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Anesth Analg 2003;97:506-511
© 2003 International Anesthesia Research Society

PAIN MEDICINE

Neurotrophic Factors Can Partially Reverse Morphological Changes Induced by Mepivacaine and Bupivacaine in Developing Sensory Neurons

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
 
Both bupivacaine and mepivacaine induce morphological changes in growing neurons. We designed this study to investigate the role of some neurotrophic factors (NTFs) in supporting developing neurons exposed to the deleterious effects of these drugs. Dorsal root ganglia were isolated from chick embryos and exposed to either bupivacaine or mepivacaine. After 60 min of exposure, the culture media were replaced with fresh culture media free from local anesthetics. NTFs—brain-derived NTF, glial-derived NTF, or neurotrophin-3—were added to the replacement media, and the cells were examined up to 48 h after the washout. The growth cone collapse assay was applied by a quantitative method of assessment. When the replacement media were not supported by any NTF, the growth cone collapse values were significantly larger than the control values at 20 h after the washout of mepivacaine and 48 h after the washout of either bupivacaine or mepivacaine (P < 0.05). However, when any of the NTFs were used, the collapsing activity was significantly attenuated, and growth cone collapse values showed no statistically significant differences in comparison with the control values at these time points (P > 0.05). We conclude that several NTFs support the recovery of neurons after exposure to local anesthetics. The supporting effects of NTFs on the reversibility of mepivacaine-induced collapse tended to be more obvious than those seen after the bupivacaine washout.

IMPLICATIONS: Three neurotrophic factors (NTFs) can partially support the reversibility of mepivacaine- and bupivacaine-induced growth cone collapse in growing primary cultured sensory neurons. The effect of NTFs is more apparent after mepivacaine than after bupivacaine washout.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Both clinical reports and laboratory experiments have suggested that local anesthetics can be neurotoxic (1). Local anesthetics exert deleterious effects in the developing nervous system in vitro (2,3). Their effects on developing neurons are a concern, because they are sometimes applied to nervous tissues that may be growing or regenerating after injury. In a previous study, we demonstrated that both bupivacaine and mepivacaine induce morphological changes in growing neurons. Their effects on cultured dorsal root ganglia (DRGs) continued even after removal of the local anesthetic from the culture media (2,3).

Developing neurons have access to and are responsive to a number of neurotrophic factors (NTFs); a family of peptide growth factors appears to function broadly as neuronal survival factors and as promoters of axon growth and branching (4). NTFs specifically influence neuronal activity by promoting development and maturation during embryonic life and by sustaining maintenance during adult life and regeneration after injury (5). Also, NTFs can protect neurons against several types of insults (e.g., excitotoxic, ischemic, and oxidative insults) (6).

The delivery of NTFs to primary neurons in culture after the washout of local anesthetics was designed to examine the capacity of NTFs to rescue these neurons. Embryonic chick DRGs were isolated for primary explant culture. Reversibility of the local anesthetic-induced morphological changes after the washout of local anesthetics was examined with and without the support of NTFs. We have already reported the effects of NTFs on the reversibility of neurological damage induced by lidocaine (7). In this study, we examined the effects of three NTFs—brain-derived NTF (BDNF), glial-derived NTF (GDNF), and neurotrophin-3 (NT-3)—after exposure of these sensory neurons to either bupivacaine or mepivacaine.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval by Institutional Animal Care Committee (Gunma, Japan), DRGs were isolated from lumbar paravertebral sites of chick embryos at the seventh embryonic day. DRGs were plated on laminin-coated coverslips and cultured in F-12 medium, supplemented as in Bottenstein et al.’s method (8), containing 100 µg/mL of bovine pituitary extract, 2 mM glutamine, 100 U/mL of penicillin, 100 µg/mL of streptomycin, and 20 ng/mL of mouse 7S nerve growth factor (NGF) (Gibco BRL, Rockville, MD). Cultures were maintained at 37°C and at 5% carbon dioxide. After 20 h in culture, the local anesthetic was prepared in prewarmed fresh culture media and gently added to the DRGs in culture. Bupivacaine was purchased from Sigma Co. Ltd. (St. Louis, MO), and mepivacaine was purchased from US Pharmacopeia (Rockville, MD). The volume of the added local anesthetic solution was 1:100 of the total volume of the culture media, to produce a final concentration of 4 mM for bupivacaine and 20 mM for mepivacaine. These concentrations were proven to produce comparable degrees of growth cone collapse in DRG neurons in a previous study (3). They produced 85%–90% collapse of the growth cones of the cultured neurons after 60 min of exposure.

Human recombinant BDNF and human recombinant GDNF were purchased from Gibco BRL. Human recombinant NT-3 was purchased from Sigma. To examine the washout effect with the different NTFs, the tissues were kept in the incubator for 60 min after the addition of the local anesthetic. Then, the media were gently replaced twice with the fresh prewarmed media that were free from the local anesthetics. NGF was not added to the replacement media, to investigate the effect of each of the other NTFs individually. The tissues were kept in the incubator for a further 48 h after the exchange of the media. Cells were scored for the growth cone collapse percentage after 1, 2, 20, and 48 h of washout. The replacement media contained either no NTF or one of the three NTFs—BDNF, GDNF, or NT-3—each in a separate experiment. All NTFs were tested at the concentration of 20 ng/mL. This concentration was previously shown to support the reversibility of lidocaine-induced growth cone collapse in vitro (7). A negative control (where the media exchanged though the cells were not exposed to the local anesthetics) was included in every experiment, to detect any time effect during the experiments or mechanical disturbances potentially associated with the washout.

The tissues were fixed with 4% paraformaldehyde in phosphate-buffered saline, pH 7.4, containing 10% sucrose, as described previously (9), and were viewed with a 40x phase objective by using a phase-contrast microscope (Axiovert; Zeiss, Germany). Growth cones at the periphery of the explants were scored for the growth cone collapse assay providing that they were not in contact with or in close proximity to the other growth cones or neurites. One-hundred growth cones were randomly chosen and viewed on a coverslip for scoring. The chosen regions were marked and repeatedly assessed at each time point throughout the experiment. Growth cones without filopodia or lamellipodia were counted as collapsed (10). Six measurements were recorded for each experimental condition.

Data are presented as mean and SD of six independent measurements. One-way analysis of variance for repeated measurements 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 Scheffé’s method by using StatView 5.0 (SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
When the DRGs were examined after 20 h in culture, most of neurites carried growth cones with lamellipodia and filopodia at their leading edges (Fig. 1, a and b). Addition of bupivacaine and mepivacaine to the culture media induced 89.3% ± 1.7% and 92.8% ± 1.1% growth cone collapse, respectively, as scored 60 min after exposure (Fig. 1, c and d).



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  		Figure 1. The growth cone collapse induced by mepivacaine and that after washout with and without the support of 20 ng/mL of neurotrophin-3 (NT-3). Photographs a, c, and e show a chosen group of neurites illustrated repeatedly, whereas photographs b, d, and f show another group. Photographs labeled a and b are for the dorsal root ganglia (DRG) neurons before the application of mepivacaine. Photographs labeled c and d show neurons after 60 min of exposure to 20 mM mepivacaine. Photograph e shows the neurons at 20 h after the washout with 20 ng/mL of NT-3. Photograph f shows DRG neurons without the support of neurotrophic factors at 20 h after washout of mepivacaine. Scale bar in photograph a indicates 25 µm.

 
At 1 and 2 h after the mepivacaine washout, the growth cone collapse values were significantly less than those observed before the washout for all NTFs (P < 0.05). There was no statistically significant difference between the values obtained with the addition of NTFs and those with no NTF at these time points (P > 0.05). After 20 and 48 h of washout, the growth cone collapse values scored with the addition of any of the NTFs were significantly less than those scored in the absence of NTFs (P < 0.05; Fig. 1e; Table 1). There was no statistically significant difference between the growth cone collapse values at 20 h after mepivacaine washout with NTFs and the preexposure values (P > 0.05). However, when no NTF was applied, the values of growth cone collapse were significantly increased compared with the preexposure values (P < 0.05; Figs. 1f and 2 ). The growth of the neurites was much diminished or even stopped in the absence of NTFs, blebs were formed at the leading edges and alongside the neurites, and neurites’ shafts were narrowed and ultimately destroyed (Fig. 1f). However, with the support of NTFs, the neurites showed greater outgrowth, with intact shafts and healthy growth cones (Fig. 1e).


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  		Table 1. Reversibility of Growth Cone Collapse at 20 and 48 Hours After the Washout With and Without Neurotrophic Factors (NTFs)
 


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  		Figure 2. The growth cone collapse induced by mepivacaine and that after the washout with and without neurotrophic factors (NTFs). Pre-exposure = before application of mepivacaine; pre-wash = 60 min of exposure to 20 mM mepivacaine. *Significantly larger than the preexposure values; {pi}significantly larger than the control values; #significantly less than values scored without NTFs. BDNF = brain-derived NTF; GDNF = glial-derived NTF; NT-3 = neurotrophin-3.

 
After the bupivacaine washout, the growth cone collapse was greatly attenuated up to 20 h after the washout, with some relapse observed at 48 h after washout (Fig. 3). However, the growth cone collapse values scored at all time points after the washout were significantly less than the prewash values (P < 0.05). There were no significant differences between the cells supported by NTFs and those with no NTF at 1, 2, 20, or 48 h after washout (P > 0.05). However, after 20 h of washout, the growth cone collapse values obtained with the addition of BDNF, GDNF, or NT-3 were not significantly different from the preexposure values (P > 0.05). On the other hand, significantly larger growth cone collapse values were observed at 20 h after washout with no NTF compared with the preexposure values (P < 0.05; Fig. 3), but they were not different from the control values (P > 0.05). At 48 h after washout, the growth cone collapse values obtained in the absence of the NTFs were significantly higher than the control values (P < 0.05). The growth cone collapse values scored 20 and 48 h after the washout of either bupivacaine or mepivacaine with the support of any of the NTFs were not statistically different from the control values (cells not exposed to local anesthetic) (P > 0.05; Figs. 2 and 3).



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  		Figure 3. The growth cone collapse induced by bupivacaine and that after the washout with and without neurotrophic factors (NTFs). *Significantly higher than the preexposure values; {pi}significantly higher than the control values. BDNF = brain-derived NTF; GDNF = glial-derived NTF; NT-3 = neurotrophin-3.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In a previous study, we demonstrated that both bupivacaine and mepivacaine induced morphological changes in growing neurons, impairing their growth in vitro (3). By washing out the local anesthetic-containing media after one hour of 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 mepivacaine than the control values (3). The growth cone collapse induced by bupivacaine was significantly attenuated at 20 hours after washout but did not return to the preexposure values. The reversibility of growth cone collapse was not improved by increasing the NGF concentration in the replacement media up to 100 ng/mL (3). In this study, the effects of mepivacaine and bupivacaine were observed up to 48 hours after the washout. The attenuation of growth cone-collapsing activity observed up to 20 hours after bupivacaine washout was followed by a significant relapse after 48 hours of washout. These late deleterious effects of local anesthetics on nerve growth could result from a mechanism that is independent of the initial toxicity. In a previous study, lidocaine inhibited axonal transport in vivo (11). Recently, Fagiolini et al. (12) showed that 0.2% lidocaine causes axonal transport blockade of NTFs and induces retinal ganglion cell death in rats. According to these studies, the late effects of local anesthetics observed in our study could be the result of a deficiency of NTFs in neuronal cells, a condition that initiates enzymatic activation, leading to nuclear fragmentation (13).

This study demonstrated that some NTFs can support the reversibility of two local anesthetic-induced growth cone collapses in cultured growing neurons. When the replacement media were not supported by any NTF, the growth cone collapse values were significantly larger than the control values 48 hours after the washout of either bupivacaine or mepivacaine and 20 hours after the washout of mepivacaine. However, when BDNF, GDNF, or NT-3 was added to the replacement media, the collapsing activity was significantly attenuated, and growth cone collapse values showed no statistically significant differences in comparison with the control values at these time points. The supporting effects of NTFs on the reversibility of mepivacaine-induced collapse tended to be more obvious than those seen after the bupivacaine washout. Although significantly larger growth cone collapse values were observed after 20 hours of bupivacaine washout with no NTF compared with the preexposure values, there were no significant differences between these values and those scored with the addition of NTFs. One possible explanation could be that the collapsing effect of bupivacaine was more significantly attenuated 20 hours after the washout without the addition of NTFs, whereas the mepivacaine-induced changes showed less reversibility so that the supportive effect of NTFs was more apparent after exposure to mepivacaine. However, when a relapse of growth cone collapse was observed 48 hours after the bupivacaine washout, the NTFs had a more significant role in preventing this relapse. In our previous study, the growth cone collapse values recorded 48 hours after lidocaine washout without the application of NTFs were significantly larger than those obtained with the support of NTFs (7). The reversing effect of NTFs on the local anesthetic-induced neuronal damage observed in this study is comparable to that observed after lidocaine washout, especially in the case of mepivacaine. Although the role of NTFs in reversing the local anesthetic-induced neural damage was well established in these studies, significant differences in the response to NTFs were observed among different local anesthetics.

The three NTFs—BDNF, GDNF, and NT-3—almost equally supported the reversibility of growth cone collapse induced by local anesthetic exposure. However, it is difficult to assess the comparative effectiveness of these factors depending on one variable: the growth cone collapse. Further morphological assessment of cytoskeletal elements and biochemical analysis of axonal transport may clarify the role of NTFs and differences between factors.

NTFs were previously shown to protect neurons against a number of adverse in vivo and in vitro conditions. In the developing nervous system, both BDNF and GDNF offered in vivo protection to embryonic chick spinal cord motor neurons against ethanol-induced neuronal damage (14). Both NT-3 and BDNF prevented or reduced the neurotoxicity of ototoxins in the cultured vestibular ganglion neurons (15). In addition, BDNF mitigates the neurotoxicity of ethanol and ethanol combined with hypoxic conditions in cultured hippocampal cells (16). Also, GDNF rescued dopaminergic neurons after 6-hydroxydopamine-induced trauma (17). The results of this study are also consistent with our recent observation that the NTFs—BDNF, GDNF, and NT-3—can rescue the cultured sensory neurons after lidocaine exposure (7). However, the NGF in a concentration up to 100 ng/mL did not significantly attenuate the growth cone-collapsing effect of local anesthetics (3). In another study, NT-3 supported the survival and neurite outgrowth of developing muscle sensory neurons from chicken lumbar DRGs better than NGF (18).

It was demonstrated that the action of NTFs is receptor mediated (19). Both BDNF and NT-3 exert their action through receptors belonging to the tyrosine kinase (trk) receptor family (18). As noted previously, the trk receptors are expressed in sensory neurons during the preinnervative stage of development (20). Of the trk receptor family, trkB and trkC are the high-affinity receptors responsible for signal transduction of BDNF and NT-3, respectively (21,22). The signal transduction component of the receptor for GDNF is the Ret messenger RNA that is also expressed in primary sensory neurons (23). NTFs may protect neurons against excitotoxic or metabolic insults by enhancement of calcium homeostatic mechanisms and suppression of reactive oxygen species accumulation (24). In addition to modulating the expression of calcium-regulating proteins, NTFs may induce the expression of antioxidant enzymes (25–27).

It has been proposed that accumulation of intracellular Ca2+ ions is involved with the lidocaine-induced toxicity (28). Also, there was a recent report of increased concentrations of glutamate in the cerebrospinal fluid after intrathecal injections of large concentrations of local anesthetics (29). It may be significant that the same events have been shown to be modulated by NTFs. NTFs attenuated glutamate-induced accumulation of peroxides and increases in intracellular Ca2+ concentration in hippocampal neurons in a previous study (30). Also, Ca2+ responses to glutamate were markedly attenuated in cultured hippocampal neurons pretreated with BDNF (31). However, NGF was less effective in suppressing Ca2+ responses to glutamate (32). The differences in the relative abilities of different NTFs to suppress Ca2+ and reactive oxygen species are likely due to differences in their specific signal transduction mechanisms and the gene products affected (30). Although the mechanism is obscure, these reports can provide some mechanistic explanation of our observations in this study. However, future studies should investigate the mechanism of this positive role of NTFs in reversing local anesthetic-induced changes in the nervous tissue. In addition, experiments should be designed to determine whether similar effects could be obtained in vivo or when NTFs are applied preemptively.

In conclusion, our study shows that some NTFs support the reversibility of the morphological changes induced by two local anesthetics—bupivacaine and mepivacaine—in developing neurons. The positive effect of NTFs on the reversibility of local anesthetic-induced collapse was more pronounced after exposure to mepivacaine than bupivacaine.


   Acknowledgments
 
Supported by Grant-in-Aid 13671562 for Scientific Research from the Ministry of Education, Science and Culture of Japan, Tokyo, Japan.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication March 13, 2003.





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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