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Acta Orthopaedica et Traumatologica Turcica logoLink to Acta Orthopaedica et Traumatologica Turcica
. 2021 Mar;55(2):87–93. doi: 10.5152/j.aott.2021.19183

Effects of tamoxifen therapy on sciatic nerve crush injury: An experimental study in rats

Ezgi Akar 1,✉, Selin Tural Emon 1, Mustafa Efendioğlu 1, Barış Erdoğan 1, Taner Engin 1, Fügen Vardar Aker 2
PMCID: PMC11229617  PMID: 33847568

Abstract

Objective

This study aimed to determine the effects of tamoxifen on sciatic nerve crush injury in a rat model using histopathological, histomorphometric, and immunohistochemical approaches.

Methods

In this study, 24 male Sprague-Dawley rats aged of 5 to 7 weeks and weighing between 300 g and 400 g were used. The rats were randomly divided into 3 groups: control (group C), sciatic nerve injury (group SNI), and sciatic nerve injury with tamoxifen (group SNT). The sciatic nerve crush injury model was performed using the De Koning’s crush force method. In group C, only a skin incision was made and then the skin was sutured. In group SNI, the injury model was performed but no treatment was applied. In group SNT, the injury model was executed, and then 40 mg/kg/day tamoxifen was given for 4 weeks by intraperitoneal methods. At the end of 4 weeks, all animals were killed using high doses of an anesthetic. Approximately, 2-cm sciatic nerve samples were obtained for histopathological, histomorphometric, and immunohistochemical analyses using the old skin incision.

Results

In the histopathological examination, vascular congestion and density of vacuolization were significantly lower in group SNT than in group SNI (p<0.05). In the histomorphometric examination, the mean sciatic nerve diameter was 306±62 μm in group C, 510±42 μm in group SNI, and 204±23 μm in group SNT. A significant difference was observed in the sciatic nerve diameter measurements among the 3 groups (p<0.05). In pairwise comparisons, the mean sciatic nerve diameter was significantly lower in group SNT than in group SNI (p=0.00002). Sciatic nerve diameter measurements of both groups were found to be significantly higher than group C (p<0.05). The mean epineurium thickness was 17±0.8 μm in group C, 32±2.5 μm in group SNI, and 17±0.8 μm in group SNT. A significant difference was observed in the epineurium thickness measurements among the 3 groups (p<0.05). In pairwise comparisons, the epineurium thickness was significantly higher in group SNI than in groups SNT and C (p<0.05). In the immunohistochemical analysis, S100 immunoreactivity was found significantly higher in group SNI than in the other 2 groups (p<0.05).

Conclusion

The histomorphometric, histopathological, and immunohistochemical data obtained from this study have shown that tamoxifen has a beneficial effect on sciatic nerve crush injury in the experimental rat model.

Keywords: Injury, Rat, S100, Sciatic nerve, Tamoxifen

Introduction

Peripheral nerve injury (PNI) is a common clinical condition that adversely affects the quality of life. Several causes, such as blunt or penetrating trauma, acute compression injury, and burns, can result in nerve injury, demyelination, and axonal degeneration (1). PNI has been reported in 2.8% of all trauma cases. The findings of crush injuries usually include development of endoneural–perineural edema, release of free oxygen radicals, and inflammatory responses as well as axonolysis, degeneration, regeneration, and remyelination (1). Furthermore, scar formation inside and around the nerves is among the pathological findings of this condition. Intraneural scar formation is also possible with the slightest manipulation of the nerves, and it forms a barrier to axonal regeneration that interrupts nerve conduction (2). Similarly, an extraneural scar prevents axonal regeneration and can increase nerve damage from scar tissues around the nerve (3). As a result, the loss of sense and/or motor functions can be seen on the affected nerve.

The treatment of PNIs is extremely challenging and depends on the type and location of the injury, the condition of the surrounding tissues, and other traumas affecting the patient. Both surgical and medical treatment options are available to treat these injuries. No treatment modality can provide an exact outcome for a PNI; however, surgical exploration seems to be the most effective treatment option despite its efficiency varying with the extent of injury. The treatment outcomes of PNIs are unfortunately not very satisfactory and have been the subject of several experimental studies. Steroids, anti-inflammatory agents, erythropoietin, insulin-like growth factor, nerve growth factors, ozone, as well as hormonal therapies have been used in this treatment regimen (1, 2).

Tamoxifen is an agent with antifibrotic and anti-inflammatory features, and it is a synthetic nonsteroidal selective estrogenic receptor modulator that prevents fibroblast proliferation via downregulation of primary TGF-1β (including IGF and VEGF). It is especially useful in the treatment of breast cancer. Moreover, tamoxifen has been found to be effective in the treatment of keloid formation and renal, retroperitoneal, pulmonary, and perivascular fibrosis (4). The antifibrinolytic efficiency of tamoxifen has been proved to be beneficial in the treatment of these diseases. Several studies supporting tamoxifen efficiency in the treatment of osteoporosis, infertility, gynecomastia, and cardiovascular diseases have been reported. Tamoxifen possesses antifibrotic and anti-inflammatory properties owing to the actions of TGF-β, IGF, and VEGF. Therefore, tamoxifen, which is used in the primary treatment for breast cancer, has been safely administered in the treatment of several diseases (4–6). Even if nerve integrity is preserved anatomically, adhesion of the nerve to the surrounding tissues directly prevents functional recovery. In clinical practice, new treatment modalities are essential to reduce both intraneural and extraneural scar tissues, prevent nerve degeneration, and perhaps contribute to regeneration. No study has so far been reported in the literature on the efficiency of tamoxifen for the treatment of PNIs. Therefore, to evaluate the efficiency of tamoxifen in sciatic nerve injury, vascular congestion, vacuolization, epineurium thickness, diameter measurement of the damaged nerves, and S100 immunoreactivity have been measured in rat models of sciatic nerve damage.

Materials and Methods

This study was conducted with 24 healthy, male Sprague-Dawley rats weighing 300–400 g. We did not use the female rats to avoid possible bias in statistical analyses owing to the effect of tamoxifen’s anti-estrogenic activity. All the rats were maintained at room temperature (22°C–26°C) under a 12-hour light/dark cycle. They were allowed to move freely in steel cages with ad libitum access to food and water. The rats were separated into the following 3 groups: control (group C), sciatic nerve injury (group SNI), and sciatic nerve injury with tamoxifen (group SNT). The sciatic nerve injury was induced using the De Koning’s crush force method (7). Anesthesia was administered using an intraperitoneal injection of ketamine hydrochloride (100 mg/kg) and xylazine (10 mg/kg). The animals were placed and fixed on an operating table in the prone position, and the surgical field was prepared by shaving the hair and applying betadine solution to the area. Next, a 3-cm skin incision was created between the trochanter major and knee joint. The vastus lateralis and biceps femoris muscles were separated, and the sciatic nerve was exposed. Using hemostatic forceps for 30 s, a crush injury was created on the nerves. The skin incision was closed by using a non-absorbable suture. Skin incision was only created on the rats in group C, and their skin was then sutured. The rats in group SNI were subjected to the sciatic nerve crush and received no treatment for the same. The sciatic nerve was crushed in the rats in group SNT, after which they received 40 mg/kg/day tamoxifen for 4 weeks with the intraperitoneal approach (8, 9). At the end of 4 weeks, all the rats were killed with the use of high doses of an anesthetic. By creating an old skin incision, approximately 2-cm sciatic nerve samples were collected en bloc with the surrounding muscle tissues.

The pathology samples were fixed in 10% neutral buffered formalin for 24 hours, and the tissue blocks were dehydrated in graded ethanol (80%, 95%, and 100% sequentially). After the blocks were sterilized with xylene, they were embedded in paraffin wax and 4 separate tissue samples of 5-μm length each were stained with hematoxylin and eosin. The prepared sections were finally subjected to histopathological and immunohistochemical examinations. The diameter and epineurium thicknesses of the sciatic nerve were measured to assess the development of fibrosis. The vacuolization and vascular congestion levels were also assessed for all nerve fibers. After histopathological evaluation, all images were transferred from the light microscope to the computer. All measurements were performed using the image analysis system.

Immunohistochemical analysis

After deparaffinization of the tissues, the nerve sample sections of 5-μm length were treated with primary antibody S100 by the streptavidin-biotin method and prepared for immunohistochemistry analysis. Semiquantitative analyses were then performed for the tissue materials to determine the immunoreactivity in the sample sections. For each slide, 4 random sections were selected and stained. The resultant S100 immunoreactivity of the 3 groups was recorded. The development of a brown precipitate in the preparations was considered as a positive response to S100 antibody. The following equation was used to calculate the H score:

H score=∑Pi (i+I) where i indicates weak, moderate, or strong labeling (scored 1, 2, or 3, respectively), and Pi is the percent of labeled cells for each intensity, ranging from 0% to 100%.

Statistical analysis

Data analysis was conducted using the Kruskal–Wallis and Mann–Whitney U-tests. The latter was used to compare the parameters without normal distribution within the same group, whereas the former was used to compare among more than 2 groups. For all groups alike, the maximum, minimum, mean, and standard deviation values were determined. A p value of <0.05 was considered to be statistically significant.

Results

Histopathological examination

Hemorrhage was recorded in the sciatic nerve samples of rats in the groups SNI and SNT. When all the nerve fibers were examined, the levels of vascular congestion and vacuolization were estimated for the rats of groups SNI and SNT (Figure 1). On statistical evaluation, the levels of vascular congestion and vacuolization in the rats from group SNT were found to have significantly decreased than those in group SNI rats (Table 1, 2).

Figure 1. a–c.

Figure 1. a–c

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Sciatic nerve light microscopic findings among the groups (hematoxylin and eosin)

Star: macrovacuolation; Arrow: vascular congestion

Table 1.

Comparison of vascular congestion among the groups

Groups
C SNI SNT Total
None, n (%) 6 (75) 0 (0) 4 (50) 10 (41.7)
Mild, n (%) 2 (25) 1 (12.5) 1 (12.5) 4 (16.6)
Moderate, n (%) 0 (0) 2 (25) 1 (12.5) 3 (12.6)
Severe, n (%) 0 (0) 5 (62.5) 2 (25) 7 (29.1)
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C: control; SNI: sciatic nerve injury; SNT: sciatic nerve injury with tamoxifen

Table 2.

Comparison of vacuolization among groups

Groups
C SNI SNT Total
None, n (%) 8 (100) 0 (0) 4 (50) 12 (50)
Mild, n (%) 0 (0) 0 (0) 1 (12.5) 1 (4.2)
Moderate, n (%) 0 (0) 2 (25) 1 (12.5) 3 (12.5)
Severe, n (%) 0 (0) 6 (75) 2 (25) 8 (33.3)
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C: control; SNI: sciatic nerve injury; SNT: sciatic nerve injury with tamoxifen

Histomorphometric examination

The diameter and epineurium thickness of the sciatic nerves were measured in all groups and statistically analyzed. The values were expressed as mean and standard deviation.

The mean sciatic nerve diameter measurements were found to be 306 μm (standard, 62 μm), 510 μm (standard, 42 μm), and 204 μm (standard, 23 μm) in the groups C, SNI, and SNT, respectively. A significant difference was observed among the sciatic nerve diameter measurements of all the groups. In pairwise comparisons, the sciatic nerve diameter measurement of the group SNT was found to be significantly lower than that of group SNI. The sciatic nerve diameter measurements of both the groups were significantly greater than those of group C (p<0.05) (Figure 2, Table 3).

Figure 2.

Figure 2

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Distribution of sciatic nerve diameter measurements among the groups

Table 3.

Statistical analysis of 3 groups

Thickness of epineurium
Groups Mean, μm Standard, μm Median, μm p
Control 16.95 0.8 16.85 CG-SNI CG-SNT SNI-SNT
Sciatic nerve injury 32.52 2.54 33 0.0011 0.9456 0.0035
Sciatic nerve injury with tamoxifen 17.16 0.8 17.25
Sciatic nerve diameter
Mean, μm Standard, μm Median, μm p
Control 306 62 305.6 CG-SNI CG-SNT SNI-SNT
Sciatic nerve injury 510 42 520 0.0512 0.0855 0.00002
Sciatic nerve injury with tamoxifen 204 23 200
H score
Mean, μm Standard, μm Median, μm p
Control 52.25 2.49 53 CG-SNI CG-SNT SNI-SNT
Sciatic nerve injury 89.75 3.45 90 0.0002 0.4933 0.0128
Sciatic nerve injury with tamoxifen 55.37 3.77 55.5
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CG: control group; SNI: sciatic nerve injury group; SNT: sciatic nerve injury with tamoxifen group

The mean epineurium thickness measurements were 17 μm (standard, 0.8 μm), 32 μm (standard, 2.5 μm), and 17 μm (standard, 0.8 μm) in the groups C, SNI, and SNT, respectively. The epineurium thicknesses among the groups were significantly different. In pairwise comparisons, the epineurium thickness was found to be significantly higher in the group SNI than in the groups SNT and C (p<0.05) (Figure 3, Table 3). However, no difference was noted between the epineurium thicknesses of groups SNT and C.

Figure 3.

Figure 3

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Distribution of epineurium thickness among the groups

Immunohistochemical examination

The H scores were found to be 52 (standard, 2.5), 90 (standard, 3.45), and 55 (standard, 3.78) in the groups C, SNI, and SNT, respectively. A significant difference was noted among the H score measurements of the groups. In pairwise comparisons, the H score was found to be significantly higher in the group SNI than in the groups SNT and C (p<0.05) (Table 3, Figure 4, 5). However, no significant difference was noted between the H scores of groups SNT and C.

Figure 4.

Figure 4

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Distribution of H score values among the groups

Figure 5. a–c.

Figure 5. a–c

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S100 expression in all groups; a: group control; b: group sciatic nerve injury; c: group sciatic nerve injury with tamoxifen. 400x. Arrow: positive staining

Discussion

PNIs are associated with the loss of sensory and motor function, leading to serious psychological and economic losses. Traffic accidents, firearm injuries, chemical injuries, cutting tool injuries, and crush traumas are some of the traumas that can be counted as the main causes (1). Although the most effective treatment after peripheral nerve trauma seems to be surgical repair (nerve anastomoses, flap, free-fat graft, and silicone cuffing), several healing-stimulating agents have been tested both in vitro and in clinical trials, although functional nerve regeneration with them has often been found insufficient (10–12). After inducing a sciatic nerve injury, functional response to medication can be evaluated by performing extremity changes and walking analysis in rats. The recorded items include limb paralysis or paresthesis, denervated adermotrophia, disappearance or decrease of reflexes, dragging, swollen and detached toe, foot position, toe spread, extensor postural thrust, hopping tests, and skin ulcer in the extremity (13, 14). Electrophysiological evaluation can be performed in rats to observe for electrophysiological changes that occur after experimental damage to the nerve, with possible improvement and regeneration after the treatment. The data recorded for this purpose include motor nerve conduction velocity, incubation period time, and amplitude (15). In our study, we performed only histopathological and immunohistochemical examinations to evaluate the response to tamoxifen treatment after the nerve injury.

Demyelination and axonal degeneration can develop in the damaged nerves. Incomplete nerve healing occurs in case of insufficient stimulus to stimulate regeneration in damaged neurons (8, 10, 11). In peripheral nerve crush trauma, demyelination and endoneurial edema occur in the nerve. In addition, IL-1, IL-6, and IL-10 from the traumatized nerve lead to the release of cytokines and transcription factors (NF-kappa B and c-Jun), such as TNF, and this inflammatory response causes accumulation of neutrophil infiltration in the distal nerve stump, pro-inflammatory monocytes, and macrophages (12, 16, 17). In addition, the decrease in the oxygenation level in the lesion area can causes changes in the arachidonic acid metabolism, resulting in the formation of superoxide anion radicals in the intracellular and extracellular regions. With nerve damage, an increase in the amounts of malondialdehyde, superoxide dismutase, and TNF levels secondary to oxidative stress in the tissues can occur (18). Antioxidant and anti-inflammatory agents can be used to prevent these activities in experimental studies and in clinical practice (11, 12). Improvement in the nerve tissues with the medications used can be evaluated biochemically by measuring these parameters (18).

Tamoxifen, which is a selective estrogen receptor modulator, has been used since several years for the treatment of breast cancer. Because of its antifibrotic efficacy, it has been shown to be effective in the treatment of desmoid tumors, retroperitoneal fibrosis, keloid formation, fibrotic mediastinitis, renal fibrotic disease, and pulmonary fibrosis both in vitro and in clinical settings (4, 5). In addition to its antifibrotic and anti-estrogenic activities, tamoxifen has also been shown to possess anti-inflammatory properties (19). However, no study on the evaluation of the effectiveness of tamoxifen in the PNIs has yet been reported in the literature. In this study, we evaluated the efficacy of tamoxifen in a the rat model of sciatic nerve crush injury.

The anti-inflammatory activity of tamoxifen occurs with the reduction in the synthesis of TGF-β, IGF, VEGF, and IL-1 (4). Macrophages and Schwann cells initiate wallerian degeneration, resulting in axon and myelin degeneration. Inflammatory cytokines (IL-1, IL-6, IL-10, and TNF-α), transcription factors (NF-kappa B and c-Jun), complement system, and arachidonic acid metabolites modulate this system (18, 20). PNI in the acute phase can lead to the development of dedifferentiation of the Schwann cells. With the redifferentiation of the Schwann cells over a period of time, the formation of new myelin sheath and axonal wrapping become essential for functional neural healing. In the early period (2–4 weeks) after a PNI, thickening of the nerve occurs owing to the formation of new myelin. The S100 expression of the Schwann cells is used to demonstrate the amount of myelination, and S100 immunoreactivity correlates with the amount of myelin in the Schwann cells (21). After a nerve injury, when the amount of Schwann cells and myelin production and the nerve thickness are at their maximum, S100 immunoreactivity is also at its maximum in the second week; after 4 weeks, myelin degeneration occurs and the expression of S100 decreases (22). Tamoxifen has also been demonstrated to stop the proliferation of malignant Schwann cells in malignant peripheral nerve sheath tumors with a mechanism that is independent of estrogen receptors (23). In our study, S100 immunoreactivity was found to be higher in the SNI group than in the SNT and control groups, which conforms to the literature data. This outcome has been associated with increased nerve thickness and increased myelin production. We also believe that the reduced wall thickness and S100 immunoreactivity in the SNT group is caused by the preventive effect of tamoxifen on Schwann cell proliferation. In the presence of local factors and compression of the surrounding tissues to the nerve, fibrosis and scar can develop in the epineural and perineural connective tissues. Excessive fibroblast proliferation causes contracture formation in the tissues around the nerve; this condition causes both deformation of the nerve structure and compression of the nerve by the surrounding tissues. Reportedly, 80%–90% of the reductions in the nerve diameter occur within 3 months of the injury (24, 25). Extraneural scar tissues reduce the blood flow in the damaged area owing to mechanical compression, leading to hypoxia of the nerve that prevents functional recovery (26). Therefore, several surgical and medical methods have been used to prevent the development of extraneural scar tissues. Doxorubicin, cis-hydroxyproline (27), anti-transforming growth factor-β1 antibody (28), and citicoline (29) have been reported to reduce scar formation when applied locally around the experimentally damaged nerves, although they have not yet been used in the clinic. Past studies have demonstrated that tamoxifen reduces scar formation and fibrosis. However, no study has yet evaluated its effectiveness on scar and epineural fibrosis after nerve damage (4–6, 30). Methylprednisolone acetate, which is commonly used for anti-inflammatory purposes, is also applied on surgical sites to reduce adhesion and scar tissues. However, Ikeda (31) has compared the effectiveness of hyaluronic acid and methylprednisolone and found that hyaluronic acid is more effective in reducing the intraneural and extraneural scar tissues and that methylprednisolone is not effective. Human amniotic membrane wrapping around or at the proximal end of damaged nerves (32), nerve wrapping with a synthetic material, autologous tissue flap technique, free fat graft (33), and silicone cuffing (34) are some of the treatment methods that are used to prevent fibrosis. Past experimental studies have reported that fibroblast count, scar formation, and nerve degeneration decrease with the application of the abovementioned methods for 4 weeks. In our study, we aimed to reduce intraneuronal fibrosis and Schwann cell proliferation that developed secondary to nerve injury. The antifibrotic and anti-inflammatory activities of tamoxifen, which we used in this study and which has been used by several in vitro studies, has been claimed by many clinical studies (4, 5, 35). Tamoxifen, an antineoplastic agent that is widely used in the treatment of breast cancer, reduces the antifibrotic activity, RNA transcription, and fibroblast proliferation through the inhibition of growth factors, such as TGF-β and IGF-1 (36). TGF-β is involved in inflammation modulation, inhibition of lymphocyte proliferation, and scar formation by stimulating fibroblast proliferation (8, 37). A past study has reported that tamoxifen suppresses paclitaxel-, vincristine-, and bortezomib-induced neuropathy via the inhibition of protein kinase C/extracellular signal-regulated kinase pathway (9). Tamoxifen has been reported to possess properties that inhibit Schwann cell proliferation (23). In addition, tamoxifen reduces collagen synthesis in mesangial cell cultures, prevents dermal fibroblast proliferation, impairs fibroblast function, and reduces wound contraction (38). Reduction of collagen-I and collagen-III expression by the action on myofibroblasts has been reported to inhibit the production of fibronectin, thereby disrupting the formation of extracellular matrix (19). In a rat model of sciatic nerve injury, we noted a decrease in the epineural thickness and sciatic nerve diameter in the tamoxifen-treated group, which reduced fibrosis and inhibited Schwann cell proliferation. Moreover, we estimated that the efficacy of tamoxifen improved fibrotic changes and nerve damage via TGF-β downregulation. The decrease in the S100 activity in the treatment group suggested that tamoxifen possesses healing efficacy through not only its antifibrotic activity but also reduction in the number of Schwann cells. In addition to its anti-estrogenic activities, tamoxifen possesses antifibrotic and anti-inflammatory activities.

Although tamoxifen is widely used in the clinic, its use is restricted owing to its side effects. The most common side effects in its long-term use include visual impairment, toxic neuropathy, cataract, and thromboembolic events (39, 40). The use of tamoxifen may not be suitable in different fibrotic phenomena owing to the risk of endometrial hypertrophy and endometrial cancer considering the weak estrogenic effect of the drug (41). Furthermore, its use in combination with radiotherapy may not be suitable for the lungs and skin considering the possible induction of fibrosis (42).

Our study had some limitations. First, we did not conduct any clinical evaluations to measure the sciatic nerve damage and the post-treatment responses. Histomorphometric changes with experimental injury and healing response after treatment were made only by histological and immunohistochemical evaluations. In addition, we did not conduct electrophysiological evaluation and walking analysis.

In conclusion, our histomorphometric, histological, and immunohistochemical data suggest that tamoxifen had a beneficial effect in the experimental rat sciatic nerve injury model. We thereby assume that the effect of tamoxifen can be primarily attributed to its antifibrotic and anti-inflammatory activities. In addition, the decrease in nerve diameter may also be related to the effect of tamoxifen on Schwann cells. In a PNI model, tamoxifen could reduce vacuolization and reduction of vascular congestion, nerve thickness, and epineurium thickness, as well as the S100 immunoreactivity. The treatment outcomes of PNIs are generally, unfortunately, not very satisfactory and debatable. Per our histomorphometric findings obtained from the experimental rat model of PNI, we believe that tamoxifen has a promising potential for clinical application. However, for the clinical application of tamoxifen in the treatment of PNI in humans, electromyographical findings of clinical studies using different experimental models and even clinical trials are warranted.

HIGHLIGHTS.

  • Tamoxifen has beneficial effects on sciatic nerve healing following crush injury and has a promising potential for clinical application.

  • Tamoxifen’s healing effect is primarily attributed to its antifibrotic and anti-inflammatory activities.

Footnotes

Ethics Committee Approval: Ethics committee approval was received for this study from the Ethics Committee of Sultan Abdülhamidhan Hospital (46418926-605.02).

Informed Consent: Because of this study is a experimental study informed consent was not received.

Author Contributions: Concept - E.A., S.T.E.; Design - E.A., M.E., T.E., B.E.; Supervision - F.V.A., M.E., E.A., S.T.E.; Resources - E.A., F.V.A., S.T.E.; Materials - M.E., B.E., T.E.; Data Collection and/or Processing - E.A., S.T.E., T.E., B.E.; Analysis and/or Interpretation - E.A., S.T.E.; Literature Search - E.A., S.T.E., M.E.; Writing - E.A., G.K.; Critical Review - E.A., S.T.E.

Conflict of Interest: The authors have no conflicts of interest to declare.

Financial Disclosure: The authors declared that this study has received no financial support.

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