Nerve growth factor and S100B: Molecular marker of neuroregeneration after injection of freeze-Dried platelet rich plasma

Rahmi; Desiana Radithia; Bagus Soebadi; Adiastuti Endah Parmadiati; Saka Winias

doi:10.1016/j.jobcr.2022.07.006

. 2022 Jul 19;12(5):570–574. doi: 10.1016/j.jobcr.2022.07.006

Nerve growth factor and S100B: Molecular marker of neuroregeneration after injection of freeze-Dried platelet rich plasma

Rahmi ¹, Desiana Radithia ¹, Bagus Soebadi ¹, Adiastuti Endah Parmadiati ¹, Saka Winias ^1,^∗

PMCID: PMC9361313 PMID: 35957941

Abstract

Introduction

Chronic orofacial pain is associated with nerve tissues damage. Pharmacological therapy has limited therapeutic results because it is generally only symptomatic treatment. Neuroregeneration is a process which is needed to repair damaged of nerve tissue through healing or regrowth of nerve tissue. The survival of nerve cells need neurotrophic factors including Nerve Growth Factor (NGF) and S100B. High platelet concentrations in Platelet Rich Plasma contain of many trophic factors which play an important role in peripheral nerve regeneration following nerve injury. The aim of the present study is to analyze the increased expression of NGF and S100B following injection of Freeze-Dried Platelet Rich Plasma (FD-PRP) on axonotmesis injury.

Methods

Fifty-four male wistar rats aged 3 months randomly divided into 3 groups; negative control group (without nerve injury and without FD-PRP injection), positive control group (nerve injury but without FD-PRP injection) and treatment group (nerve injury and FD-PRP injection). Axonotmesis nerve injury created by clamping the infraorbital nerve for 15 s. Application of FD-PRP by injection technique. Examination of NGF and S100B expression was obtained by immunohistochemistry examination with monoclonal antibodies (anti-NGF and anti-S100B). Samples were taken on the 14th day and 21st day.

Results

Treatment group showed significant increase on both NGF and S100B compare to positive control (p = 0,000 and p = 0,000, respectively).

Conclusion

FD-PRP injection is effective in inducing neuroregeneration by increasing NGF and S100B expression.

Keywords: Freeze-dried platelet rich plasma, Nerve growth factor, S100B, Neuroregeneration, Crush injury

Graphical abstract

1. Introduction

Orofacial pain is pain that occurs around the face and neck area. This pain can occur episodically, can also occur continuously and can be acute or chronic. Nociceptive pain is acute pain and is not accompanied by minimal nerve damage or nerve tissue damage. While neuropathic pain is pain that comes from nerve tissue damage that generally goes on chronically.¹^,²^,³ Orofacial pain is estimated to occur in about 23% of the general population, where 7%–11% experience chronic pain.¹ The results of international epidemiological studies indicate if orofacial pain is experienced by about 10% of the adult population, especially women.⁴ Chronic ongoing pain will cause emotional, psychological and social disorders which will ultimately affect the quality of life of patients.¹^,⁵

Neuropathic pain which is chronic pain can accompany several diseases such as diabetic peripheral neuropathy, HIV-associated neuropathy, chemotharp-induced peripheral neuropathy (CIPN), Post herpetic neuralgia (PHN) and trigeminal neuralgia.⁶ Neuropathic pain is a form of chronic pain that is very challenging to treat. During this pharmacological therapy to cope with neuropathic pain has many limitations on the results of therapy, where the drugs given are generally only symptomatic.⁷^,⁸ Only about 50% of patients who receive neuropathic pain treatment feel that the pain decreases but does not disappear completely, besides that often the side effects of the drug cannot be tolerated by the patient, so the most rational approach to neuropathic pain therapy is based on the mechanism of neuropathic pain.⁹

Neuroregeneration is a process needed for the treatment of neuropathic pain, in which nerve tissue repair occurs through regrowth or healing of nerve tissue, cells, or cell products. To survive nerve cells need neurotropic factors.¹⁰^,¹¹ These neurotrophic factors include Nerve Growth Factor (NGF) and S100B. Neural networks are able to produce these neurotropic factors, but sometimes they cannot be produced quickly or cannot be produced in sufficient quantities.¹² Exogenous neurotropic factor supplies will maintain an environment conducive to nerve regeneration, prevent nerve cell damage and will promote nerve regeneration.¹³

One technique that can be used in supplying exogenous neurotropic factors is by administering Platelet Rich Plasma (PRP)¹⁴^,¹⁵^,¹⁶ High platelet concentrations in PRP contain many neurotropic factors that play a major role in peripheral nerve regeneration after nerve injury.¹⁷^,¹⁸

2. Materials and methods

This study obtained ethical approval from the Institutional Research Ethics Commission with certificate number: 048/HRECC.FODM/II/2019. The research conducted was an experimental laboratory study with the research design is Post Test Only Control Group Design.

Fifty-four male Wistar rats aged 3 months, kept for a week to adapt in a cage that has been placed in a room with enough air and light to keep it moist, away from noise and not directly exposed to the sun. Wistar rats are fed with protein, carbohydrates, crude fiber, energy and water. Wistar rats are further divided into 3 groups namely; K1 group as negative control (without nerve injury and without FD-PRP injection) known as A group in day 14 and D group in day 21, K2 group as positive control group (nerve injury but without FD-PRP injection) known as B group in day 14 and E group in day 21and PRP group as treatment group (nerve injury and in FD-PRP injection) known as C group in day 14 and F group in day 21, where each group is divided into groups that will be observed on the 14th day and 21st day.

Freeze-Dried Platelet Rich Plasma is made at the Bank Tissue of Dr. Soetomo General Hospital from the heart of 20 wistar rats were centrifuged twice. The first centrifugation is at 4000 rpm for 10 min, to separate red blood cells from plasma while the second centrifugation is done at 4000 rpm for 10 min to remove platelet-rich plasma (1/3 the bottom of the tube) and a little platelet (2/3 the top of the tube). The 1/3 section under the tube is a Platelet Rich Plasma (PRP). Platelet concentrates were dissolved in PBS, collected and incubated at room temperature (30 °C) and centrifuged to remove platelet clots, calibrated and frozen at −83 °C for subsequent use. The PRP was then frozen for 12 h in −83 °C freezer before being lyophilized for 8–12 h. Allogenic PRP is lyophilized using the freeze-drying procedure, which involves freezing the PRP and then drying it using the sublimation drying technique.

Axonotmesis nerve injury that can induce neuropathic pain is done in the positive control group and the treatment group through infraorbital nerve clamping techniques using arterial clamps that are held for 15 s. This technique is based on the results of preliminary experiments that modify the technique.¹⁹^,²⁰^,²¹^,²²^,²³ This form of axonotmesis nerve injury will allow the nerve tissue to heal effectively through the regeneration process without involving surgery.²⁴

On the first day after crushing the infraorbital nerve (24 h post traumatic) an injection of FD-PRP gel was carried out, by adding Carboxymethyl cellulose (CMC 1%) to the FD-PRP with a ratio of 1: 1 so that the injection preparation was obtained with a 50% FD-PRP concentration in a volume of 1 mL with needle 23 G. The injection preparations were injected into each treatment group on the 14th day and 21st day. The 14th day observation group and the 21st day group were each terminated based on the day of observation. The infraorbital nerve tissue is then processed until a preparation to be stained is obtained. The immunohistochemistry perform on paraffin-embedded tissue section. NGF and S100B expression were observed by immunohistochemical examination using anti-NGF antibodies (SANTA CRUZ®⁾ while S100B expression was observed by using anti-S100B antibodies (SIGMA-ALDRICH®). NGF and S100B expressions were observed using a Nikon Eclipse E100light microscope which was® 400× magnification then calculated by modifying the method from Van de Schepop HAM. Research data were analyzed using ANOVA. ANOVA results that show the significant influence of FD-PRP on the expression of NGF and S100B, then further tests will be carried out further with the Fisher's Least Significant Difference (LSD).

3. Results

On immunohistochemical examination using anti-NGF monoclonal antibodies, a positive result is indicated by the brownish color on the result of painting. Furthermore, the brown area was observed using a Nikon Eclipse E100 light microscope with a magnification of 400×. In order to guarantee representation and reduce yield errors, observations are needed in a number of approximately 20 visual fields with a magnification of 1000×. The results of observations of NGF expression in the treatment can be seen in Fig. 1. The results show that the FD-PRP group as a treatment group that suffered a nerve injury and were given an injection of FD-PRP resulted in a greater increase in expression when compared to the K1 and K2 groups as a group that was not injected with FD-PRP.

Fig. 1 — Expression of NGF in infra orbital nerves by immunohistochemistry staining using anti-NGF antibodies and observations using a 400× magnification light microscope. The NGF expression is designated by the red arrow. (A) 14 days K1 group, (B) 14 days K2 group, (C) 14 days PRP group, (D) 21 days K1 group, (E) 21 days K2 group, and (F) 21 days PRP group.

From the analysis of the test statistical data Kolmogorov-Smirnov, the significance value of NGF expression was p = 0.515 (p > 0.05), so it can be concluded if the data of this study were normally distributed. Homogeneity test data was carried out with the Levene test in which the value of p = 0.025 (p <0.05), which indicates if the variants of the groups are not the same or there are significant differences (very varied) In cases where the results of the Levene test, the results show significant probability means the variance is not the same (different), this is not fatal to ANOVA and the analysis can still be continued as long as the group has the same sample size (proportionally). In this study, the overall number of samples in each group is the same, namely 9 samples in each group. ANOVA test results obtained NGF expression p value = 0,000 (p < 0.05), so it is obtained if there is a significant influence of the administration of FD-PRP on NGF expression (Table 1). The treatment group that has a significant difference from the other treatment groups can be seen from LSD post hoc test. The PRP group or treatment group that was injected with FD-RP days 14 and 21 overall had an increase compared to the K1 and K2 groups both on the 14th day and 21st day. The K2 groups on the 14th and 21st days were the group with nerve injuries however PRP was not injected, it also appeared to have increased expression but was lower when compared to the PRP group on day 14 and day 21. The mean NGF expression in the 21st day PRP group was seen to decrease. However, this decrease was not significant p = 0.919.

Table 1.

Statistical analysis data expression of NGF.

	Group	Mean ± SD	One-way ANOVA test	LSD test
	Group	Mean ± SD	One-way ANOVA test	A	B	C
Day 14	A	7,00 ± 0,816	0,000	–	0.007*	0.000*
	B	5,43 ± 0,976		–	–	0.000*
	C	10,71 ± 1,113		–	–	–
				D	E	F
Day 21	D	5,71 ± 0,488	0,000	–	0.001*	0.000*
	E	7,57 ± 0,976		–	–	0.004*
	F	9,14 ± 1,069		–	–	–

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* = there is a significant difference (p < 0.05).

On immunohistochemical examination using anti-S100B monoclonal antibodies, the expression of S100B was seen as a brownish color on the results of painting. The browning area was then observed using a Nikon Eclipse E100 light microscope at 400× magnification. In order to guarantee representation and reduce yield errors, observations are needed in a number of approximately 20 visual fields with a magnification of 1000×. The results of observations of S100B expression in the treatment can be seen in Fig. 2. The results showed that the PRP group as the treatment group that suffered sarfa injury and FD-PRP injections resulted in a greater increase in expression when compared to the K1 and K2 groups as the group not injected with FD-PRP.

Fig. 2 — S100B expression in infra orbital nerves by immunohistochemistry staining using anti-S100B antibodies and observation using a 400× magnification light microscope. The S100B expression is pointed out by a red arrow. (A) 14 days K1 group, (B) 14 days K2 group, (C) 14 days PRP group, (D) 21 days K1 group, (E) 21 days K2 group, and (F) 21 days PRP group.

The results of statistical analysis Kolmogorov-Smirnov on the S100B expression obtained significance value p = 0.698 (p > 0.05), so it was concluded if the data of this study were also normally distributed. Homogeneity test data was performed with the Levene test in which the value of obtained p = 0.177 (p > 0.05) was, which indicates if the variants of the groups are the same or there are no significant differences. ANOVA test results obtained S100B expression p value = 0,000 (p < 0.05), so it is obtained if there is a significant influence of the administration of FD-PRP on S100B expression (Table 2). The treatment group that has a significant difference from the other treatment groups can be seen from LSD post hoc test. The results showed that the PRP group had greater S100B expression when compared to the K1 group and the K2 group. In the PRP group as the treatment group that suffered nerve injury and injected FD-PRP seen a significant decrease in S100B expression on day 21 when compared with the PRP group on day 14, where p = 0.005.

Table 2.

Statistical analysis data expression of S100 expression.

	Group	Mean ± SD	One-way ANOVA test	LSD test
	Group	Mean ± SD	One-way ANOVA test	A	B	C
Day 14	A	7,00 ± 0,816	0,000	–	0.007*	0.000*
	B	5,43 ± 0,976		–	–	0.000*
	C	10,71 ± 1,113		–	–	–
				D	E	F
Day 21	D	5,71 ± 0,488	0,000	–	0.001*	0.000*
	E	7,57 ± 0,976		–	–	0.004*
	F	9,14 ± 1,069		–	–	–

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* = there is a significant difference (p < 0.05).

4. Discussion

The infraorbital nerve of the wistar rat is a sensory nerve and is a branching of the trigeminal nerve.²⁵^,²⁶^,²⁷ Research conducted by Moldovan M et al. in 2006, shows that there is no difference in growth capacity in the neuroregeneration process both in the sensory nerve and in the motor nerve.²⁸ The infraorbital nerves in the facial area are easy to access so that they will provide convenience when carrying out experimental procedures. Axonotmesis injury in experimental animals resulted from mechanical trauma in the form of infraorbital nerve clamping using artery clamp for 15 s.¹⁹^,²⁰^,²¹^,²²^,²³ This nerve damage will cause interference with nerve axons and myelin layers, but some or all mesenchymal structures such as perineurium are still intact.²⁴^,²⁹^,³⁰ This form of axonotmesis nerve injury will allow injured nerve tissue to heal effectively through the regeneration process without involving surgery.²⁴

Clinical applications of PRP are generally autologous (from the same individual), but in this study the PRP used was an allogenic PRP, that is, a PRP taken from different wistar rats. From studies comparing the effectiveness between autologous PRP and allogenic PRP obtained if there is no potential difference between the two.³¹ Zhang ZY in 2013 promoted that if allogenic PRP in gel form would not increase the immune response, so allogenic PRP could be an alternative choice when autologous PRP was not available or autologous PRP was inadequate.³² The administration of PRP was carried out by injection technique based on a study conducted by Ma in 2013, which found that if administering growth factors directly to an area injured by a nerve, it would protect nerve cells from death and would significantly increase the process of nerve regeneration.³³

The results indicate if the addition of exogenous neurotropic factors derived from FD-PRP will increase NGF expression. Schwann cells play an important role in the process of nerve regeneration where the schwann cells will make repairs themselves through the process of degeneration of axons and clearing myelin debris, promoting the regrowth of axons which will eventually regenerate axons through the process of remielinization.³⁴ In the degeneration process, Schwann cells will produce a variety of neurotropic factors, one of which is NGF released by Schwann cells and subsequently diffused diffusely in areas undergoing axon regeneration.³⁵ The process of nerve repair that takes place earlier and the supply of exogenous neurotropic factors and from schwann cells will be able to maintain an environment conducive to nerve regeneration and increase positive changes in nerve cells.¹³ The mean NGF expression in the 21st day treatment group (PRP group) was seen to decrease. But this decrease was not significant (p = 0.919). Ma et al. Stated that exogenous NGF in vivo would degrade rapidly. NGF is also known to be very sensitive to temperature, pH and other factors, so exogenous NGF activity in peripheral nerve regeneration is generally relatively short.³³ The rapid proliferation and viability of Schwann cells will support a faster regeneration process by providing bioactive substrates for axonal migration and the release of molecules that will regulate axon development.³⁶ K2 groups days 14 and 21 which were groups with nerve injuries but were not injected with PRP, also appeared to have increased expression but were lower when compared to the PRP groups on days 14 and 21 days. Immediately after the occurrence of nerve injury, schwann cells and macrophages will produce and secrete a number of neurotropic factors, but the improvement will not last long and is only temporary, especially in chronic nerve injuries.¹³^,³⁷^,³⁸ K1 groups in the 14th day and 21st day which were the normal group showed the lowest mean increase in NGF expression. NGF has a low concentration of healthy nerves, its expression will experience a significant increase after nerve injury.²³

From this study it was seen that the addition of exogenous neurotropic factors in the area of nerve injury had increased S100B expression. In acute peripheral nerve injury, S100B will be released from Schwann cells in the area of nerve injury that will activate the Receptor for Advanced Glycation End (RAGE) on infiltration macrophages as well as on activated Schwann cells. Further infiltration macrophages will release beneficial effects through cleansing of debris cells, as well as dead neutrophils. Macrophages will also release cytokines and neurotrophic factors Meanwhile, schwann cells that have been activated in the area of nerve injury also release cytokines and neurotrophic factors which are very important factors for repairing injured nerves.³⁹^,⁴⁰^,⁴¹The effect of S100B is very dependent on its concentration. Neurotropic factor is one of the factors that can regulate S100B expression in the form of increased expression.³⁹ K2 groups 14th and 21st days which are a group with nerve injuries that were not injected with PRP, appeared to have an increase in S100B expression that was higher than K1 14 and 21 days groups, but had lower S100B expression values when compared to PRP 14 and 21 days. S100B concentrations will be normal under physiological conditions but when a nerve injury occurs it will increase locally, which will release a number of tropic effects on the peripheral nervous system.⁴⁰

In the PRP group, it was seen that PRP 21st day experienced a significant decrease in S100B expression on PRP 14th day (p = 0.005). In inflammatory conditions, PRP has an anti-inflammatory effect.⁴² S100B is a neurotropic protein found in Schwann cells, where when a nerve injury occurs, the Schwann cells will be activated and carry out an immune reaction in the form of the production of S100B protein in large quantities. S100B is a very important protein in recruiting macrophages which in turn will produce pro-inflammatory cytokines.⁴³^,⁴⁴^,⁴⁵ The inflammatory process is an absolute process for the occurrence of the degeneration process which is subsequently followed by the regeneration process. During the inflammatory process, a number of pro-inflammatory cytokines show increased expression in a variety of cells, including schwann cells.

One of the pro-inflammatory cytokines produced by Schwann cells is IL-1β.⁴⁴^,⁴⁶ IL-1β is secreted by Schwann cells after stimulation by S100B.⁴⁴ Thioredoxin interacting protein (TXNIP) is a protein found in Schwaan cells. TXNIP has an important role for the receptor for advanced glycation end (RAGE) along with its ligand (protein S100B) in inducing IL-1β expression and secretion. RAGE and S100B themselves are also secreted by Schwann cells. The study of Sbai Q et al. in 2010 reported that when a nerve injury occurs, an increase in transient TXNIP expression will subsequently experience decreased expression and downregulation on the 15th day after a nerve injury.⁴⁴ This condition will give effect to the production of pro-inflammatory cytokines especially IL-1β, so that the inflammatory process soon ends. This is in line with the results of this study, which can be seen if the addition of PRP initially showed an increase in expression on the 14th day and subsequently decreased S100B expression significantly on the 21st day, so that from this study it was seen that the addition of PRP was likely to further shorten the process acute inflammation which is part of the process of nerve tissue degeneration so that the process of nerve regeneration can begin immediately.

Declaration of competing interest

The authors declare no conflict of interest.

Acknowledgement

This research funding supported by Faculty of Dental Medicine Universitas Airlangga Surabaya.

Contributor Information

Rahmi, Email: rahmikg28@gmail.com.

Desiana Radithia, Email: deisy.radithia@fkg.unair.ac.id.

Bagus Soebadi, Email: b.soebadi@gmail.com.

Adiastuti Endah Parmadiati, Email: adiastuti-e-p@fkg.unair.ac.id.

Saka Winias, Email: saka.winias@fkg.unair.ac.id.

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Nerve growth factor and S100B: Molecular marker of neuroregeneration after injection of freeze-Dried platelet rich plasma

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