMedPubMedCentral
4.
go back to reference Zhang H, Wang W, Du Q. Andrographolide attenuates bupivacaine-induced cytotoxicity in SH-SY5Y cells through preserving Akt/mTOR activity. Drug Des Devel Ther. 2019;13:1659.PubMedPubMedCentral Zhang H, Wang W, Du Q. Andrographolide attenuates bupivacaine-induced cytotoxicity in SH-SY5Y cells through preserving Akt/mTOR activity. Drug Des Devel Ther. 2019;13:1659.PubMedPubMedCentral
5.
go back to reference Zheng Q, Peng X, Zhang Y. Cytotoxicity of amide-linked local anesthetics on melanoma cells via inhibition of Ras and RhoA signaling independent of sodium channel blockade. BMC Anesthesiol. 2020;20(1):1–9. Zheng Q, Peng X, Zhang Y. Cytotoxicity of amide-linked local anesthetics on melanoma cells via inhibition of Ras and RhoA signaling independent of sodium channel blockade. BMC Anesthesiol. 2020;20(1):1–9.
6.
go back to reference Li L, Zhang Q-g, Lai L-y, Wen X-j, Zheng T, Cheung C-w, Zhou S-q, Xu S-y. Neuroprotective effect of ginkgolide B on bupivacaine-induced apoptosis in SH-SY5Y cells. Oxidative Med Cell Longev. 2013;2013. Li L, Zhang Q-g, Lai L-y, Wen X-j, Zheng T, Cheung C-w, Zhou S-q, Xu S-y. Neuroprotective effect of ginkgolide B on bupivacaine-induced apoptosis in SH-SY5Y cells. Oxidative Med Cell Longev. 2013;2013.
7.
go back to reference Lu J, Xu SY, Zhang QG, Lei HY. Bupivacaine induces reactive oxygen species production via activation of the AMP-activated protein kinase-dependent pathway. Pharmacology. 2011;87(3–4):121–9.PubMed Lu J, Xu SY, Zhang QG, Lei HY. Bupivacaine induces reactive oxygen species production via activation of the AMP-activated protein kinase-dependent pathway. Pharmacology. 2011;87(3–4):121–9.PubMed
8.
go back to reference Zhang H, Wang K. Downregulation of MicroRNA-33-5p protected bupivacaine-induced apoptosis in murine dorsal root ganglion neurons through GDNF. Neurotox Res. 2019;35(4):860–6.PubMed Zhang H, Wang K. Downregulation of MicroRNA-33-5p protected bupivacaine-induced apoptosis in murine dorsal root ganglion neurons through GDNF. Neurotox Res. 2019;35(4):860–6.PubMed
9.
go back to reference Wang S, Xia B, Qiao Z, Duan L, Wang G, Meng W, Liu Z, Wang Y, Zhang M. Tetramethylpyrazine attenuated bupivacaine-induced neurotoxicity in SH-SY5Y cells through regulating apoptosis, autophagy and oxidative damage. Drug Des Devel Ther. 2019;13:1187.PubMedPubMedCentral Wang S, Xia B, Qiao Z, Duan L, Wang G, Meng W, Liu Z, Wang Y, Zhang M. Tetramethylpyrazine attenuated bupivacaine-induced neurotoxicity in SH-SY5Y cells through regulating apoptosis, autophagy and oxidative damage. Drug Des Devel Ther. 2019;13:1187.PubMedPubMedCentral
10.
go back to reference Yu X-j, Zhao W, Li Y-j, Li F-x, Liu Z-j, Xu H-l, Lai L-y, Xu R, Xu S-y. Neurotoxicity comparison of two types of local anaesthetics: amide-bupivacaine versus ester-procaine. Sci Rep. 2017;7:45316.PubMedPubMedCentral Yu X-j, Zhao W, Li Y-j, Li F-x, Liu Z-j, Xu H-l, Lai L-y, Xu R, Xu S-y. Neurotoxicity comparison of two types of local anaesthetics: amide-bupivacaine versus ester-procaine. Sci Rep. 2017;7:45316.PubMedPubMedCentral
11.
go back to reference Radwan IA, Saito S, Goto F. The neurotoxicity of local anesthetics on growing neurons: a comparative study of lidocaine, bupivacaine, mepivacaine, and ropivacaine. Anesth Analg. 2002;94(2):319–24.PubMed Radwan IA, Saito S, Goto F. The neurotoxicity of local anesthetics on growing neurons: a comparative study of lidocaine, bupivacaine, mepivacaine, and ropivacaine. Anesth Analg. 2002;94(2):319–24.PubMed
12.
go back to reference Maurice JM, Gan Y, Chang Y-c, Hibner M, Huang Y. Bupivacaine causes cytotoxicity in mouse C2C12 myoblast cells: involvement of ERK and Akt signaling pathways. Acta Pharmacol Sin. 2010;31(4):493.PubMedPubMedCentral Maurice JM, Gan Y, Chang Y-c, Hibner M, Huang Y. Bupivacaine causes cytotoxicity in mouse C2C12 myoblast cells: involvement of ERK and Akt signaling pathways. Acta Pharmacol Sin. 2010;31(4):493.PubMedPubMedCentral
13.
go back to reference Antonio AM, Druse MJ. Antioxidants prevent ethanol-associated apoptosis in fetal rhombencephalic neurons. Brain Res. 2008;1204:16–23.PubMedPubMedCentral Antonio AM, Druse MJ. Antioxidants prevent ethanol-associated apoptosis in fetal rhombencephalic neurons. Brain Res. 2008;1204:16–23.PubMedPubMedCentral
14.
go back to reference Yu T, Lin W. Small-molecule GSK-3 inhibitor rescued apoptosis and neurodegeneration in anesthetics-injured dorsal root ganglion neurons. Biomed Pharmacother. 2016;84:395–402.PubMed Yu T, Lin W. Small-molecule GSK-3 inhibitor rescued apoptosis and neurodegeneration in anesthetics-injured dorsal root ganglion neurons. Biomed Pharmacother. 2016;84:395–402.PubMed
15.
go back to reference Tan Z, Dohi S, Chen J, Banno Y, Nozawa Y. Involvement of the mitogen-activated protein kinase family in tetracaine-induced PC12 cell death. Anesthesiology. 2002;96(5):1191–201.PubMed Tan Z, Dohi S, Chen J, Banno Y, Nozawa Y. Involvement of the mitogen-activated protein kinase family in tetracaine-induced PC12 cell death. Anesthesiology. 2002;96(5):1191–201.PubMed
16.
go back to reference Lirk P, Haller I, Peter H, Lang L, Tomaselli B, Klimaschewski L, Gerner P. In vitro, inhibition of mitogen-activated protein kinase pathways protects against bupivacaine-and ropivacaine-induced neurotoxicity. Anesth Analg. 2008;106(5):1456–64.PubMed Lirk P, Haller I, Peter H, Lang L, Tomaselli B, Klimaschewski L, Gerner P. In vitro, inhibition of mitogen-activated protein kinase pathways protects against bupivacaine-and ropivacaine-induced neurotoxicity. Anesth Analg. 2008;106(5):1456–64.PubMed
17.
go back to reference Al-Enazy S, Ali S, Albekairi N, El-Tawil M, Rytting E. Placental control of drug delivery. Adv Drug Deliv Rev. 2017;116:63–72.PubMed Al-Enazy S, Ali S, Albekairi N, El-Tawil M, Rytting E. Placental control of drug delivery. Adv Drug Deliv Rev. 2017;116:63–72.PubMed
18.
go back to reference Morishima HO, Heymann MA, Rudolph AM, Barrett CT, James LS. Transfer of lidocaine across the sheep placenta to the fetus: hemodynamic and acid-base responses of the fetal lamb. Am J Obstet Gynecol. 1975;122(5):581–8.PubMed Morishima HO, Heymann MA, Rudolph AM, Barrett CT, James LS. Transfer of lidocaine across the sheep placenta to the fetus: hemodynamic and acid-base responses of the fetal lamb. Am J Obstet Gynecol. 1975;122(5):581–8.PubMed
19.
go back to reference Santos AC, Arthur GR, Lehning EJ, Finster M. Comparative pharmacokinetics of ropivacaine and bupivacaine in nonpregnant and pregnant ewes. Anesth Analg. 1997;85(1):87–93.PubMed Santos AC, Arthur GR, Lehning EJ, Finster M. Comparative pharmacokinetics of ropivacaine and bupivacaine in nonpregnant and pregnant ewes. Anesth Analg. 1997;85(1):87–93.PubMed
20.
go back to reference Kennedy R, Miller R, Bell J, Doshi D, deSousa H, Kennedy M, Heald D, David Y. Uptake and distribution of bupivacaine in fetal lambs. Anesthesiology. 1986;65(3):247–53.PubMed Kennedy R, Miller R, Bell J, Doshi D, deSousa H, Kennedy M, Heald D, David Y. Uptake and distribution of bupivacaine in fetal lambs. Anesthesiology. 1986;65(3):247–53.PubMed
21.
go back to reference Gordon HR. Fetal bradycardia after paracervical block: correlation with fetal and maternal blood levels of local anesthetic (mepivacaine). N Engl J Med. 1968;279(17):910–4.PubMed Gordon HR. Fetal bradycardia after paracervical block: correlation with fetal and maternal blood levels of local anesthetic (mepivacaine). N Engl J Med. 1968;279(17):910–4.PubMed
22.
go back to reference Morishima HO, Ishizaki A, Zhang Y, Whittington RA, Suckow RF, Cooper TB. Disposition of bupivacaine and its metabolites in the maternal, placental, and fetal compartments in rats. Anesthesiology. 2000;93(4):1069–74.PubMed Morishima HO, Ishizaki A, Zhang Y, Whittington RA, Suckow RF, Cooper TB. Disposition of bupivacaine and its metabolites in the maternal, placental, and fetal compartments in rats. Anesthesiology. 2000;93(4):1069–74.PubMed
23.
go back to reference Eslamian L, KABIRI NM, AGHA HM, Azimaraghi O, Barzin G, Movafegh A. Adding sufentanil to TAP block hyperbaric bupivacaine decreases post-cesarean delivery morphine consumption; 2016. Eslamian L, KABIRI NM, AGHA HM, Azimaraghi O, Barzin G, Movafegh A. Adding sufentanil to TAP block hyperbaric bupivacaine decreases post-cesarean delivery morphine consumption; 2016.
24.
go back to reference Council NR. Guide for the care and use of laboratory animals: eighth edition. Washington, DC: The National Academies Press; 2011. Council NR. Guide for the care and use of laboratory animals: eighth edition. Washington, DC: The National Academies Press; 2011.
25.
go back to reference Kau Y-C, Hung Y-C, Zizza AM, Zurakowski D, Greco WR, Wang GK, Gerner P. Efficacy of lidocaine or bupivacaine combined with ephedrine in rat sciatic nerve block. Reg Anesth Pain Med. 2006;31(1):14–8 14-18.PubMed Kau Y-C, Hung Y-C, Zizza AM, Zurakowski D, Greco WR, Wang GK, Gerner P. Efficacy of lidocaine or bupivacaine combined with ephedrine in rat sciatic nerve block. Reg Anesth Pain Med. 2006;31(1):14–8 14-18.PubMed
26.
go back to reference Memari E, Hosseinian M-A, Mirkheshti A, Arhami-Dolatabadi A, Mirabotalebi M, Khandaghy M, Daneshbod Y, Alizadeh L, Shirian S. Comparison of histopathological effects of perineural administration of bupivacaine and bupivacaine-dexmedetomidine in rat sciatic nerve. Exp Toxicol Pathol. 2016;68(10):559–64.PubMed Memari E, Hosseinian M-A, Mirkheshti A, Arhami-Dolatabadi A, Mirabotalebi M, Khandaghy M, Daneshbod Y, Alizadeh L, Shirian S. Comparison of histopathological effects of perineural administration of bupivacaine and bupivacaine-dexmedetomidine in rat sciatic nerve. Exp Toxicol Pathol. 2016;68(10):559–64.PubMed
27.
go back to reference Ni J, Hou X, Wang X, Shi Y, Xu L, Zheng X, Liu N, Qiu A, Zhuang S. 3-deazaneplanocin a protects against cisplatin-induced renal tubular cell apoptosis and acute kidney injury by restoration of E-cadherin expression. Cell Death Dis. 2019;10(5):355.PubMedPubMedCentral Ni J, Hou X, Wang X, Shi Y, Xu L, Zheng X, Liu N, Qiu A, Zhuang S. 3-deazaneplanocin a protects against cisplatin-induced renal tubular cell apoptosis and acute kidney injury by restoration of E-cadherin expression. Cell Death Dis. 2019;10(5):355.PubMedPubMedCentral
28.
go back to reference Knight Z, Shokat K. Chemically targeting the PI3K family. In: Portland Press Limited; 2007. Knight Z, Shokat K. Chemically targeting the PI3K family. In: Portland Press Limited; 2007.
29.
go back to reference Chung H, Seo S, Moon M, Park S. Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3b and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells. J Endocrinol. 2008;198(3):511–22.PubMed Chung H, Seo S, Moon M, Park S. Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3b and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells. J Endocrinol. 2008;198(3):511–22.PubMed
30.
go back to reference Ma R, Wang X, Lu C, Li C, Cheng Y, Ding G, Liu L, Ding Z. Dexamethasone attenuated bupivacaine-induced neuron injury in vitro through a threonine–serine protein kinase B-dependent mechanism. Neuroscience. 2010;167(2):329–42.PubMed Ma R, Wang X, Lu C, Li C, Cheng Y, Ding G, Liu L, Ding Z. Dexamethasone attenuated bupivacaine-induced neuron injury in vitro through a threonine–serine protein kinase B-dependent mechanism. Neuroscience. 2010;167(2):329–42.PubMed
31.
go back to reference Gündüz Ş, Yalçın SE, Karakoç G, Akkurt MÖ, Yalçın Y. Comparison of bupivacaine and ropivacaine in combination with fentanyl used for walking epidural anesthesia in labor. Turkish J Obstet Gynecol. 2017;14(3):170. Gündüz Ş, Yalçın SE, Karakoç G, Akkurt MÖ, Yalçın Y. Comparison of bupivacaine and ropivacaine in combination with fentanyl used for walking epidural anesthesia in labor. Turkish J Obstet Gynecol. 2017;14(3):170.
32.
go back to reference B-s L, Wang W, Wang Z-q, Wang X-w, Wang J-h, Fang F, Mi W-d. Efficacy and safety of local anesthetics bupivacaine, ropivacaine and levobupivacaine in combination with sufentanil in epidural anesthesia for labor and delivery: a meta-analysis. Curr Med Res Opin. 2014;30(11):2279–89. B-s L, Wang W, Wang Z-q, Wang X-w, Wang J-h, Fang F, Mi W-d. Efficacy and safety of local anesthetics bupivacaine, ropivacaine and levobupivacaine in combination with sufentanil in epidural anesthesia for labor and delivery: a meta-analysis. Curr Med Res Opin. 2014;30(11):2279–89.
33.
go back to reference Lee JM, Shin TJ. Use of local anesthetics for dental treatment during pregnancy; safety for parturient. J Dent Anesth Pain Med. 2017;17(2):81–90.PubMedPubMedCentral Lee JM, Shin TJ. Use of local anesthetics for dental treatment during pregnancy; safety for parturient. J Dent Anesth Pain Med. 2017;17(2):81–90.PubMedPubMedCentral
35.
go back to reference Baniasadi M, Manaheji H, Maghsoudi N, Danyali S, Zakeri Z, Maghsoudi A, Zaringhalam J. Microglial-induced apoptosis is potentially responsible for hyperalgesia variations during CFA-induced inflammation. Inflammopharmacology. 2019:1–11. Baniasadi M, Manaheji H, Maghsoudi N, Danyali S, Zakeri Z, Maghsoudi A, Zaringhalam J. Microglial-induced apoptosis is potentially responsible for hyperalgesia variations during CFA-induced inflammation. Inflammopharmacology. 2019:1–11.
36.
go back to reference Brull R, McCartney CJ, Chan VW, El-Beheiry H. Neurological complications after regional anesthesia: contemporary estimates of risk. Anesth Analg. 2007;104(4):965–74.PubMed Brull R, McCartney CJ, Chan VW, El-Beheiry H. Neurological complications after regional anesthesia: contemporary estimates of risk. Anesth Analg. 2007;104(4):965–74.PubMed
37.
go back to reference Graham MR. Clinical update regarding general anesthesia-associated neurotoxicity in infants and children. Curr Opin Anaesthesiol. 2017;30(6):682–7.PubMed Graham MR. Clinical update regarding general anesthesia-associated neurotoxicity in infants and children. Curr Opin Anaesthesiol. 2017;30(6):682–7.PubMed
38.
go back to reference Vutskits L, Davidson A. Update on developmental anesthesia neurotoxicity. Curr Opin Anesthesiol. 2017;30(3):337–42. Vutskits L, Davidson A. Update on developmental anesthesia neurotoxicity. Curr Opin Anesthesiol. 2017;30(3):337–42.
39.
go back to reference Santos AC, Pedersen H, Sallusto JA, Johnson HV, Morishima HO, Finster M, Arthur GR, Covino BG. Pharmacokinetics of ropivacaine in nonpregnant and pregnant ewes. Anesth Analg. 1990;70(3):262–6.PubMed Santos AC, Pedersen H, Sallusto JA, Johnson HV, Morishima HO, Finster M, Arthur GR, Covino BG. Pharmacokinetics of ropivacaine in nonpregnant and pregnant ewes. Anesth Analg. 1990;70(3):262–6.PubMed
40.
go back to reference Pacifici GM, Nottoli R. Placental transfer of drugs administered to the mother. Clin Pharmacokinet. 1995;28(3):235–69.PubMed Pacifici GM, Nottoli R. Placental transfer of drugs administered to the mother. Clin Pharmacokinet. 1995;28(3):235–69.PubMed
41.
go back to reference Guillén-Dolores Y. Bupivacaine pharmacokinetics in pregnant women. In: Local Anesthetics edn: IntechOpen; 2019. Guillén-Dolores Y. Bupivacaine pharmacokinetics in pregnant women. In: Local Anesthetics edn: IntechOpen; 2019.
43.
go back to reference Nair VD, Olanow CW. Differential modulation of Akt/glycogen synthase kinase-3β pathway regulates apoptotic and cytoprotective signaling responses. J Biol Chem. 2008;283(22):15469–78.PubMedPubMedCentral Nair VD, Olanow CW. Differential modulation of Akt/glycogen synthase kinase-3β pathway regulates apoptotic and cytoprotective signaling responses. J Biol Chem. 2008;283(22):15469–78.PubMedPubMedCentral
44.
go back to reference Zhao W, Liu Z, Yu X, Lai L, Li H, Liu Z, Li L, Jiang S, Xia Z, Sy X. iTRAQ proteomics analysis reveals that PI3K is highly associated with bupivacaine-induced neurotoxicity pathways. Proteomics. 2016;16(4):564–75.PubMed Zhao W, Liu Z, Yu X, Lai L, Li H, Liu Z, Li L, Jiang S, Xia Z, Sy X. iTRAQ proteomics analysis reveals that PI3K is highly associated with bupivacaine-induced neurotoxicity pathways. Proteomics. 2016;16(4):564–75.PubMed
45.
go back to reference Wang Z, Shen J, Wang J, Lu T, Li C, Zhang X, Liu L, Ding Z. Lithium attenuates bupivacaine-induced neurotoxicity in vitro through phosphatidylinositol-3-kinase/threonine-serine protein kinase B-and extracellular signal-regulated kinase-dependent mechanisms. Neuroscience. 2012;206:190–200.PubMed Wang Z, Shen J, Wang J, Lu T, Li C, Zhang X, Liu L, Ding Z. Lithium attenuates bupivacaine-induced neurotoxicity in vitro through phosphatidylinositol-3-kinase/threonine-serine protein kinase B-and extracellular signal-regulated kinase-dependent mechanisms. Neuroscience. 2012;206:190–200.PubMed
Metadata
Title
Maternal sciatic nerve administered bupivacaine induces hippocampal cell apoptosis in offspring
Authors
Alireza Mirkheshti
Alireza Shakeri
Elham Memary
Mansoureh Baniasadi
Jalal Zaringhalam
Ardeshir Tajbakhsh
Marzieh Mirzaei
Elena Lak
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Anesthesiology / Issue 1/2020
Electronic ISSN: 1471-2253
DOI
https://doi.org/10.1186/s12871-020-01143-2

Other articles of this Issue 1/2020

BMC Anesthesiology 1/2020 Go to the issue