In vivo and in vitro evidence of the neurotoxic effects of ropivacaine: The role of the Akt signaling pathway

Sun,Zhihua; Liu,Huining; Guo,Qulian; Xu,Xiaoping; Zhang,Zhong; Wang,Na

doi:10.3892/mmr.2012.1115

In vivo and in vitro evidence of the neurotoxic effects of ropivacaine: The role of the Akt signaling pathway

Authors:
- Zhihua Sun
- Huining Liu
- Qulian Guo
- Xiaoping Xu
- Zhong Zhang
- Na Wang
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Affiliations: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China, Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China, Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha 410008, P.R. China
Published online on: October 1, 2012 https://doi.org/10.3892/mmr.2012.1115
Pages: 1455-1459

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Abstract

There is a growing body of evidence that suggests common complications in regional anesthesia, including transient neurological syndrome, are caused by the neurotoxicity of local anesthetics (LAs). Ropivacaine is thought to be one of the safest LAs, however, there have been several studies detailing possible neurotoxic effects. At present, the exact molecular mechanism of ropivacaine-mediated neurotoxicity is unknown. The present study was designed to explore the possible mechanisms underlying the neurotoxicity of ropivacaine. The neurotoxic effects of ropivacaine were assessed in spinal cord by TUNEL staining for apoptosis and in cultured PC12 cells by cell viability assays. Protein kinase B (Akt) activation was evaluated by immunoblotting. Ropivacaine promoted apoptosis and caused cell death in a treatment group compared with a sham-operated group. Furthermore, ropivacaine significantly diminished Akt activation. There were significantly lower Akt levels in cells exposed to ropivacaine compared with controls. The present study demonstrated ropivacaine neurotoxicity in vivo and in vitro, mediated by the Akt signaling pathway. The neurotoxicity of apoptosis with concomitant cell death, mediated by ropivacaine, may offer an explanation for its adverse effects (e.g., transient neurological syndrome).

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1	Malhotra N, Chanana C, Roy KK, Kumar S, Rewari V and Sharma JB: To compare the efficacy of two doses of intraperitoneal bupivacaine for pain relief after operative laparoscopy in gynecology. Arch Gynecol Obstet. 276:323–326. 2007. View Article : Google Scholar : PubMed/NCBI
2	Iida H, Watanabe Y, Dohi S and Ishiyama T: Direct effects of ropivacaine and bupivacaine on spinal pial vessels in canine. Assessment with closed spinal window technique. Anesthesiology. 87:75–81. 1997. View Article : Google Scholar : PubMed/NCBI
3	Lee SJ, Shin TJ, Kang IS, Ha JH, Lee SC and Kim HJ: AMPK attenuates bupivacaine-induced neurotoxicity. J Dent Res. 89:797–801. 2010. View Article : Google Scholar : PubMed/NCBI
4	Radwan IA, Saito S and Goto F: The neurotoxicity of local anesthetics on growing neurons: a comparative study of lidocaine, bupivacaine, mepivacaine, and ropivacaine. Anesth Analg. 94:319–324. 2002.PubMed/NCBI
5	Maurice JM, Gan Y, Ma FX, Chang YC, Hibner M and Huang Y: Bupivacaine causes cytotoxicity in mouse C2C12 myoblast cells: involvement of ERK and Akt signaling pathways. Acta Pharmacol Sin. 31:493–500. 2010. View Article : Google Scholar : PubMed/NCBI
6	Zink W and Graf BM: Local anesthetic myotoxicity. Reg Anesth Pain Med. 29:333–340. 2004. View Article : Google Scholar
7	Zink W and Graf BM: The toxicity of local anesthetics: the place of ropivacaine and levobupivacaine. Curr Opin Anaesthesiol. 21:645–650. 2008. View Article : Google Scholar : PubMed/NCBI
8	Manning BD and Cantley LC: AKT/PKB signaling: navigating downstream. Cell. 129:1261–1274. 2007. View Article : Google Scholar : PubMed/NCBI
9	Werdehausen R, Fazeli S, Braun S, et al: Apoptosis induction by different local anaesthetics in a neuroblastoma cell line. Br J Anaesth. 103:711–718. 2009. View Article : Google Scholar : PubMed/NCBI
10	Xu F, Li T and Zhang B: An improved method for protecting and fixing the lumbar catheters placed in the spinal subarachnoid space of rats. J Neurosci Methods. 183:114–118. 2009. View Article : Google Scholar : PubMed/NCBI
11	Zhong Z, Qulian G, Yuan Z, Wangyuan Z and Zhihua S: Repeated intrathecal administration of ropivacaine causes neurotoxicity in rats. Anaesth Intensive Care. 37:929–936. 2009.PubMed/NCBI
12	Rose FX, Estebe JP, Ratajczak M, et al: Epidural, intrathecal pharmacokinetics, and intrathecal bioavailability of ropivacaine. Anesth Analg. 105:859–867. 2007. View Article : Google Scholar : PubMed/NCBI
13	Tan Z, Dohi S, Chen J, Banno Y and Nozawa Y: Involvement of the mitogen-activated protein kinase family in tetracaine-induced PC12 cell death. Anesthesiology. 96:1191–1201. 2002. View Article : Google Scholar : PubMed/NCBI
14	Lirk P, Haller I, Colvin HP, et al: In vitro, inhibition of mitogen-activated protein kinase pathways protects against bupivacaine- and ropivacaine-induced neurotoxicity. Anesth Analg. 106:1456–1464. 2008. View Article : Google Scholar : PubMed/NCBI
15	Huang Y, Li J, Zhang Y and Wu C: The roles of integrin-linked kinase in the regulation of myogenic differentiation. J Cell Biol. 150:861–872. 2000. View Article : Google Scholar : PubMed/NCBI
16	Greene LA and Tischler AS: Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci USA. 73:2424–2428. 1976. View Article : Google Scholar
17	Fasolato C, Zottini M, Clementi E, Zacchetti D, Meldolesi J and Pozzan T: Intracellular Ca²⁺ pools in PC12 cells. Three intracellular pools are distinguished by their turnover and mechanisms of Ca²⁺ accumulation, storage, and release. J Biol Chem. 266:20159–20167. 1991.
18	Boselli E, Duflo F, Debon R, et al: The induction of apoptosis by local anesthetics: a comparison between lidocaine and ropivacaine. Anesth Analg. 96:755–756. 2003. View Article : Google Scholar : PubMed/NCBI
19	McLure HA and Rubin AP: Review of local anaesthetic agents. Minerva Anestesiol. 71:59–74. 2005.PubMed/NCBI
20	Wildsmith JA and Selander DE: Measuring the relative potencies of bupivacaine and ropivacaine in spinal anesthesia. Reg Anesth Pain Med. 34:73–74; author reply 734–735. 2009. View Article : Google Scholar : PubMed/NCBI
21	Guryay D, Karaege GT, Katircioglu K, Ozkalkanli MY, Ozgurbuz U and Savaci S: The effects of an epidural infusion of ropivacaine versus saline on sensory block after spinal anesthesia. Reg Anesth Pain Med. 33:217–221. 2008. View Article : Google Scholar : PubMed/NCBI
22	Michalek-Sauberer A, Kozek-Langenecker SA, Heinzl H, Deusch E and Chiari A: Median effective local anesthetic doses of plain bupivacaine and ropivacaine for spinal anesthesia administered via a spinal catheter for brachytherapy of the lower abdomen. Reg Anesth Pain Med. 33:4–9. 2008. View Article : Google Scholar
23	Yuan Y, Guo Q, Ye Z, Pingping X, Wang N and Song Z: Ischemic postconditioning protects brain from ischemia/reperfusion injury by attenuating endoplasmic reticulum stress-induced apoptosis through PI3K-Akt pathway. Brain Res. 1367:85–93. 2011. View Article : Google Scholar
24	Nakajima T, Iwabuchi S, Miyazaki H, et al: Preconditioning prevents ischemia-induced neuronal death through persistent Akt activation in the penumbra region of the rat brain. J Vet Med Sci. 66:521–527. 2004. View Article : Google Scholar : PubMed/NCBI
25	Koike T, Tanaka S, Oda T and Ninomiya T: Sodium overload through voltage-dependent Na(+) channels induces necrosis and apoptosis of rat superior cervical ganglion cells in vitro. Brain Res Bull. 51:345–355. 2000.
26	Mukherjee PK, Marcheselli VL, Serhan CN and Bazan NG: Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci USA. 101:8491–8496. 2004. View Article : Google Scholar
27	Haller I, Hausott B, Tomaselli B, et al: Neurotoxicity of lidocaine involves specific activation of the p38 mitogen-activated protein kinase, but not extracellular signal-regulated or c-jun N-terminal kinases, and is mediated by arachidonic acid metabolites. Anesthesiology. 105:1024–1033. 2006. View Article : Google Scholar
28	Capdevila X, Pirat P, Bringuier S, et al: Continuous peripheral nerve blocks in hospital wards after orthopedic surgery: a multicenter prospective analysis of the quality of postoperative analgesia and complications in 1,416 patients. Anesthesiology. 103:1035–1045. 2005. View Article : Google Scholar
29	Kitagawa N, Oda M and Totoki T: Possible mechanism of irreversible nerve injury caused by local anesthetics: detergent properties of local anesthetics and membrane disruption. Anesthesiology. 100:962–967. 2004. View Article : Google Scholar