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Effect of Brain-Derived Neurotrophic Factor

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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 ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 124, APR 1998 501 ©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 de- livered 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 administra- tion 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 ani- mals 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 ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 124, APR 1998 502 ©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.
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