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Acta Orthopaedica et Traumatologica Turcica logoLink to Acta Orthopaedica et Traumatologica Turcica
. 2023 Jan 1;57(1):23–29. doi: 10.5152/j.aott.2023.22121

Clinical, electrophysiological, and histomorphological effects of local coenzyme Q10 and vitamin E use in a rat model of peripheral nerve injury

Hakkı Can Ölke 1, Ömer Sunkar Biçer 2,✉, Akif Mirioğlu 2, Dilek Şaker 3, Işıl Öcal 4, Cenk Özkan 2
PMCID: PMC10152051  PMID: 36939361

Abstract

Objective:

This study aimed to investigate the clinical, electrophysiological, and histomorphological effects of local use of coenzyme Q10 and vitamin E combination in a rat model of peripheral nerve injury.

Methods:

Forty adult female Wistar-Albino rats weighing 250-350 g were kept in a room with a temperature of 20-22°C and a light/dark cycle of 12 hours. They had free access to food and water. The right sciatic nerves of 40 rats were transected and repaired. Subjects were divided into 4 groups: controls (control-4 weeks and control-8 weeks) and treatments (treatment-4 weeks and treatment-8 weeks). A combination of coenzyme Q10 and vitamin E was applied to the repair site by a catheter placed subcutaneously in the treatment group. Only transection-repair was done in the control group. All groups were divided into 2 subgroups for histomorphological, clinical, and electrophysiological experiments because of concerns about possible interference with histomorphological preparation (5 rats in each group). The experiment results were examined by the thermal plantar test, action potential and latency time measurements, and electron microscopy at the end of 4 and 8 weeks. The intact group was studied as the uninterrupted 10 left sciatic nerves of control for 4 weeks.

Results:

The mean thermal plantar test results of the intact group were better than those of the control groups (P < .05). However, there was no significant difference between the intact and treatment groups. In the histomorphological examination, the number of myelinated axons increased significantly, and the myelin structure was closer to that of the intact group, especially when the treatment-8 group was compared with the control groups (control-4: P < .0001, control-8: P < .01).

Conclusion:

Local use of coenzyme Q10 and vitamin E seems useful in the experimental rat sciatic nerve transection-repair model.

Keywords: Coenzyme Q10, Vitamin E, Sciatic nerve, Nerve injury, Nerve repair, Nerve regeneration

Highlights

  • The neuroprotective effect of coenzyme-10 has been demonstrated in previous studies. This study aimed to investigate the effects of local use of coenzyme Q10 and vitamin E combination derivatives in peripheral nerve injury in a rat sciatic nerve transection-repair model.

  • The results showed that local use of Coenzyme Q 10 and vitamin E improves nerve healing in rat sciatic nerve transection-repair model. Moreover, better results were obtained in eight weeks than four weeks CoenzymeQ 10 and vitamin E use.

  • The results indicate that local use of Coenzyme Q 10 and vitamin E may be beneficial in nerve injury in human however further clinical studies are needed to show this effect.

Introduction

Peripheral nerve injury, which is one of the important causes of functional morbidity, may occur for various reasons, including blunt or penetrating trauma, acute compression injuries, and burns, and is the most common injury form of the nervous system.1,2 Lipid peroxidation occurs due to nerve damage. Free radicals from lipid peroxidation cause oxidative stress and subsequent tissue damage.3,4 The healing process after nerve injury is adversely affected by free radicals rather than inflammation and edema.5

In experimental studies, steroids, anti-inflammatory agents, erythropoietin, insulin-like growth factor, nerve growth factors, ozone, antioxidants, and hormonal treatments have shown that antioxidant agents improve nerve regeneration by removing free oxygen radicals from the environment.2,6 Coenzyme Q10, acting as the primary free-radical scavenger in mitochondria, protects phospholipids, mitochondrial membrane proteins, and DNA from peroxidation and oxidative damage.7 The activity of coenzyme Q10 is restricted by p-glycoprotein, the product of the multidrug-resistance (MDR-1) gene.8 Vitamin E, which inhibits p-glycoprotein activity, increases the effectiveness of coenzyme Q10.8-10

The neuroprotective effect of coenzyme 10 has already been demonstrated in previous studies using either intraperitoneal or parenteral routes.11,12 To our knowledge, there are no reported studies in the English literatur on the effects of local use of coenzyme Q10 and vitamin E combination derivatives in peripheral nerve injury. In our study, the clinical, electrophysiological, and histomorphological effects of local coenzyme Q10 and vitamin E use in peripheral nerve injury were examined.

Materials and Methods

The animal study was conducted in accordance with the internationally accepted principles for laboratory animal use and care. An independent ethics committee approved all study protocols in Cukurova University (Date: January 15, 2021, Meeting number 1, Decision number 1).

Forty adult female Wistar-Albino rats, weighing 250-350 g, were maintained at a room temperature of 20-22°C with a 12-hour light/dark cycle and free access to water and food. The right sciatic nerves of 40 rats were transected and repaired. The rats were divided into 2 groups: treatment and control groups. Treatment and control groups were further divided according to the clinical, electrophysiological, and histomorphological examinations conducted at 4 and 8 weeks in each group and were named “control 4 weeks, test 4 weeks, control 8 weeks, and test 8 weeks groups,” with 10 rats in each group.

Five rats in each group were used in electrophysiological studies, and the remaining 5 rats were used in histomorphological studies separately because of concerns about possible interference from histomorphological preparation.

Uninterrupted 10 left sciatic nerves of control-4 weeks were evaluated as the intact group.

Surgical procedure

Anesthesia was achieved with the intraperitoneal administration of a mixture of 50 mg/kg ketamine and 5 mg/kg xylazine. Rats were placed and fixed on the operating table in the left lateral decubitus position. The surgical field was prepared by shaving the hair and applying betadine solution. Then, a 3-cm lateral longitudinal skin incision was created along the right thigh. The sciatic nerve was exposed by the dissection of the interval between the vastus lateralis and biceps femoris muscles. Sciatic nerves were transected with the scalpel, and the transected sciatic nerves were repaired with 10-0 prolene suture under microscopic magnification (Figure 1). Transection and repair method was performed in control groups without additional treatment. In the treatment groups (test-4 and test-8), a subcutaneous tunnel reaching the dorsal cervical region from the right thigh incision was created with the help of a clamp. The port was created with a pediatric feeding catheter, and a spinal needle was placed between the sciatic nerve repair line and the cervical region (Figure 2). In the treatment groups, rats received 0.01 mg/kg/day of coenzyme Q10 and vitamin E combination for 4-8 weeks with the port.

Figure 1.

Figure 1.

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Epineural repair of sciatic nerve.

Figure 2.

Figure 2.

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Creation and implementation of port. Spinal needle and pediatric feeding catheter (A). Merging of needle and catheter (B). Implementation of port (C). Connection between sciatic nerve and port (D).

Thermal plantar test

In the fourth and eighth weeks of the experiment, the rats were evaluated by measuring the response time on the Ugo Basile Thermal Plantar Test device. The rat was placed in a heat-conducting cage, and the conditions suitable for the measurement were provided. Both hind paws of the rat were heated with the Ugo Basile Thermal Plantar Test device (Varese, Italy) at 25°C and 20% power. The cut-off time was set at 25 seconds to avoid thermal damage. The response times of the rats were automatically detected and recorded by the device. This process was repeated 10 times for each paw, and the mean times were calculated.

Electrophysiological evaluation

Following the thermal plantar tests, rats were sacrificed by cervical dislocation, and right and left sciatic nerve segments were excised from the sciatic notch to the bifurcation and protected with the Krebs solution [(mM/L); NaCl 120, MgSO4 1.2, KCl 4.6, CaCl2 1.5, Glucose 11, KHPO4 1.2, NaHCO3 20] (Figure 3). After the Biopac Nerve Chamber (Goleta, Calif, USA) assembly was prepared with Krebs solution, it was connected to the computer with the Biopac MP30 device (Goleta, Calif, USA), and measurements were made with the BSL Pro program. During the electrophysiological experiment, 10 mV of stimulation was applied with the electrodes, and the action potential and the latency time measurements were made and recorded.

Figure 3.

Figure 3.

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Discrimination of response time (A), latency (B), and action potential (C) between the groups.

Electron microscopy

For electron microscopy, the sciatic nerve tissue of each animal was fixed in 5% glutaraldehyde in a phosphate buffer for 4 hours. The tissues were shaken twice in the buffer for 10 minutes and then fixed for the second time in a 1% osmium tetraoxide solution for 2 hours. Afterward, the tissue was dehydrated in graded ethanol, embedded in Araldite, and processed for electron microscopy. The stained sections were examined with a JEOL-JEM 1400 transmission electron microscope (Tokyo, Japan), and their micrographs were obtained.

Histomorphometric method

Semi-thin sections of 1 μm thickness were taken from sciatic nerve blocks, stained with toluidine blue, and examined under an Olympus BX50 light microscope (Tokyo, Japan), and 5 randomly selected areas were photographed. The numbers of myelinated fibers were counted using the Bioquant Omega II software analysis program (Heidelberg, Germany) connected to the microscope.

Statistical analysis

For the thermal plantar test and electrophysiological evaluation, categorical measurements were summarized as numbers and percentages, and numerical measurements were summarized as mean and standard deviation (median and minimum-maximum where necessary). The Kruskal–Wallis test was performed to compare non-normally distributed numerical measurements between more than 2 groups. The Mann–Whitney U test with Bonferroni correction was used for pairwise comparisons of the groups. Student’s t-tests were used for histomorphological evaluation. IBM’s Statistical Package for Social Sciences Version 20.0 package program (Westchester County, NY, USA) was used. The statistical significance level was taken as.05 in all tests.

Results

Thermal plantar test

The mean thermal plantar test response time measurements are given in Figure 3A. The mean thermal plantar test response time of the intact group was lower than the control-4 and control-8 groups (P < .05). However, there was no significant difference between the intact and treatment groups. The mean response times of the test-4 and test-8 groups had shorter mean times than both the control-4 and control-8 groups, although not statistically significant.

Electrophysiological evaluation

The mean latency times were 9.30 ± 0.27 ms in the intact group, 11.88 ± 0.70 ms in the control-4 group, and 10.50 ± 0.35 ms in the test-4 group. The mean latency times were 10.80 ± 0.27 ms in the control-8 group and 10.00 ± 0.35 ms in the test-8 group (Figure 3B).

The mean action potentials were 51.47 ± 0.77 mV in the intact group, 15.77 ± 5.57 mV in the control-4 group, and 21.22 ± 2.29 mV in the test-4 group. The mean action potentials were 16.51 ± 2.54 mV in the control-8 group and 24.65 ± 3.50 mV in the test-8 group (Figure 3C).

The median latency time in the intact group was lower than in the control-4 and control-8 groups (P < .05 for both). Although the mean action potential measurements of the treatment groups were higher than the control groups, they were not statistically significant (P > .05).

The mean response and latency times, also the action potentials were significantly better in the intact groups than the control groups (Table 1).

Table 1.

Mean, median, and standard deviation of latency, action potential, and thermal plantar test response time

Intact (n = 5) Control-4 (n = 5) Control-8 (n = 5) Test-4 (n = 5) Test-8 (n = 5) P
Latency 9.30 ± 0.27α,β
9.50 (9.00-9.50)		 11.88 ± 0.70ε
12.00 (11.00-12.90)		 10.80 ± 0.27
11.00 (10.50-11.00)		 10.50 ± 0.35
10.50 (10.00-11.00)		 10.00 ± 0.35
10.00 (9.50-10.50)		 <.001
Action potential 51.47 ± 0.77α,β
51.73 (50.42-52.34)		 15.77 ± 5.57
12.78 (11.12-23.46)		 16.51 ± 2.54
15.78 (13.98-19.61)		 21.22 ± 2.29
22.34 (17.90-23.27)		 24.65 ± 3.50
24.45 (20.67-28.24)		 .001
Thermal plantar test response time 10.60 ± 0.55α,β
11.00 (10.00-11.00)		 12.81 ± 0.89
13.10 (11.56-13.85)		 11.77 ± 0.09
11.81 (11.64-11.86)		 11.74 ± 0.31
11.68 (11.36-12.08)		 11.18 ± 0.39
11.04 (10.69-11.62)		 .001
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Data are summarized as mean ± standard deviation, and median (min-max).

α P < .05 compared to Control-4.

β P < .05 compared to Control-8.

ε P < .05 compared to Test-8.

Histomorphological evaluation

Electron microscopy of the intact group demonstrated that the mitochondria, agranular endoplasmic reticulum cisterns, neurofilaments, and neurotubules preserved their fine structures. The myelin sheath of the myelinated axons preserved their normal concentric lamellar structure. It was noted that in unmyelinated nerve fibers, a Schwann cell usually wraps more than one axon (Figure 4).

Figure 4.

Figure 4.

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Electron micrograph of the intact group. (A and B) In the intact group, myelinated nerve fibers (A) and unmyelinated nerve fibers (Um) are seen in normal fine structure. Schwann cells (Sc) show normal ultrastructure with cytoplasmic organelles and nucleus (N). Mitochondria (M), collagen fibers (Col), and myelin sheath (Ms) are indicated. Bar: 2 µm. (C) Semi-thin representative sections were used to count axons in the intact group.

In the electron microscopic examination of the control groups, diffuse edematous areas, especially hemorrhagic areas in the periphery of the blood vessels, were noted. Significant degenerative changes were observed in Schwann cells’ nucleus and cytoplasmic organelles. It was determined that the normal organization of myelin lamellae was disrupted in myelinated nerve fibers; the myelin sheath lamellae were invaginated into the axonal zone, and in some nerve fibers, they “evaginated” toward the nerve surface. Severe organelle destruction was observed in the axon, especially in the mitochondria. Lamellar disruption of the myelin sheaths was observed, and lamellar detachment was noted in some areas (Figures 5 and 6).

Figure 5.

Figure 5.

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Electron micrograph of the control group. (A and B) In the control group at week 4, the Schwann cell (Sc) reveals an increase in heterochromatin of the nucleus (N) and organelle destruction, especially in the cytoplasm. Axonal shrinkage (A) (*) and myelin sheath (Ms) destructions are seen in myelinated nerve fibers (arrows). Mitochondria (M), unmyelinated nerve fibers (Um), and collagen fibers (Col) are indicated. Bar: 2 μm. (C) Semi-thin representative sections are used to count axons in the Control-4 group

Figure 6.

Figure 6.

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Electron micrograph of the control group. (A and B) In the control group at week 8, destruction in Schwann cells cytoplasm (Sc) and nucleus (N) is observed. Degeneration of myelin sheath (ms) and myelin lamellae (arrows) is observed. Collagen fibers (Col), axon (A), perineurium (P), and unmyelinated nerve fibers (Um) are indicated. Bar: 2 μm. (C) Semi-thin representative sections were used to count axons in the Control-8 group.

According to the control groups, edema and hemorrhagic areas decreased in the treatment groups. Especially in the evaluation of test-8 groups, it was observed that degenerative changes occurred in some nerve fibers; even so, it was noted that in many myelinated nerve fibers, both the myelin sheaths and the typical delicate structures of organelles such as mitochondria, neurotubules, and neurofilaments in the axoplasm are preserved, and the axons maintain their structural integrity. Myelinated axons were surrounded by the Schwann cells (Figures 7 and 8).

Figure 7.

Figure 7.

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Electron micrograph of the test group. (A and B) In the test group at week 4, in some fibers (A) lamellar (Ms) destructions (arrows) are observed. The Schwann cell (Sc) shows nuclear chromatin increase in nucleus (N). Capillary vessels (CVs) are observed in the injury site. Unmyelinated nerve fibers (Um), collagen fibers (Col), endothelial cells (En), and erythrocytes (E) are indicated. Bar: 2 μm. (C) Semi-thin representative sections were used to count axons in the Test-4 group

Figure 8.

Figure 8.

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Electron micrograph of the test group. (A and B) In the test group at week 8, most of the myelinated nerve fibers generally show regular fine structures. Myelin sheath structure (Ms) in myelinated axons (A) and unmyelinated nerve fibers (Um) are normal. Schwann cells (Sc) are in normal ultrastructure with their nucleus (N) and cytoplasm. Fibroblast (F), collagen fibers (Col), capillary vessel (CV), erythrocyte (E), mast cell (Mh), and granules (gr) are indicated. Bar: 2 μm. (C) Semi-thin representative sections were used to count axons in the Test-8 group.

Sections obtained by staining with toluidine blue of sciatic nerves of rats belonging to intact, control, and treatment groups were examined with light microscopy. The number of myelinated nerve fibers belonging to the groups is given in Figure 9. Myelinated axons were increased significantly in the test-8 group compared with the control groups.

Figure 9.

Figure 9.

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Mean myelinated nerve fiber counts in all groups. (***P < .0001 and **P < .001).

Evaluation of light and electron microscopic sections was made by considering the severity of pathological changes according to the scoring in Table 2.

Table 2.

Microscopic scoring of groups

Intact group Control group Test group
4th week 8th week 4th week 8th week
Microscopic assessment − +++ +++ ++ −/+
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Normal histological structure: −; hemorrhage, edema, and cavitation areas: +; hemorrhage, edema, cavitation areas, and myelin sheath destruction: ++; hemorrhage, edema, cavitation areas, severe myelin sheath destruction, and degenerative changes in Schwann cells: +++.

Discussion

In our study, we found that the local use of the combination of ­coenzyme Q10 and vitamin E improves peripheral nerve repair in rat sciatic nerve transection-repair model compared to the control group, although the difference in electrophysiological assessment was not statistically significant.

Peripheral nerve injury is a widespread injury that severely affects the patients’ life due to their functional limitations.13,14 Despite the long history of peripheral nerve surgery, it is still difficult for surgeons and has unsatisfactory results for patients.15 To improve peripheral nerve injury treatment, steroids, anti-inflammatory drugs, and many vitamins have been studied in experimental animal models.16-18 Neuroprotective effects of antioxidants and the critical role of coenzyme Q10 in the renewal of other antioxidants have been shown. coenzyme Q10 protects phospholipids, mitochondrial membrane proteins, and DNA from peroxidation and oxidative damage.7,19,20 Galeshkalami et al21 demonstrated the antioxidant and neuroprotective activity of coenzyme Q10 based on its reducing effect on reactive oxygen species. A dose-dependent neuroprotective effect of coenzyme Q10 has been shown in a study on neurodegenerative diseases such as Huntington's and Parkinson's.22 Optic nerve studies have shown that the neuroprotective effect of a single dose of vitamin E is insufficient and that its effect increases when combined with coenzyme Q10.23,24

Histopathological examination is performed to evaluate nerve regeneration after peripheral nerve repair by evaluating Schwann cells, inflammatory edema, neurofibrillary structure, and fibroblast activity with light and electron microscopy.25 The number and diameter of axons at the level of injury can also be used to evaluate nerve regeneration.26 Histomorphological methods can evaluate the sensory function of peripheral nerves but are insufficient for assessing motor function.27-29 Electrophysiological evaluations of amplitude, latency, and conduction velocity are the best methods for demonstrating functional status after peripheral nerve injury.30 Due to the limitations of clinical, histomorphological, and electrophysiological tests and the correlation inconsistencies shown in some studies, it is recommended to apply histomorphological, clinical, and electrophysiological tests together to evaluate the regeneration after peripheral nerve injury.31,32 In our study, both histomorphological and clinical and electrophysiological methods were applied to overcome the limitations of the single use of these methods.

Moradi et al11 investigated the effects of intraperitoneal coenzyme Q10 use in the rat sciatic nerve crush model. They found that the number of myelinated fibers, axon diameter, and myelin sheath thickness were better in the treatment group than in the control group on the 14th day, and they showed that the recovery peak started on the 14th day and equalized on the 57th day in the treated group.11 However, in our study, the histomorphological evaluation of the eighth-week groups was superior to the fourth-week groups. Janzade et al12 evaluated the thermal plantar test and histomorphological assessment in their experimental study with rats, and they showed that the treatment group, which received coenzyme Q10, had superior results according to these evaluations. In our study, we found that the myelin structures, the number of myelinated axon fibers, and the morphological evaluation of organelles were significantly better in the treatment groups than in the control groups (P < .01).

Histological evaluations such as myelin structure and thickness in the coenzyme Q10 treatment group and normal groups were similar in Yildirim et al’s25 facial nerve crush injury study.25 Likewise, the myelin structure and thicknesses of the test-8 group were found to be close to normal in our study.

The importance of electrophysiological measurements has been emphasized in the literature, and the increase in the action potential value has been associated with the multiplicity of regenerated motor units. However, the decrease in latency time has been associated with myelination.33,34 Huang et al35 demonstrated that electrophysiological tests significantly show recovery and regeneration. The test-8 group’s latency time average was significantly less than the control-8 group in our study. On the other hand, the latency time average of the intact group was significantly less than the control group. Still, there was no significant difference between the treatment groups and the intact group.

Martins et al’s31 study has shown no correlation between histomorphological and electrophysiological evaluations. Likewise, the histomorphological evaluation of the test-8 group was significantly better than the control groups in our study, but neither the electrophysiological (except latency time) nor the thermal plantar test was statistically significant.

Effects of parenteral use of coenzyme Q10 and vitamin E have been reported in the literature, but there has been no study on local use. We preferred to use the dosage of local use which was described by previous optic nerve studies because local use dosage in peripheral nerve injury was not defined, which was a limitation for our study. Considering that clinical studies have notified dose-dependent neuroprotective effects of coenzyme Q10 in neurodegenerative diseases in the literature, it would be helpful to compare the efficacy of different doses.

In conclusion, local use of coenzyme Q10 and vitamin E improves nerve healing in a rat sciatic nerve transection-repair model. Better results were obtained in 8 weeks than in 4 weeks of treatment.

Footnotes

Ethics Committee Approval: Ethical committee approval was received from the Ethics Committee of Cukurova University, (Aproval Date and Number: 15.01.2021/1).

Author Contributions: Concept – H.C.Ö, Ö.S.B.; Design – H.C.Ö; Supervision – Ö.S.B.; Funding, Materials – Cukurova University; Data Collection and/or Processing – H.C.Ö, A.M.; Analysis and/or Interpretation – Ş.D., I.Ö.; Literature Review – A.M.; Writing – H.C.Ö, Ö.S.B.; Critical Review – C.Ö.

Acknowledgments: The authors would like to thank Doç. Dr. Aykut PELİT who has contributed to the data and analysis of the study.

Declaration of Interests: The authors have no conflicts of interest to declare.

Funding: Çukurova University.

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