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Anesth Analg 2002;94:319-324
© 2002 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Neurotoxicity of Local Anesthetics on Growing Neurons: A Comparative Study of Lidocaine, Bupivacaine, Mepivacaine, and Ropivacaine

Inas A. M. Radwan, MD, Shigeru Saito, MD, PhD, and Fumio Goto, MD, PhD

Department of Anesthesiology & Reanimatology, Gunma University School of Medicine, Gunma, Japan

Address correspondence and reprint requests to Shigeru Saito, MD, PhD, Department of Anesthesiology & Reanimatology, Gunma University School of Medicine, 3-39-22, Showa-machi, Maebashi, 371-8511, Gunma, Japan. Address e-mail to shigerus{at}showa.gunma-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Local anesthetics can be neurotoxic. To test the hypothesis that exposure to local anesthetics produces morphological changes in growing neurons and to compare this neurotoxic potential between different local anesthetics, we performed in vitro cell biological experiments with isolated dorsal root ganglion neurons from chick embryos. The effects of lidocaine, bupivacaine, mepivacaine, and ropivacaine were examined microscopically and quantitatively assessed using the growth cone collapse assay. We observed that all local anesthetics produced growth cone collapse and neurite degeneration. However, they showed significant differences in the dose response. The IC50 values were approximately, 10-2.8 M for lidocaine, 10-2.6 M for bupivacaine, 10-1.6 M for mepivacaine, and 10-2.5 M for ropivacaine at 15 min exposure. Some reversibility was observed after replacement of the media. At 20 h after washout, bupivacaine and ropivacaine showed insignificant percentage growth cone collapse in comparison to their control values whereas those for lidocaine and mepivacaine were significantly higher than the control values. Larger concentrations of the nerve growth factor (NGF) did not improve this reversibility. In conclusion, local anesthetics produced morphological changes in growing neurons with significantly different IC50. The reversibility of these changes differed among the four drugs and was not influenced by the NGF concentration.

IMPLICATIONS: Local anesthetics induce growth cone collapse and neurite degeneration in the growing neurons. Mepivacaine was safer than lidocaine, bupivacaine, and ropivacaine for the primary cultured chick neurons.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Neurotoxicity is a concern because of reports of neurologic sequelae after spinal and epidural administration of local anesthetics (1). Also, laboratory experiments suggested that local anesthetics have the potential to be neurotoxic (2,3). Lidocaine may have more potential for neurotoxicity than bupivacaine; however, studies about other local anesthetics such as mepivacaine and ropivacaine are lacking (4).

Substantial evidence suggests that, in some cases, impairment results from a direct neurotoxic effect of the local anesthetic (2,5,6). The neural trauma and transient ischemia were suggested to be contributing factors in the neurological complications that accompanied regional anesthesia in clinical settings (7). The precise morphological changes induced by direct application of local anesthetics to neurons are not yet fully understood. Recently, Saito et al. (8) have showed that tetracaine produced irreversible changes in growing cultured neurons, and the growth cones were the most quickly affected. This report implies that the clinically used local anesthetic, tetracaine, might have significant effects on neuronal extension in developing or regenerating nervous tissue. Because local anesthetics are sometimes applied to sites where peripheral nerves may be growing or regenerating after injury (e.g., after exposure to chemical injury, mechanical injury, or neurodegenerative disease), their effects on growing neurons should not be ignored in clinical practice. In the present study, we have morphologically examined and compared the effects of the local anesthetics; lidocaine, bupivacaine, mepivacaine, and ropivacaine on growing neurites. To assess these effects quantitatively, we assayed growth cone collapse of cultured chick peripheral neurons. Growth cones play an important role in the development of the nervous system, such as guidance of neurite extension and establishment of neurite cytoarchitecture (9). The growth cone collapse assay is the established quantifying method of examining the effects of substances on developing neurites (10).


   Methods
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 Abstract
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 Methods
Results
 Discussion
 References
 
After approval by the Institutional Animal Care Committee, dorsal root ganglia (DRG) were dissected from lumbar paravertebral region of chick embryos at their seventh or eighth embryonal day. The tissues were plated to laminin-coated coverslips and cultured in F-12 medium supplemented as in Bottenstein et al.’s method (11) containing 100 µg/mL bovine pituitary extract, 2 mM glutamine, 100 U/mL penicillin, 100 µg/mL streptomycin, and 20 ng/mL mouse 7S nerve growth factor (NGF). Cultures were maintained at 37°C and at 5% carbon dioxide. The growth cones were microscopically examined at least 1 h before each experiment to check for the viability of the culture.

Lidocaine and bupivacaine were purchased from Sigma Co. Ltd. (St Louis, MO). Mepivacaine was purchased from US Pharmacopeia (Rockville, MD). Ropivacaine was obtained from AstraZeneca (London, UK). The local anesthetics were prepared in prewarmed fresh culture media at concentrations 100 times those to be obtained in the media. The volume of the added local anesthetic solution was 1/100 of the total volume of the culture media to obtain final concentrations of 10-4, 10-3, 10-2.3, 10-2, and 10-1.3 M of each of the local anesthetics for the dose response experiments. The local anesthetic solution was gently added to culture media of the DRG after 20 h in cultures. The pH of the culture media was measured using stat profile 5 and was not changed after the addition of the local anesthetic in each experiment. The osmolality of all solutions was measured with a vapor pressure osmometer; it was maintained within an acceptable range. A negative control was included in every experiment where no local anesthetic was added to the culture media to detect any time effect during the experiments. The cultured neurons were examined for the dose responses at 15, 30, and 60 min after the addition of the local anesthetics. In the experiment in which the effect of washout was examined, the tissues were kept in the incubator for 60 min after the addition of the drugs, and then the media were gently replaced twice with the fresh prewarmed media that was free from any local anesthetic drug. In an experiment to detect if the application of a larger concentration of NGF will affect the results of washout, fresh media with 100 ng/mL NGF was used as the replacement media

After the exchange of the media, the tissues were incubated for further 1, 2, and 20 h. The tissues were fixed with 4% paraformaldhyde in phosphate-buffered saline pH 7.4 containing 10% sucrose as described previously (12), and viewed with a 40 x phase objective using a phase-contrast microscope. Growth cones at the periphery of the explants were scored for the growth cone collapse assay providing that they were not in contact or close proximity to the other growth cones or neurite. Fifty to 100 growth cones were viewed on a coverslip for scoring and those without filopodia or lamellipodia were counted as collapsed (10).

Data are presented as mean and SD of six independent measurements. IC50 values in the growth cone collapse assays were calculated with the conventional Hill equation, Y = 100 x X/(X + IC50), using a curve fitting software, Origin 6.0J (Microcal Software, Northampton, MA). As Y = the percentage of growth cone collapse induced by the local anesthetic drug and X = the corresponding concentration of that drug. One-way analysis of variance for repeated mea-surements was used to determine statistically significant differences between the curves of growth cone collapse. Each result of the growth cone collapse assays was statistically analyzed by two-way analysis of variance with the Scheffe’s method using StatView 5.0 (SAS Institute, Cary, NC).


   Results
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Discussion
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Collapse of filopodia and lamellipodia of the DRG was observed after their exposure to local anesthetics followed by narrowing of the neurite shafts that were finally destroyed. All local anesthetics induced dose-dependent growth cone collapse. However, the dose response was significantly among between the four local anesthetics both at 15 and 60 min after exposure (Fig. 1).



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  		Figure 1. Dose response relations of local anesthetics-induced growth cone collapse. Percentage growth cone collapse assayed at 15 min exposure (A), and 60 min exposure (B). L.A. = local anesthetic; a = significantly different from the corresponding values of bupivacaine, mepivacaine (P<0.01); b = significantly different from the corresponding values of bupivacaine, mepivacaine, and ropivacaine (P < 0.01); c = significantly different from the corresponding values of ropivacaine and lidocaine (P<0.01); d = significantly different from the corresponding values of lidocaine, mepivacaine, and ropivacaine (P < 0.05, P < 0.01, P < 0.05 respectively); e = significantly different from the corresponding values of lidocaine, bupivacaine, and ropivacaine (P < 0.01).

 
The IC50 values for the growth cone collapse activity were approximately 10-2.8 M for lidocaine, 10-2.6 M for bupivacaine, 10-1.6 M for mepivacaine, and 10-2.5 M for ropivacaine at 15 min exposure. At 30 min after exposure, the approximate IC50 values were 10-3.8 M for lidocaine, 10-2.6 M for bupivacaine, 10-2 M for mepivacaine, and 10-2.9 M for ropivacaine. The IC50 values at 60 min were, 10-3.1 M for lidocaine, 10-2.7 M for bupivacaine, 10-2.3 M for mepivacaine, and 10-3 M for ropivacaine (Fig. 2). The time course trends of growth cone collapse showed no statistically significant differences among the four local anesthetics.



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  		Figure 2. The IC50 values of different local anesthetics at 15, 30, and 60 min exposure. L.A. = local anesthetic; a = significantly different from the corresponding values of lidocaine, bupivacaine, and ropivacaine (P < 0.01); b = significantly different from the corresponding values of bupivacaine, mepivacaine, and ropivacaine (P < 0.01); c = significantly different from the corresponding values of bupivacaine and mepivacaine (P < 0.05, P < 0.01 respectively); d = significantly different from the corresponding values of lidocaine and ropivacaine (P < 0.01).

 
The effects of washout were examined after the application of 1 mM lidocaine, 3 mM bupivacaine, 20 mM mepivacaine, and 4 mM ropivacaine. The percentage growth cone collapse was reduced to 24% ± 11.4% for lidocaine, 43% ± 17.7% for bupivacaine, 25% ± 13.8% for mepivacaine, and 11.3% ± 6.3% for ropivacaine after 1 h of the washout. Two hours after washout, the percentage growth cone collapse was reduced further except for the lidocaine-exposed DRG. The percentage of growth cone collapse at 20 h after washout was 94% ± 4.2% for lidocaine, 23.3% ± 16.4% for bupivacaine, 60% ± 20% for mepivacaine, and 21.3% ± 6.3% for ropivacaine with statistically significant differences between both lidocaine and mepivacaine and the control values (Fig. 3).



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  		Figure 3. Growth cone collapse after the washout of local anesthetics. Pre-exposure = the time point immediately before application of local anesthetics; Pre-wash = the time point immediately before washing out the local anesthetics-containing media (1 h after exposure); a = significantly different from the corresponding value of the four local anesthetic drugs (P < 0.01); b = significantly different from the corresponding control value and that of ropivacaine (P < 0.05); c = significantly different from the corresponding values of lidocaine and bupivacaine (P < 0.05); d = significantly different from the corresponding values of control cells and the other three drugs (P < 0.01).

 
Increasing the concentration of NGF in the culture media after the washout did not improve the reversibility of growth cone collapse. There were no statistically significant differences between the percentage growth cone collapse after the washout using the media with 100 ng/mL NGF and the corresponding values with the 20 ng/mL NGF-containing media, except at 2 h after washout of lidocaine. (P < 0.05) (Table 1).


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  		Table 1. Growth Cone Collapse Percentage After the Washout of Local Anesthetics-Containing Media
 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The growth cone, a highly motile structure at the end of the growing axons and dendrites, has a crucial role in neurological development. The direction and pattern of neurite growth is determined by the growth cone (13). Growth cones continuously explore their environment with special receptor molecules (14,15). Motile growth cones normally have a distinctive spreading morphology that support axonal extension and this morphology changes dramatically when they are confronted with repulsive molecules on the post-cell surface (12). There are several growth cone-collapsing factors naturally expressed in some areas of the developing nervous system (12). They are thought to be serving as repellent guidance cues, which prohibit neurites from extending into an inappropriate region (14). However, a general destruction of growth cones in growing or regenerating nervous tissues by externally applied substances could lead to the disturbance of the normal establishment of cytoarchitecture in the developing nervous system (16,17). In this study, we examined the growth cone collapsing activity of four local anesthetics at concentrations up to 10-1.3 M. All had a significant collapsing effect on the growth cones. However, the IC50 determined by the growth cone collapse assay was highest for mepivacaine and lowest for lidocaine. There was no statistically significant difference between the IC50 of bupivacaine and ropivacaine. This implies that lidocaine has a more intense potential neurotoxic effect on the developing or regenerating primary cultured neurons. In a previous study, we demonstrated that tetracaine has a growth cone collapsing activity with logarithmic IC50 of -2.9 ± 0.3 at 60 min exposure (8). Thus we suggest that tetracaine has a less growth cone collapsing effect than lidocaine (IC50 10-3.1 M at 60 min exposure).

In a previous histopathological study, Kanai et al. (18) demonstrated that 80 mM (2.17%) lidocaine induced neuronal damage in rat sciatic nerve. Electrophysiological studies have used desheathed peripheral nerve models to assess electrophysiologic neurotoxicity of clinically relevant concentrations of some local anesthetics. These studies showed that 5% (184.5 mM) lidocaine causes irreversible conduction block, whereas 1.5% (55.4 mM) lidocaine and 0.75% (23.1 mM) bupivacaine do not (19–21). No structural nerve damage was detected after intrafascicular injection of 0.5% (15.4 mM) bupivacaine in peripheral nerves of neonatal and juvenile rats (22). However, 1.9% (58.5 mM) bupivacaine induced significant histologic damage after intrathecal infusion in rats (23). It was difficult to compare these results, as the exposure methods were completely different from the present study. Gold et al. (24) showed that the application of lidocaine to DRG neurons isolated from adult rat causes neuronal death at concentrations larger than 10 mM. Thus, the potential neurotoxic effects observed in this study might be unique to growing neurons.

Local anesthetics can be neurotoxic, particularly in concentrations and doses larger than those used clinically (4). In the present study, we observed that four of the commonly used local anesthetics induced growth cone collapse at concentrations smaller than the clinically prepared concentrations. Lidocaine caused more extensive nerve damage than bupivacaine and mepivacaine in previous studies (3). In histopathologic, electrophysiologic, behavioral, and neuronal cell models, lidocaine seems to have a greater potential for neurotoxicity than bupivacaine at clinically relevant concentrations (4). These results are comparable to our results in respect to the comparative toxicity of local anesthetics.

Our observations suggest that local anesthetic-induced toxicity results from direct action of the drug. The pH of the culture media was not changed with the application of local anesthetics. Also, osmolality was maintained within an acceptable range. Sodium chloride, sodium salicylate, and sodium sulfate induced no significant growth cone collapse at concentrations up to 10-1 M in a previous study (25). Other histological studies support the suggestion that local anesthetics produce direct neurological damage (3,4). Increase in intracellular Ca2+ ions (24), and irreversible loss of membrane potential, which implies membrane disruption (18,20), have been reported as underlying mechanisms of lidocaine-induced toxicity and irreversible loss of membrane potential.

By washing out the local anesthetics-containing media after one-hour exposure, some reversibility of growth cone collapse was observed. However, when the assay was performed 20 hours after the washout, the percentage of growth cone collapse was significantly larger for lidocaine and mepivacaine than the control values (Fig. 3). However, the growth cone collapse induced by bupivacaine and ropivacaine was significantly attenuated at 20 hours after washout. Perhaps, the neurotoxic effects of bupivacaine and ropivacaine are more reversible compared with the other local anesthetics. Although the results of these washout experiments could not be directly applied in clinical settings, the issue that the neurotoxic effects induced by bupivacaine and ropivacaine were more reversible in vitro compared with the other local anesthetics should be considered. However, it is a remarkable fact that the growth cone collapse continued after removal of local anesthetics from the culture media and the number of intact growth cones did not completely return to the control values for any of the local anesthetics. It is suggested that the cellular processes involved in local anesthetic induced neuronal toxicity are initiated by exposure and proceed further even after stoppage of this exposure. Although the mechanism is not completely understood, the increase in intracellular Ca2+ ions as short as 5 min may be sufficient to induce delayed neuronal death (26). The washout effects were studied within 48 hours of plating (20 hours after the washout) to avoid contact of DRG with each other and the possibility of direct interactions among the cells.

If the effects demonstrated in this study occur in vivo, application of local anesthetics may interfere with the growth and regeneration of neuronal tissue. Thus, the potential risk of using local anesthetics in very young children should be considered.

In conclusion, local anesthetics induced morphological changes in growing neurons, impairing their growth in vitro. There are significant differences in this neurotoxic potential among local anesthetics. Also, different degrees of reversibility were observed after replacement of culture media. Although the results of this in vitro study could not be directly applied in vivo, the detrimental effects of local anesthetics to growing or regenerating neurons should be considered.


   Acknowledgments
 
Supported, in part, by Grants-in-Aid 10470313 and 11770834 for Scientific Research from the Ministry of Education, Science and Culture of Japan.


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Accepted for publication September 26, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press