Effect of Brain-Derived Neurotrophic Factor

ORIGINAL ARTICLE Delayed Repair of Transected Nerves Effect of Brain-Derived Neurotrophic Factor

Melinda S. Moir, MD; Michelle Z. Wang, BA; Michael To; Joanne Lum, BS; David J. Terris, MD

Objective: To determine if administration of brain- Results: The SFI maximal recovery was superior in the derived neurotrophic factor (BDNF) after peripheral nerve BDNF groups, but this difference did not reach statisti- transection can improve the functional outcome in situ- cal significance (SFI, −90.1 ± 9.6 [LR group], −85.7 ± 7.6 ations where epineurial repair must be delayed. [BDNF-early group], and −84.6 ± 4.8 [BDNF-late group], where normal function is 0 and complete loss of func- Design: Randomized, blinded, controlled trial. tion is −100; P = .27). The mean axon diameter tended to be greater in the BDNF groups compared with the LR Subjects: Thirty-four Sprague-Dawley rats. group, ie, 2.43 ± 0.23 µm (LR group), 2.80 ± 0.44 µm (BDNF-early group), and 2.83 ± 0.38 µm (BDNF-late Intervention: Sciatic nerves were transected and, after group) (P = .05). a 2-week delay, repaired with epineurial sutures. Ani- mals were assigned to receive daily administration of lac- Conclusions: The local administration of BDNF to nerves tated Ringer solution (LR [control] group); BDNF de- that underwent transection and then repair after a delay livered at the time of nerve transection through 2 weeks resulted in an increase in axonal diameters and maxi- after nerve repair, for a total of 4 weeks (BDNF-early mal SFIs, a difference that did not reach statistical sig- group); or BDNF delivered at the time of nerve repair nificance. The timing of BDNF administration after nerve through 2 weeks after repair (BDNF-late group). Out- transection did not affect neuronal regeneration. come was assessed using sciatic functional indices (SFIs) and histomorphometric analysis. Arch Otolaryngol Head Neck Surg. 2000;126:501-505

RECENT area of intense in- muscle.4 Messenger RNA from BDNF is vestigation has been the up-regulated in adult peripheral nerves af- role of neurotrophic fac- ter axotomy and in muscle after denerva- tors in the process of pe- tion.5,6 Brain-derived neurotrophic factor ripheral nerve regenera- has been shown to prevent degeneration tion after injury and repair. After nerve of transected motor neurons in the neo- A 6-8 transection, a series of events occur dur- natal rat. These characteristics and ac- ing regeneration that involve the nerve cell tions of BDNF suggest a role in the sup- body, the axonal fiber, the target muscle, port of peripheral motor neurons. and the surrounding chemical and cellu- Attention has been directed toward lar environment. Distal nerve endings un- the clinical utility of BDNF in the treat- dergo wallerian degeneration, and skel- ment of neurodegenerative disorders and etal muscle begins to atrophy because of peripheral nerve injury. After nerve in- lack of electrical stimulation and a de- jury and immediate repair, local admin- crease in myotrophic factors. Nerve cell istration of BDNF has been shown to im- bodies enter a restorative phase that is criti- prove functional outcome in the rat sciatic cal for successful regeneration to occur. nerve model.9-11 In clinical situations of Trophic factors appear to play an impor- nerve injury, however, immediate neural tant role in supporting the neuronal cell repair is not always possible. Because of body and the axons during this period of its neurotrophic and myotrophic charac- regeneration.1,2 teristics, we speculated that the early ad- From the Division of 3 Otolaryngology–Head and First identified by Barde et al, brain- ministration of BDNF may be beneficial in Neck Surgery, Stanford derived neurotrophic factor (BDNF) is a supporting neural cell bodies and in de- University Medical Center, 27-kd homodimer with transcripts found creasing muscle atrophy after nerve tran- Stanford, Calif. in many organ tissues, including skeletal section when immediate nerve repair is not

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 METHODS AND MATERIALS transected nerve.14 The top of the injection dome is soft, which allowed for serial percutaneous injections of BDNF or LR delivered to the site of the transected nerve. The wounds were A total of 34 male Sprague-Dawley rats were assigned in a closed, and the animals were allowed to recover. random, blinded fashion to one of the following 3 treatment After surgery, the animals were housed at the Stan- groups: lactated Ringer solution (LR [control] group); BDNF ford Research Animal Facility, where they received rat chow delivered at the time of nerve transection through 2 weeks and water ad libitum. The animals in the LR and BDNF- after the time of delayed nerve repair, for a total of 4 weeks late groups received daily injections of 0.3 mL of LR into (BDNF-early group); and BDNF delivered at the time of de- the implanted reservoir. The animals in the BDNF-early layed nerve repair through 2 weeks (BDNF-late group). A color group received daily injections of 10 µg of BDNF dis- code was applied to the base of each animal’s tail so that the solved in 0.3 mL of LR. The syringes were prepared and investigators could remain blinded to the group designation coded by a third party so that the investigators were blinded until the completion of the study. Throughout the protocol, to their content. all animals were housed in the Stanford Research Animal Fa- Two weeks after nerve transection, all animals were cility, Stanford University, Stanford, Calif. The research de- reanesthetized, and their wounds were opened. The sci- sign was approved by the Institutional Animal Care and Use atic nerve ends were exposed, and the identifying sutures Committee of Stanford University. were removed. The nerves were then repaired, as shown in Figure 2, with 6 interrupted epineurial stitches of 9-0 SURGICAL TECHNIQUES polypropylene suture swaged on a tapered needle (BV 130-3; Ethicon Inc). The wounds were closed, and the animals were The animals were anesthetized with intraperitoneal pen- allowed to recover. The animals in the LR group contin- tobarbital sodium (80 mg/kg). By use of a sterile tech- ued to receive daily injections of LR, whereas the animals nique, the left sciatic nerve was exposed with a muscle- in the BDNF-early and BDNF-late groups were given daily splitting incision at the middle of the thigh. The sciatic nerve injections of BDNF for 2 weeks. was transected sharply, and a single 10-0 polypropylene su- Two weeks after nerve repair, all animals were reanes- ture tag (Prolene; Ethicon Inc, Somerville, NJ) was placed thetized, and the microdome reservoir and silicone tubing through the epineurium of the proximal and distal nerve were removed. Care was taken not to disturb the neural ends to facilitate identification of the nerve endings for sub- repair. The wounds were closed, and the animals were al- sequent neurorrhaphy. A silicone microdome injection res- lowed to recover. ervoir (Micro Injection Dome, model 350-MICRO; Men- tor Corporation, Goleta, Calif), shown in Figure 1, was FUNCTIONAL ANALYSIS then implanted over the dorsum of the animal. A silicone delivery cannula was tunneled from the reservoir to the nerve Recovery of sciatic nerve function was assessed using walk- and sutured to the muscle immediately adjacent to the ing track measurements, which provide a means to quantify

Figure 1. Photograph of a silicone microdome reservoir (Micro Injection Dome, model 350-MICRO; Mentor Corporation, Goleta, Calif) with a silicone delivery cannula. The microdome reservoir was implanted over the dorsum of the animals, with the silicone delivery cannula tunneled from the reservoir to the nerve and sutured to the muscle immediately adjacent to the transected nerve.

possible. Neural cell regenerative activity reaches its peak Figure 2. Photomicrograph of a sciatic nerve repair with interrupted during the first 3 weeks after nerve injury, a period of epineurial stitches (original magnification ϫ40). time when the action of BDNF may be quite impor- tant.12,13 Our goal was to determine whether administration of BDNF after nerve injury would improve the func- experimental foot, requiring humane killing; there were 9 tional outcome in a setting of delayed neural repair in a animals each in the LR group and BDNF-late group, and rat sciatic nerve model. 11 animals in the BDNF-early group. Muscle contractures of the experimental leg developed in 2 of the animals in RESULTS the LR group and in 3 of the animals in the BDNF-early group. These animals were included in the functional and We were able to evaluate the data from 29 of the 34 ani- histological data analysis. The maximal SFI for these animals studied. Five animals (15%), 2 in the LR group and 3 mals was measured at the time point before the develop- in the BDNF-late group, suffered automutilation of their ment of muscle contracture. At the time of extraction, the

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 the function of the sciatic nerve.15 Animals underwent walk- undergoing operation in 10 rats were harvested at random ing track analysis before nerve transection, again just be- to serve as controls. The animals were then killed hu- fore nerve repair, and every 10 days after nerve repair for a manely in a carbon dioxide chamber. total of 60 days. Paw prints were obtained by moistening Histological slides were made by cutting 0.6-mm sec- the animals’ hind paws and having them walk across bro- tions and staining with Bielschowsky silver stain for nerve mophenol blue–treated paper.16 Measurements were ob- axons. The slides were examined with a light microscope tained of paw print length, outer toe spread, and interme- (Nikon Alphaphot 2YS2; Technical Instruments, San Fran- diary toe spread for control and experimental sides. Sciatic cisco, Calif) equipped with a single-chip color video cam- functional indices (SFIs) were calculated using the follow- era (CCD #70-5110; JEDMED, St Louis, Mo) projected onto ing formula modified by Bain et al17: a color monitor (#PM-1971A; NEC, Tokyo, Japan). The monitor was connected to a computer (Performa 6115 CD SFI = −38.3[(EPL − NPL)/NPL] + 109.5[(ETS − NTS)/ MacIntosh; Apple Computers, Cupertino, Calif) equipped NTS] + 13.3[(EIT − NIT)/NIT] − 8.8, with a program to capture images from the video screen where EPL indicates experimental print length; NPL, nor- and to digitize the analog signal for editing on the com- mal print length; ETS, experimental outer toe spread; NTS, puter (Scion Frame Grabber Card and Scion Image pro- normal toe spread; EIT, experimental intermediary toe gram, Model LG3; Scion Corporation, Bethesda, Md). spread; and NIT, normal intermediary toe spread. The SFI The axon counts were derived from digitized images is a standardized formula in which normal function is 0 of the nerves at 40ϫ magnification. The Scion Image pro- and complete loss of function is −100. gram randomly selected 10 areas, each measuring 1290 µm2, Sixty days after the time of nerve repair, differences within each nerve section. Axon counts within these areas in maximal functional recovery and rate of recovery were were then performed manually, using crosshairs to iden- compared using linear regression analysis. Early muscle con- tify and mark each axon. The axon count for the entire nerve tractures in the experimental leg developed in several ani- was calculated by multiplying the mean axon count per ran- mals, such that interpretable data could no longer be ob- dom area by the nerve cross-sectional area and dividing by tained. The SFI walking track data collected until the time 1290 µm2. of muscle contracture were used in the data analysis. The mean axon diameters were derived from digitized images of the nerves at 100ϫ magnification. Twenty HISTOMORPHOMETRIC ANALYSIS axons were chosen randomly and outlined individually on the computer screen. Using the Scion Image program, the At the completion of the experiment, animals (including areas of the axons were measured, and the diameters were those with muscle contractures) were anesthetized, and calculated from the areas, assuming a circular geometric 5-mm segments of nerve 5 mm distal to the repair site were shape. The mean axon diameter of each nerve section was harvested and fixed in 10% buffered formalin solution. Ten- then calculated. Unless otherwise indicated, data are given millimeter segments from the contralateral nerves not as mean ± SD.

microdome reservoirs were found to be appropriately po- 0 Nerves Transected sitioned and functional in all animals. LR Group BDNF-Late Group –20 The mean SFIs are shown in Figure 3. Normal BDNF-Early Group function approaches 0, as seen at the first time point –40 (day 0), before nerve transection (day 1). Maximal loss of function is evident at the second time point (day 15), –60 obtained immediately before nerve repair. The SFI maximal recovery was better in the BDNF groups, but –80

this difference did not reach statistical significance (SFI Sciatic Functional Index Nerves Repaired maximal recovery, −90.1 ± 9.6 [LR group], −85.7 ± 7.6 –100

[BDNF-early group], and −84.6 ± 4.8 [BDNF-late –120 group]; P = .27) (Table 1). The rate of recovery was 0 15 25 35 45 55 65 75 also similar among the 3 groups as measured by linear Time, d regression analysis (P = .56). Control nerves not oper- Figure 3. The mean sciatic functional indices are shown, where 0 is normal ated on had lower axon counts and a higher mean axon and −100 represents complete absence of function. Preoperative function diameter than repaired nerves (Table 2). The mean approaches 0, as seen at the first time point, before nerve transection (day axon diameter was higher in the BDNF groups com- 0). Maximal loss of function is evident at the second time point (day 15), obtained immediately before nerve repair. A gradual return of function is then pared with the LR group, although this difference did detected. LR indicates lactated Ringer solution; BDNF-early, brain-derived not reach statistical significance (2.43 ± 0.23 µm [LR neurotrophic factor delivered at the time of nerve transection through 2 group], 2.80 ± 0.44 µm [BDNF-early group], and weeks after the time of nerve repair, for a total of 4 weeks; and BDNF-late, 2.83 ± 0.38 µm [BDNF-late group]; P = .05). Photomi- BDNF delivered at the time of nerve repair, and continued for 2 weeks. crograph of a normal sciatic nerve (Figure 4, left) and a nerve repaired by epineurial coaptation (Figure 4, COMMENT right) demonstrates the decreased myelination in the repaired nerve (Bielschowsky silver stain, original mag- The ideal timing for peripheral nerve repair after injury nification ϫ200). has been a source of controversy. A series of studies in

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Groups Maximum SFI Recovery† Slope of SFI Recovery‡ Groups Mean Axon Count† Mean Axon Diameter, µm‡ LR −90.1 ± 9.6 0.53 ± 0.27 LR 10 944 ± 2082 2.43 ± 0.23 BDNF-early −85.7 ± 7.6 0.51 ± 0.23 BDNF-early 9025 ± 2611 2.80 ± 0.44 BDNF-late −84.6 ± 4.8 0.43 ± 0.16 BDNF-late 9087 ± 2272 2.83 ± 0.38 Control nerves 6331 ± 984 3.48 ± 0.42 *LR indicates lactated Ringer solution; BDNF-early, brain-derived neurotrophic factor delivered at the time of nerve transection through *Abbreviations are given in the first footnote to Table 1. Data are given as 2 weeks after the time of nerve repair, for total of 4 weeks; BDNF-late, BDNF mean ± SD. delivered at the time of nerve repair, and continued for 2 weeks; and SFI, †P = .05, differences between treatment groups only. sciatic functional index. Data are given as mean ± SD. ‡P = .16, differences between treatment groups only. †P = .27, differences between groups. ‡P = .56, differences between groups.

Figure 4. Photomicrograph of a normal sciatic nerve (left) and a nerve repaired by epineurial coaptation (right) demonstrates the decreased myelination in the repaired nerve (Bielschowsky silver stain, original magnification ϫ200). There was no qualitative difference on results of histological examination between transected nerves that had been treated with brain-derived neurotrophic factor vs lactated Ringer solution.

the 1970s demonstrated that axonal regenerative activ- generative activity after nerve transection would im- ity peaks at 3 weeks after injury.18-20 This finding led to prove ultimate functional recovery when nerve repair was the concept that neurorrhaphy should be delayed for 3 delayed by 2 weeks. Our data did not support the role weeks. More recent investigations have conclusively for the early administration of BDNF, as the histological demonstrated, however, that despite this delayed peak and functional results were similar regardless of the tim- of activity, clinical outcomes are clearly superior the ing of BDNF administration. earlier nerve repair is able to be accomplished.21-23 Nev- Although the administration of BDNF resulted in an ertheless, a number of factors, including the stability of increase in mean axonal diameters and maximal SFIs, the the patient, may prevent timely performance of nerve data did not reach statistical significance. Since previous repair. studies had confirmed that BDNF is effective in enhanc- The ability to enhance the microenvironment of a tran- ing functional recovery of transected and immediately re- sected motor neuron through the addition of neuro- paired nerves, it may be that the delay before repair re- trophic factors is desirable when repair must be delayed. sulted in irrevocable muscle contractures or loss of viable Neurotrophic factors, including nerve growth factor (NGF) muscle endplates that were unable to be rescued by BDNF. and BDNF, are a family of structurally related polypep- Since we anticipated this potential problem, BDNF was de- tides that originally were discovered to have a major role livered immediately after nerve transection in 1 group in in the development and support of the nervous system dur- an effort to sustain the muscle target tissue. This group, ing embryogenesis. In models of peripheral nerve regen- however, fared no better than the group in which BDNF eration, the use of NGF has been disappointing, espe- administration was delayed until the nerve repair was ac- cially when functional recovery is measured.24,25 We chose complished. The daily dose of BDNF administered was to use BDNF, which has been shown in a number of stud- based on previous studies in animal models of immediate ies to improve functional recovery after nerve repair.9-11 The nerve repair.9,10 It is possible that higher doses of BDNF expression of receptors specific for BDNF, but not NGF, would be beneficial during the period of delayed nerve re- in mature spinal and cranial motor neurons may explain pair, but we did not explore that potential. the improved results when using BDNF in animal models The findings of a higher number of axons in the tran- of nerve regeneration.6,26 sected and repaired nerves compared with the nerves not Our study differs from previous work in that we in- undergoing operation are consistent with the phenom- vestigated the potential role of BDNF in the setting of nerve enon of “axonal sprouting,” in which a high number of transection and delayed repair. We speculated that the smaller, poorly formed axonal sprouts grow from the tran- addition of a neurotrophic factor during a period of re- sected axon seeking a distal target and increasing the over-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 all number of distal axonal numbers.27 Axon counts have 9. Utley DS, Cheng ET, Lewin SL, Verity AN, Terris DJ. Brain-derived neurotrophic not been found to correlate well with recovery.3,28 Axo- factor and collagen tubulization enhance functional recovery after peripheral nerve injury and repair. Arch Otolaryngol Head Neck Surg. 1996;122:399-403. nal diameter directly correlates with conduction veloc- 10. Lewin SL, Utley DS, Cheng ET, Verity AN, Terris DJ. Simultaneous treatment with 29,30 ity and is generally a better reflection of the vigor of BDNF and CNTF after peripheral nerve transection and repair enhances rate of regeneration.31 functional recovery compared with BDNF treatment alone. Laryngoscope. 1997; 107:992-999. 11. Cheng ET, Utley DS, Ho P, et al. Functional recovery of transected nerves treated CONCLUSIONS with systemic BDNF and CNTF. Microsurgery. 1998;18:35-41. 12. Sunderland S. Nerves and Nerve Injuries. New York, NY: Churchill Livingstone The supportive role of BDNF and other neurotrophic Inc; 1978:449-585. factors in the setting of delayed peripheral nerve repair 13. Sunderland S. Some anatomical and pathophysiological data relevant to facial has not been studied previously. The local administra- nerve injury and repair. In: Fisch U, ed. Facial Nerve Surgery. New York, NY: Aes- tion of BDNF to nerves that were transected and then culapius Publishers Inc; 1997:47-61. 14. Santos FX, Bilbao G, Rodrigo J, et al. Experimental model for local administra- repaired after a delay resulted in an increase in axonal tion of nerve growth factor in microsurgical nerve reconnections. Microsurgery. diameters and maximal SFIs, a difference that did not 1995;16:71-76. reach statistical significance. The timing of BDNF 15. de Medinaceli L, Freed W, Wyatt R. 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