Journal of Cranio-Maxillo-Facial Surgery xxx (2013) 1e6

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Peripheral nerve regeneration following transection injury to rat sciatic nerve by local application of adrenocorticotropic hormone Rahim Mohammadi a, *, Mohammad-Javad Yadegarazadi b,1, Keyvan Amini c, 2 a

Department of Clinical Sciences, Faculty of Veterinary Medicine, Urmia University, Nazloo Road, Urmia 57153 1177, Iran Department of Clinical Sciences, Faculty of Veterinary Medicine, Urmia Branch, Islamic Azad University, Urmia, Iran c Department of Veterinary Pathology, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan S7N 5B4, Canada b

a r t i c l e i n f o

a b s t r a c t

Article history: Paper received 23 June 2013 Accepted 4 November 2013

The objective of this study was to assess local effect of adrenocorticotropic hormone (ACTH) on the functional recovery of the sciatic nerve in a transection model. Sixty male healthy white Wistar rats were randomized into four experimental groups of 15 animals each: In the sham-operated group (SHAM), the sciatic nerve was exposed and manipulated. In the transected group (TC), the left sciatic nerve was transected and the cut nerve ends were fixed in the adjacent muscle. In the silicone graft group (SIL) a 10-mm defect was made and bridged using a silicone tube. The graft was filled with phosphated-buffer saline alone. In the treatment group a silicone tube (SIL/ACTH) was filled with 10 mL ACTH (0.1 mg/mL). Each group was subdivided into three subgroups of five animals each and regenerated nerve fibres were studied at 4, 8 and 12 weeks post operation. Behavioral testing, functional, gastrocnemius muscle mass and morphometric indices showed earlier regeneration of axons in SIL/ACTH than in SIL group (p < 0.05). Immunohistochemistry clearly showed more positive location of reactions to S-100 in SIL/ACTH than in SIL group. ACTH improved functional recovery and morphometric indices of sciatic nerve. This finding supports role of ACTH after peripheral nerve repair and may have clinical implications for the surgical management of patients after nerve transection. Ó 2013 Published by Elsevier Ltd on behalf of European Association for Cranio-Maxillo-Facial Surgery.

Keywords: Nerve repair Sciatic ACTH Local

1. Introduction To bridge nerve defects, at present, autologous nerve grafting offers the best outcome (Li et al., 2008). Peripheral nerve regeneration where there is considerable nerve tissue loss is still a concern in regenerative medicine (Elizabeth et al., 2005). Changes occur on both sides of the lesion when an axon is damaged (Malizos et al., 19970). Where a gap occurs between the cut ends of a nerve, proliferating Schwann cells develop from the ends, mostly the distal end, and form sequences of nucleated cellular strands which fill the gap (Bloom et al., 2012). Various techniques and methods have been offered to enhance functional recovery following nerve injury (Lindsay et al., 2010; Byrne et al., 2005; Doolabh et al., 1996). Experimental studies and clinical reports indicate that insertion of a conduit could be an interesting alternative to direct end-to-end suturing of nerve stumps or interposition of an autograft (Belkas

* Corresponding author. Tel.: þ98 441 2770508; fax: þ98 441 277 19 26. E-mail address: [email protected] (R. Mohammadi). 1 Tel.: þ98 441 2620124; fax: þ98 441 2622042. 2 Tel.: þ306 966 7288; fax: þ306 966 7439.

et al., 2004; Lundborg et al., 1997; Quarles, 2002). The conduits act to guide axons growing from the regenerating nerve stump, provide a microenvironment for dissemination of neurotrophic and neurotropic factors secreted by the injured nerve end, and prevent infiltration of fibrous tissue (Canpolat et al., 1999). It has been reported that using silicone tubes in bridging of nerve defects could be promising because it is inert and does not induce extensive scarring or degenerate after implantation (Chen et al., 2000). The advantages such as no donor morbidity, availability, affordability and no foreign reactions make silicone rubber chamber an attractive alternative to other standard grafts (Azizi et al., 2010; Byrne, 2004). Nerve regeneration can be enhanced by various growth factors that help to sustain the growing nerve (Nakamura et al., 1984). It has been demonstrated that ACTH-Iike peptides improve recovery from peripheral nerve damage, when administered either intraperitoneally (Strand and Kung, 1980) or subcutaneously (Bijlsma et al., 1981, 1983). The ACTH-like peptide Org 2766 (Met(O2)-Glu-His-Phe-D-Lys-Phe) has been shown to be effective in stimulating recovery when administered subcutaneously either as a long acting Zn3(PO4)2 complex or in saline solution (Bijlsma et al., 1981, 1983). However, daily oral administration of 500 mg of Org 2766 (dissolved in the drinking water) has also appeared to be

1010-5182/$ e see front matter Ó 2013 Published by Elsevier Ltd on behalf of European Association for Cranio-Maxillo-Facial Surgery. http://dx.doi.org/10.1016/j.jcms.2013.11.012

Please cite this article in press as: Mohammadi R, et al., Peripheral nerve regeneration following transection injury to rat sciatic nerve by local application of adrenocorticotropic hormone, Journal of Cranio-Maxillo-Facial Surgery (2013), http://dx.doi.org/10.1016/j.jcms.2013.11.012

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R. Mohammadi et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2013) 1e6

ineffective. Others have described the efficacy of various routes of administration of Org 2766 on functional recovery from sciatic nerve crush in the rat using a hot air stream method (Dekker et al., 1987). Studies on the beneficial effects of ACTH or the analogue on peripheral nerve regeneration have been mainly focused on crush models and literature is poor regarding works on transection models. A study was designed to study the local effects of ACTH on peripheral nerve regeneration, to attempt to determine if local ACTH does in fact reduce dysfunction after small gap nerve transection injury in the rat sciatic nerve transection model. Assessment of nerve regeneration was based on functional (walking track analysis), histomorphometrical and immunohistochemical (Schwann cell detection by S100 expression) assessment at 4, 8, and 12 weeks after surgery.

limb motor function (Basso et al., 1995). Although BBB is widely used to assess functional recovery in spinal cord injured animals, it has been demonstrated that it could be very useful in assessment of nerve repair processes in peripheral nerve injuries (Dinh et al., 2009). Scores of 0 and 21 were given when there were no spontaneous movement and normal movement, respectively. A score of 14 shows full weight support and complete limb coordination (Basso et al., 1995; Dinh et al., 2009). BBB recordings were performed by a trained observer who was blinded to the experimental design. The testing was performed in a serene environment. The animals were observed and assessed over a 4-min exposure to an open area of a mental circular enclosure. BBB scores were recorded once before surgery in order to establish a baseline control and again weekly thereafter to assess functional recovery during 12 weeks. 2.4. Functional assessment of nerve regeneration

2. Material and methods 2.1. Study design and animals Sixty male Wistar rats weighing approximately 290 g were divided into four experimental groups (n ¼ 20), randomly: a shamoperation group as normal control (SHAM), a transected control (TC), a silicone graft (SIL) and ACTH treated group (SIL/ACTH). Each group was further subdivided into three subgroups of five animals each and surveyed 4, 8 and 12 weeks after surgery. Two weeks before and during the experiments, the animals were housed in individual plastic cages with an ambient temperature of (23  3)  C, stable air humidity and a natural day/night cycle. The rats had free access to standard rodent laboratory food and tap water. All measurements were made by two blinded observers unaware of the analyzed groups. 2.2. Surgical procedure Animals were anesthetized by intraperitoneal administration of ketamine-xylazine (ketamine 5%, 90 mg/kg and xylazine 2%, 5 mg/ kg). The procedure was carried out based on the guidelines of the Ethics Committee of the International Association for the Study of Pain (Zimmermann, 1983). The University Research Council approved all experiments. Following surgical preparation in the sham-operated group, the left sciatic nerve was exposed through a gluteal muscle incision and after careful homeostasis the muscle was sutured with resorbable 4/0 sutures, and the skin was closed with 3/0 nylon. In the TC group, the left sciatic nerve was transected proximal to the tibio-peroneal bifurcation where a 7 mm segment was excised, leaving a 10 mm gap due to retraction of nerve ends. Proximal and distal stumps were fixed in the adjacent muscle with 10/0 nylon epineurial suture. No graft was interposed between the stumps. In the SIL group, a 7 mm nerve segment was resected to produce a 10 mm nerve gap after retraction of the nerve transected ends. The gap was bridged using a silicone tube, entubulating 2 mm of the nerve stump at each end. Two 10/0 nylon sutures were used to anchor the graft to the epineurium at each end. In the ACTH treated group (SIL/ACTH) the graft was filled with 10 ml ACTH (0.1 mg/mL). Sterile Vaseline was used to seal the ends of the tubes to avoid leakage The animals were anesthetized and euthanized with transcardiac perfusion of a fixative containing 2% paraformaldehyde and 1% glutaraldehyde buffer (pH 7.4) 4, 8 and weeks after surgery. 2.3. Behavioral testing Functional recovery of the nerve was assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale for rat hind

Walking track analysis was performed 4, 8 and 12 weeks after surgery based on the method of others (Bain et al., 1989). The lengths of the third toe to its heel (PL), the first to the fifth toe (TS), and the second toe to the fourth toe (IT) were measured on the experimental side (E) and the contralateral normal side (N) in each rat. The sciatic function index (SFI) of each animal was calculated by the following formula:

SFI ¼ 38:3  ðEPL  NPLÞ=NPL þ 109:5  ðETS  NTSÞ=NTS þ 13:3  ðEIT  NITÞ=NIT  8:8 In general, SFI oscillates around 0 for normal nerve function, whereas around 100 SFI represents total dysfunction. SFI was assessed in the NC group and the normal level was considered as 0. SFI was a negative value and a higher SFI meant the better function of the sciatic nerve. 2.5. Muscle mass Recovery assessment was also indexed using the weight ratio of the gastrocnemius muscles 12 weeks after surgery. Immediately after sacrificing of animals, the gastrocnemius muscles were dissected and harvested carefully from the intact and injured sides and weighed while still wet, using an electronic balance. 2.6. Histological preparation and morphometric studies Nerve mid-substance in SIL group, nerve mid-substance in ACTH treated group, midpoint of normal sciatic nerve (sham) and regenerated mid-substance of TC group were harvested and fixed with glutaraldehyde 2.5%. They were post fixed in OsO4 (2%, 2 h), dehydrated through an ethanol series and embedded in Epon. The nerves were sectioned in 5 mm sections in the middle, stained with toluidine blue and examined under light microscopy. Morphometric analysis was carried out using an image analyzing software (Image-Pro Express, version 6.0.0.319, Media Cybernetics, Silver Springs, MD, USA). Equal opportunity, systematic random sampling and two-dimensional dissector rules were followed in order to cope with sampling-related, fibre-location-related and fibre-size related biases (Geuna et al., 2003). 2.7. Immunohistochemical analysis In this study, anti-S-100 (1:200, DAKO, USA) was used as a marker for myelin sheath. Specimens were post fixed with 4% paraformaldehyde for 2 h and embedded in paraffin. Prior to immunohistochemistry nerve sections were dewaxed and rehydrated in PBS

Please cite this article in press as: Mohammadi R, et al., Peripheral nerve regeneration following transection injury to rat sciatic nerve by local application of adrenocorticotropic hormone, Journal of Cranio-Maxillo-Facial Surgery (2013), http://dx.doi.org/10.1016/j.jcms.2013.11.012

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(pH 7.4). Then the nerve sections were incubated with 0.6% hydrogen peroxide for 30 min. To block non-specific immunoreactions the sections were incubated with normal swine serum (1:50, DAKO, USA). Sections were then incubated in S-100 protein antibody solution for 1 h at room temperature. They were washed three times with PBS and incubated in biotinylated anti-mouse rabbit IgG solution for 1 h. Horseradish peroxidase-labelled secondary antibody was applied for 1 h. After that all sections were incubated with 3,30 -diaminobenzidine tetrahydrochloride chromogene substrate solution (DAB, DAKO, USA) for 10 min. The results of immunohistochemistry were examined under a light microscope. 2.8. Statistical analysis The results were expressed as means  SD. Statistical analyses were performed using PASW 18.0 (SPSS Inc., Chicago, IL, USA). Model assumptions were evaluated by examining the residual plot. Results were analyzed using a factorial ANOVA with two betweensubjects factors. Bonferroni test for pairwise comparisons was used to examine the effect of time and treatments. The differences were set at P < 0.05. 3. Results

Fig. 2. Bar graph shows the effects on the sciatic nerve function index (SFI). Data are shown as mean  SD. Local administration of ACTH with silicone grafting gave better results in functional improvement of the sciatic nerve than in SIL animals. *P < 0.05 vs SIL group.

3.1. BBB recovery

3.3. Muscle mass assessment

In order to assess hind limb improvement the open field locomotor was used. Fig. 1 shows BBB scores compared to the baseline. All experimental groups, except for sham, demonstrated the maximum degree of functional insufficiency one week after surgery. The ACTH treated group showed significant improvement in locomotion of the operated limb compared to the SIL group during the study (P < 0.05).

The mean ratios of the gastrocnemius muscle mass were assessed at the end of the experiment. There was a significant difference between the muscle mass ratios of the SIL/ACTH and SIL groups (P < 0.05). We found that in the ACTH treated group, the muscle mass ratio was greater than in the SIL group, and mass deficiency in the gastrocnemius muscle was improved by local application of ACTH (Fig. 3).

3.2. Sciatic nerve function index

3.4. Histological and morphometric findings

Fig. 2 shows the sciatic function index (SFI) values in all four studied groups. Before operation, SFI values in all animals were nearly zero. Following the nerve transection, the mean SFI diminished to 100 as a result of the complete deficit of sciatic nerve function in all groups. At the end of the study period, animals in the ACTH group achieved a mean value for SFI of 35.4  3.12 while in the SIL group a mean value of 53.6  4.23 was achieved. The statistical analyses showed that the improvement of nerve function was significantly (P < 0.05) different between SIL/ACTH and SIL groups and application of the ACTH in silicone conduit significantly accelerated functional recovery in the course of time.

Figs. 4e7 show the morphometrical analyses of regenerated nerves of the study groups. Significantly greater nerve fibre, axon diameter, and myelin sheath thickness were found in ACTH treated group 4 weeks post operation, compared to SIL group (P < 0.05). Sham-operation animals showed significantly greater nerve fibre and axon diameter, and myelin sheath thickness compared to SIL/ ACTH and SIL groups animals. In the case of myelin thickness there was no significant difference between SIL/ACTH and SIL groups, morphometrically (P > 0.05).

Fig. 1. BBB score for all experimental groups. Local administration of ACTH with silicone grafting gave better scores than in SIL group. *P < 0.05 vs SIL group.

Fig. 3. Gastrocnemius muscle weight measurement. The gastrocnemius muscles of both sides (operated left and unoperated right) were excised and weighed in the experimental groups at 12 weeks after surgery. Data are shown as mean  SD. *P < 0.05 vs SIL group.

Please cite this article in press as: Mohammadi R, et al., Peripheral nerve regeneration following transection injury to rat sciatic nerve by local application of adrenocorticotropic hormone, Journal of Cranio-Maxillo-Facial Surgery (2013), http://dx.doi.org/10.1016/j.jcms.2013.11.012

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Fig. 4. The graph shows the results of number of nerve fibres. The mean number of nerve fibres in SHAM animals was nearly 8326  211 (mean  SD). Both groups of SIL and SIL/ACTH showed the lower number of fibres than the sham-operated animals even at the end of the study period. Data are presented as mean  SD. *P < 0.05 vs AG group.

3.5. Immunohistochemistry In immunohistochemistry S-100 protein was broadly detected in the semi thin sections of regenerated nerves. The expression of S100 protein signal was located mostly in the myelin sheath. The axon also presented a feeble expression, signifying that Schwann cell-like phenotype was present around the myelinated axons. In both SIL/ACTH and SIL groups, the expression of S-100 and the outcomes were similar to those of the morphometrical assessments (Fig. 8). 4. Discussion Peripheral nerve repair has always been a great challenge in regenerative medicine and various techniques have been implemented to facilitate regeneration process in damaged nerve (Rustemeyer et al., 2010; Biglioli et al., 2012; Sforza et al., 2012). The findings of this study demonstrated that use of ACTH in a silicone conduit resulted in faster functional improvement of the sciatic

Fig. 5. The graph shows the quantitative results of mean diameter of nerves fibres. The mean diameter of nerve fibres in SHAM animals was nearly 12.6  0.11 (mean  SD). Both groups of SIL and SIL/ACTH showed the lower mean diameter of nerve fibres than the sham-operated group even at the end of the study. Data are presented as mean  SD. *P < 0.05 vs AG group.

Fig. 6. The graph shows the quantitative results of mean diameter of axons. The mean diameter of axons in SHAM group was nearly 7.4  0.06 (mean  SD). Both groups of SIL and SIL/ACTH showed the lower mean diameter of axons than the sham-operated group even at the end of the study period. Data are presented as mean  SD. *P < 0.05 vs SIL group.

nerve during the study period. Left gastrocnemius muscle mass was considerably greater in the SIL/ACTH than in the SIL animals, representing indirect indication of successful end organ reinnervation in the ACTH treated animals. Although morphologic and functional data have been used to assess neural regeneration after induced crush injuries, the correlation between these two assessment types is usually poor (Kanaya et al., 1996; Dellon and Mackinnon, 1989; Shen and Zhu, 1995). Classic and newly developed methods of assessing nerve recovery, including histomorphometry, retrograde transport of horseradish peroxidase and retrograde fluorescent labelling (Mackinnon et al., 1985, 1988) do not necessarily predict the reestablishment of motor and sensory functions (Castaneda and Kinne, 2002; Almquist and Eeg-Olofsson, 1970; Varejao et al., 2004). Although such techniques are useful in studying the nerve regeneration process, they generally fail in assessing functional recovery (Shen and Zhu, 1995). Therefore, research on peripheral nerve injury needs to combine functional and morphologic assessments. At week 12 morphometric values of regenerated nerve fibres indicated significant differences between the SIL and SIL/ACTH animals, demonstrating a positive effect of local use of ACTH on the nerve repair.

Fig. 7. The graph shows the quantitative results of mean thickness of myelin sheath. The mean thickness of myelin sheath in SHAM group was nearly 2.4  0.04 (mean  SD). Both groups of SIL and SIL/ACTH showed the lower mean diameter of axons than the sham-operated group even at the end of the study period.

Please cite this article in press as: Mohammadi R, et al., Peripheral nerve regeneration following transection injury to rat sciatic nerve by local application of adrenocorticotropic hormone, Journal of Cranio-Maxillo-Facial Surgery (2013), http://dx.doi.org/10.1016/j.jcms.2013.11.012

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Fig. 8. Immunohistochemical assessment of the nerves 12 weeks post operation from (A) midpoint of TC, (B) SIL, (C) SIL/ACTH and (D) SHAM. Positive staining of the myelin sheathassociated protein S-100 (arrows) around the nerve fibre is shown. This indicates well organized structural nerve reconstruction in ACTH treated nerve compared to that of the SIL. Scale bar: 10 mm.

Castaneda and Kinne, 2002 suggested that entrance of sprouts from the proximal nerve stump at the distal nerve stump does not essentially indicate improvement in nerve function. Information taken from BBB scale may be invaluable in evaluation of peripheral nerve process. Results of the present study showed that the ACTH treated animals were improved in locomotion of the operated limb compared to the SIL group during the study period. Walking track analysis has repeatedly been used to reliably assess functional improvement after nerve regeneration in a rat model (Bain et al., 1989; De Medinaceli et al., 1982). Various materials have been employed to be used as nerve guides, including non-biodegradable and biodegradable materials. Due to its inert and flexible characteristics, the silicone tube was one of the first and most widely used conduits to repair the transected nerves (Byrne, 2004). Several studies have documented that peptides related to ACTH exert a neurotrophic effect on the nervous system that results in enhanced recovery of function after peripheral nerve crush (Strand and Kung, 1980; Bijlsma et al., 1981; Bijlsma et al., 1983; Edwards and Gispen, 1985; Strand and Smith, 1986; De Koning et al., 1986; Verhaagen et al., 1987). The ACTH-(4-9) analogue Org 2766 has enhanced recovery of function after mechanical nerve crush models. This neurotrophic action has been demonstrated at the histological, neurophysiological, and behavioural levels and involved both sensory and motor modalities in young, adult, and aging rats (Gispen et al., 1987). There is evidence that exogenously administered peptides has mimicked or amplified endogenous signals that play a role in the onset of the neuronal response to injury (Edwards and Gispen, 1985; Edwards et al., 1984). Although our initial study indicated the neuroprotective effect of local ACTH in peripheral nerve damages, findings regarding the molecular mechanisms resulting in the neuroprotective effect are still lacking. We have not given the histological and molecular evidence for neuroprotective action of ACTH. This may be considered as a limitation to our study. The authors stress that the aim of the current investigation was to evaluate a single local dose and clinical treatment potential of ACTH on nerve repair. The results of the study indicate that a single local administration of ACTH at the site of transected nerve may be of benefit after silicone conduit tubulization. The mechanism of neuroprotective action remains to be investigated. 5. Conclusion This study demonstrated that local application of ACTH could accelerate functional recovery after transection of sciatic nerve. This finding supports the role of ACTH after peripheral nerve repair and may have clinical implications for the surgical management of patients after nerve transection. We used a reduced dosage (0.1 mg/ mL) applied locally in our study design. Thus, doseeresponse investigations should be performed for ACTH to determine the

combination of the graft and compound that achieve the highest effectiveness in nerve transection models.

Acknowledgments The authors would like to thank Mr. Matin, Mr. Valinezhad and Mr. Ansarinia, the Department of Clinical Sciences, and Mr. Jaafary, Urmia Pathobiology Center, for their technical expertise.

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Please cite this article in press as: Mohammadi R, et al., Peripheral nerve regeneration following transection injury to rat sciatic nerve by local application of adrenocorticotropic hormone, Journal of Cranio-Maxillo-Facial Surgery (2013), http://dx.doi.org/10.1016/j.jcms.2013.11.012

Peripheral nerve regeneration following transection injury to rat sciatic nerve by local application of adrenocorticotropic hormone.

The objective of this study was to assess local effect of adrenocorticotropic hormone (ACTH) on the functional recovery of the sciatic nerve in a tran...
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