title: Neurotoxicity induced by bupivacaine via T-type calcium channels in SH-SY5Y cells.
abstract: There is concern regarding neurotoxicity induced by the use of local anesthetics. A previous study showed that an overload of intracellular calcium is involved in the neurotoxic effect of some anesthetics. T-type calcium channels, which lower the threshold of action potentials, can regulate the influx of calcium ions. We hypothesized that T-type calcium channels are involved in bupivacaine-induced neurotoxicity. In this study, we first investigated the effects of different concentrations of bupivacaine on SH-SY5Y cell viability, and established a cell injury model with 1 mM bupivacaine. The cell viability of SH-SY5Y cells was measured following treatment with 1 mM bupivacaine and/or different dosages (10, 50, or 100 µM) of NNC 55-0396 dihydrochloride, an antagonist of T-type calcium channels for 24 h. In addition, we monitored the release of lactate dehydrogenase, cytosolic Ca(2+) ([Ca2+]i), cell apoptosis and caspase-3 expression. SH-SY5Y cells pretreated with different dosages (10, 50, or 100 µM) of NNC 55-0396 dihydrochloride improved cell viability, reduced lactate dehydrogenase release, inhibited apoptosis, and reduced caspase-3 expression following bupivacaine exposure. However, the protective effect of NNC 55-0396 dihydrochloride plateaued. Overall, our results suggest that T-type calcium channels may be involved in bupivacaine neurotoxicity. However, identification of the specific subtype of T calcium channels involved requires further investigation.
authors: Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China. xjwen166@163.com
authors: Xianjie
authors: X
authors: Wen
authors: Shiyuan
authors: S
authors: Xu
authors: Hongzhen
authors: H
authors: Liu
authors: Quinguo
authors: Q
authors: Zhang
authors: Hua
authors: H
authors: Liang
authors: Chenxiang
authors: C
authors: Yang
authors: Hanbing
authors: H
authors: Wang
mesh_terms: D000779:Anesthetics, Local / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000633:toxicity; D002045:Bupivacaine / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000633:toxicity; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003521:Cyclopropanes / Q000633:toxicity; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009281:Naphthalenes / Q000633:toxicity; D009498:Neurotoxins / Q000633:toxicity*
chemical_list: D000779:Anesthetics, Local; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D003521:Cyclopropanes; D009281:Naphthalenes; D009498:Neurotoxins; C484287:NNC 55-0396; D007770:L-Lactate Dehydrogenase; D053148:Caspase 3; D002118:Calcium; D002045:Bupivacaine
references: J Recept Signal Transduct Res. 2010 Apr;30(2):115-20
references: 20218942
references: J Neurophysiol. 2008 Jun;99(6):3151-6
references: 18417624
references: Cell Calcium. 2006 Aug;40(2):89-96
references: 16759699
references: Reg Anesth. 1997 Sep-Oct;22(5):447-50
references: 9338907
references: Br J Anaesth. 2011 Dec;107(6):859-68
references: 22058144
references: J Neurochem. 2002 May;81(3):606-14
references: 12065669
references: J Cardiovasc Surg (Torino). 2011 Aug;52(4):567-77
references: 22034673
references: Pharmacology. 2010;85(5):295-300
references: 20453553
references: Biochem Pharmacol. 2004 Mar 15;67(6):1153-65
references: 15006551
references: Ann Surg Oncol. 2007 Feb;14(2):744-9
references: 17122989
references: Eur J Pharmacol. 2009 Aug 1;615(1-3):144-9
references: 19464284
references: Acta Pharmacol Sin. 2006 Dec;27(12):1547-52
references: 17112407
references: Anesthesiology. 2007 Jul;107(1):117-27
references: 17585223
references: Pflugers Arch. 2009 Mar;457(5):1161-72
references: 18784939
references: Brain Res. 1999 May 15;828(1-2):27-40
references: 10320722
references: Can J Anaesth. 2011 Jul;58(7):638-641
references: 21519981
references: Eur J Pharmacol. 2011 Apr 25;657(1-3):51-8
references: 21315711
references: Pharmacology. 2011;87(3-4):121-9
references: 21304223
references: Anesthesiology. 2002 Dec;97(6):1466-76
references: 12459673
references: Best Pract Res Clin Anaesthesiol. 2003 Sep;17(3):471-84
references: 14529015
references: Cardiovasc Drug Rev. 2005 Summer;23(2):173-96
references: 16007233
references: Anaesth Intensive Care. 2003 Aug;31(4):461-4
references: 12973972
references: Eur J Anaesthesiol. 2002 Aug;19(8):564-70
references: 12200945
references: Biochem J. 1997 Oct 1;327 ( Pt 1):251-8
references: 9355760
references: Reg Anesth Pain Med. 2011 Sep-Oct;36(5):444-51
references: 21857272
references: Dis Colon Rectum. 2008 Nov;51(11):1696-702
references: 18575938
references: Anesthesiology. 2005 Nov;103(5):1035-45
references: 16249678
references: Anesth Analg. 2009 Mar;108(3):997-1007
references: 19224816