Skip to content
2000
Volume 21, Issue 18
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

Lidocaine is extensively utilized as an anesthetic in clinical settings; however, it has demonstrated significant neurotoxicity when administered for spinal anesthesia. The specific mechanisms underlying lidocaine-induced neurotoxicity are poorly understood.

Objective

This study aimed to investigate the mechanisms through which lidocaine induces neurotoxicity, focusing on its effects on intracellular calcium release and the activation of CaMKII and MAPKs pathways, as well as to evaluate the potential protective effects of cilnidipine.

Methods

The investigation has employed both cell models and mouse models to conduct the experiments. Neuronal cell viability has been assessed following lidocaine treatment, and neurological function has been evaluated in mice after intrathecal injection of lidocaine. Intracellular calcium levels, CaMKII activation, and the phosphorylation of p38 and p65 have been measured in cultured hippocampal neuronal cells and mouse brain tissues. The effects of the calcium channel blocker cilnidipine on these parameters have also been examined.

Results

Lidocaine treatment led to a reduction in cell viability in cultured neuronal cells and induced neurological dysfunction in mice. It increased intracellular Ca2+ levels and activated CaMKII in both cultured neuronal cells and mouse brain tissues. Lidocaine also elevated the phosphorylation levels of p38 and p65 in neuronal cells. These effects have been suppressed by cilnidipine, indicating a calcium-dependent mechanism.

Conclusion

This study suggests that lidocaine induces neurotoxicity through a calcium-dependent activation of CaMKII and MAPK pathways, leading to neuronal apoptosis and dysfunction.

Cilnidipine has been found to exhibit promise as a protective agent against lidocaine-induced neurotoxicity.

Loading

Article metrics loading...

/content/journals/lddd/10.2174/0115701808355819241118115155
2024-11-22
2025-07-05
Loading full text...

Full text loading...

References

  1. LuoH. XiangY. QuX. LiuH. LiuC. LiG. HanL. QinX. Apelin-13 suppresses neuroinflammation against cognitive deficit in a streptozotocin-induced rat model of Alzheimer’s disease through activation of bdnf-trkb signaling pathway.Front. Pharmacol.20191039510.3389/fphar.2019.0039531040784
    [Google Scholar]
  2. DaiB. WuQ. ZengC. ZhangJ. CaoL. XiaoZ. YangM. The effect of Liuwei Dihuang decoction on PI3K/Akt signaling pathway in liver of type 2 diabetes mellitus (T2DM) rats with insulin resistance.J. Ethnopharmacol.201619238238910.1016/j.jep.2016.07.02427401286
    [Google Scholar]
  3. ChengM. LiT. HuE. YanQ. LiH. WangY. LuoJ. TangT. A novel strategy of integrating network pharmacology and transcriptome reveals antiapoptotic mechanisms of Buyang Huanwu Decoction in treating intracerebral hemorrhage.J. Ethnopharmacol.2024319Pt 111712310.1016/j.jep.2023.11712337673200
    [Google Scholar]
  4. HuiZ. Lai-FaW. Xue-QinW. LingD. Bin-ShengH. LiJ.M. Mechanisms and therapeutic potential of chinonin in nervous system diseases.J. Asian Nat. Prod. Res.2024202411610.1080/10286020.2024.237104038975978
    [Google Scholar]
  5. HuE. LiZ. LiT. YangX. DingR. JiangH. SuH. ChengM. YuZ. LiH. TangT. WangY. A novel microbial and hepatic biotransformation-integrated network pharmacology strategy explores the therapeutic mechanisms of bioactive herbal products in neurological diseases: The effects of Astragaloside IV on intracerebral hemorrhage as an example.Chin. Med.20231814010.1186/s13020‑023‑00745‑537069580
    [Google Scholar]
  6. VerlindeM. HollmannM. StevensM. HermannsH. WerdehausenR. LirkP. Local anesthetic-induced neurotoxicity.Int. J. Mol. Sci.201617333910.3390/ijms1703033926959012
    [Google Scholar]
  7. RadwanI.A.M. SaitoS. GotoF. The neurotoxicity of local anesthetics on growing neurons: A comparative study of lidocaine, bupivacaine, mepivacaine, and ropivacaine.Anesth. Analg.200294231932410.1213/00000539‑200202000‑0001611812691
    [Google Scholar]
  8. CherngC.H. WongC.S. WuC.T. YehC.C. Glutamate release and neurologic impairment after intrathecal administration of lidocaine and bupivacaine in the rat.Reg. Anesth. Pain Med.201136545245610.1097/AAP.0b013e318228cdb021857271
    [Google Scholar]
  9. TanY. WangQ. ZhaoB. SheY. BiX. GNB2 is a mediator of lidocaine-induced apoptosis in rat pheochromocytoma PC12 cells.Neurotoxicology201654536410.1016/j.neuro.2016.03.01527018092
    [Google Scholar]
  10. HuE. LiT. LiZ. SuH. YanQ. WangL. LiH. ZhangW. TangT. WangY. Metabolomics reveals the effects of hydroxysafflor yellow A on neurogenesis and axon regeneration after experimental traumatic brain injury.Pharm. Biol.20236111054106410.1080/13880209.2023.222937937416997
    [Google Scholar]
  11. ZhangY. ZhengX. LiuY. FangL. PanZ. BaoM. HuangP. Effect of oridonin on cytochrome p450 expression and activities in HepaRG.Cell. Pharmacol.20181015-624625410.1159/00048660029393278
    [Google Scholar]
  12. CaminsA. VerdaguerE. FolchJ. PallàsM. Involvement of calpain activation in neurodegenerative processes.CNS Drug Rev.200612213514810.1111/j.1527‑3458.2006.00135.x16958987
    [Google Scholar]
  13. JiangC. XieN. SunT. MaW. ZhangB. LiW. Xanthohumol inhibits TGF-β1-induced cardiac fibroblasts activation via mediating PTEN/Akt/mTOR signaling pathway.Drug Des. Devel. Ther.2020145431543910.2147/DDDT.S28220633324040
    [Google Scholar]
  14. HaoS. XinQ. XiaominZ. JialiP. XiaoqinW. RongY. CenlinZ. Group membership modulates the hold-up problem: aAn event-related potentials and oscillations study.Soc. Cogn. Affect. Neurosci.2023181nsad07110.1093/scan/nsad07137990077
    [Google Scholar]
  15. HaoS. JialiP. XiaominZ. XiaoqinW. LinaL. XinQ. QinL. Group identity modulates bidding behavior in repeated lottery contest: neural signatures from event-related potentials and electroencephalography oscillations.Front. Neurosci.202317118460110.3389/fnins.2023.118460137425015
    [Google Scholar]
  16. DingC. WuY. DabasH. HammarlundM. Activation of the CaMKII-Sarm1-ASK1-p38 MAP kinase pathway protects against axon degeneration caused by loss of mitochondria.eLife202211e7355710.7554/eLife.7355735285800
    [Google Scholar]
  17. GaertnerT.R. KolodziejS.J. WangD. KobayashiR. KoomenJ.M. StoopsJ.K. WaxhamM.N. Comparative analyses of the three-dimensional structures and enzymatic properties of alpha, beta, gamma and delta isoforms of Ca2+-calmodulin-dependent protein kinase II.J. Biol. Chem.200427913124841249410.1074/jbc.M31359720014722083
    [Google Scholar]
  18. ZalcmanG. FedermanN. RomanoA. CaMKII isoforms in learning and memory: Localization and function.Front. Mol. Neurosci.20181144510.3389/fnmol.2018.0044530564099
    [Google Scholar]
  19. ZhangC. GeH. ZhangS. LiuD. JiangZ. LanC. LiL. FengH. HuR. Hematoma evacuation via image-guided para-corticospinal tract approach in patients with spontaneous intracerebral hemorrhage.Neurol. Ther.20211021001101310.1007/s40120‑021‑00279‑834515953
    [Google Scholar]
  20. ZhouY. LiL. YuZ. GuX. PanR. LiQ. YuanC. CaiF. ZhuY. CuiY. Dermatophagoides pteronyssinus allergen Der p 22: Cloning, expression, IgE-binding in asthmatic children, and immunogenicity.Pediatr. Allergy Immunol.2022338e13835
    [Google Scholar]
  21. TianS. ChenX. WuW. LinH. QingX. LiuS. WangB. XiaoY. ShaoZ. PengY. Nucleus pulposus cells regulate macrophages in degenerated intervertebral discs via the integrated stress response-mediated CCL2/7-CCR2 signaling pathway.Exp. Mol. Med.202456240842110.1038/s12276‑024‑01168‑438316963
    [Google Scholar]
  22. ChenS. XuY. XuB. GuoM. ZhangZ. LiuL. MaH. ChenZ. LuoY. HuangS. ChenL. CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death.J. Neurochem.201111951108111810.1111/j.1471‑4159.2011.07493.x21933187
    [Google Scholar]
  23. El RawasR. AmaralI.M. HoferA. Is p38 MAPK associated to drugs of abuse-induced abnormal behaviors?Int. J. Mol. Sci.20202114483310.3390/ijms2114483332650599
    [Google Scholar]
  24. HeY. SheH. ZhangT. XuH. ChengL. YepesM. ZhaoY. MaoZ. p38 MAPK inhibits autophagy and promotes microglial inflammatory responses by phosphorylating ULK1.J. Cell Biol.2018217131532810.1083/jcb.20170104929196462
    [Google Scholar]
  25. WettschureckN. OffermannsS. Mammalian G proteins and their cell type specific functions.Physiol. Rev.20058541159120410.1152/physrev.00003.200516183910
    [Google Scholar]
  26. JohnsonM.E. Potential neurotoxicity of spinal anesthesia with lidocaine.Mayo Clin. Proc.200075992193210.4065/75.9.92110994828
    [Google Scholar]
  27. FooI. MacfarlaneA.J.R. SrivastavaD. BhaskarA. BarkerH. KnaggsR. EipeN. SmithA.F. The use of intravenous lidocaine for postoperative pain and recovery: International consensus statement on efficacy and safety.Anaesthesia202176223825010.1111/anae.1527033141959
    [Google Scholar]
  28. WoolumsB.M. McCrayB.A. SungH. TabuchiM. SullivanJ.M. RuppellK.T. YangY. MamahC. AisenbergW.H. Saavedra-RiveraP.C. LarinB.S. LauA.R. RobinsonD.N. XiangY. WuM.N. SumnerC.J. LloydT.E. TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2+.Nat. Commun.2020111267910.1038/s41467‑020‑16411‑532471994
    [Google Scholar]
  29. SahaR.N. JanaM. PahanK. MAPK p38 regulates transcriptional activity of NF-kappaB in primary human astrocytes via acetylation of p65.J. Immunol.20071791071017109
    [Google Scholar]
  30. ChandraK.S. RameshG. The fourth-generation Calcium channel blocker.Cilnidipine. Indian Heart J.201365669169510.1016/j.ihj.2013.11.00124407539
    [Google Scholar]
  31. YamashitaT. KamikasedaS. TanakaA. Tozaki-SaitohH. CaaveiroJ.M.M. InoueK. TsudaM. New inhibitory effects of cilnidipine on microglial P2X7 receptors and IL-1β release: An involvement in its alleviating effect on neuropathic pain.Cells202110243410.3390/cells1002043433670748
    [Google Scholar]
  32. LiangH. HuH. ShanD. LyuJ. YanX. WangY. JianF. LiX. LaiW. LongH. CGRP modulates orofacial pain through mediating neuron-glia crosstalk.J. Dent. Res.202110019810510.1177/002203452095029632853530
    [Google Scholar]
/content/journals/lddd/10.2174/0115701808355819241118115155
Loading
/content/journals/lddd/10.2174/0115701808355819241118115155
Loading

Data & Media loading...


  • Article Type:
    Research Article
Keyword(s): calcium; CaMKII; cilnidipine; Lidocaine; neurotoxicity; p38 MAPK
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test