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Insulin-Like Growth Factor II Stimulates Motor Nerve Regeneration (Somatomedin/Sdatic Nerve/Axon/Neurotropiuc/Neurite) STEPHANIE L

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Insulin-Like Growth Factor II Stimulates Motor Nerve Regeneration (Somatomedin/Sdatic Nerve/Axon/Neurotropiuc/Neurite) STEPHANIE L Proc. Nati. Acad. Sci. USA Vol. 89, pp. 11716-11720, December 1992 Neurobiology Insulin-like growth factor II stimulates motor nerve regeneration (somatomedin/sdatic nerve/axon/neurotropiuc/neurite) STEPHANIE L. NEAR*, L. RAYMOND WHALEN*, JAMES A. MILLERt, AND DOUGLAS N. ISHII0§ Departments of *Anatomy and Neurobiology, *Physiology, and §Biochemistry, Colorado State University, Fort Collins, CO 80523; and tAmgen Inc., Thousand Oaks, CA 91320 Communicated by Dale Purves, September 14, 1992 (receivedfor review, June 17, 1992) ABSTRACT Injury to mammalian motor nerves can lead can increase the regeneration of motor axons in vivo and (ii) to paralysis, but relatively succul regeneration may occur endogenous IGFs contribute to the spontaneous regeneration when conditions are favorable. Elucidation of the mcanism of motor axons. A positive finding for hypothesis i is poten- upholding successful regeneration is of theoretical and clincal tially ofclinical significance, irrespective ofwhether hypoth- interest. In this study, the hypothesis that insulin-like growth esis ii is validated. factor H (IGF-ll) can stimulate motor nerve regeneration was tested. When IGF-H was infused continuously near a site of MATERIALS AND METHODS crush on the sciatic nerve, the distance of motor axon regen- eration was increased snlfcantly in rats. In contrast, spon- Materials. Recombinant human IGF-II (Amgen) was >97% taneous regeneration was inhibited when an anti-IGF-H anti- pure based on HPLC; only a single band was visible on serum was infused through a "window" in the epineurium. reducing SDS/PAGE. To produce antiserum, 0.3 mg of Thus, infused IGF-il can increase, and endogenous IGFs can keyhole limpet hemocyanin was added to 50 pg of IGF-II in support, the regeneration of motor axons in lesioned nerves. 50 mM sodium phosphate buffer (pH 6.8), glutaraldehyde was added to 1% (vol/vol), and the mixture was incubated for 30 min at room temperature. Rabbit polyclonal anti-hIGF-II Successful regeneration often is encountered following injury antiserum 489-42 (Amgen) had a titer of 1:30,000 in ELISAs. to the peripheral nervous system. Nevertheless, paralysis This antiserum cross-reacts 10%6 with IGF-I, but cross- can result from injury to motor axons in nerves, particularly reactivity with insulin was not observed. when lesions are in proximal nerve regions (closer to the IGF-II and its antiserum were each prepared in Roswell spinal cord). Such paralysis might be reduced in incidence Park Memorial Institute medium 1640 (RPMI), sterilized by someday with improved understanding of the mechanisms passage through 0.2-gum filters, and stored in aliquots at supporting successful regeneration. The consequences of -20'C. In addition, 30 jug of IGF-ll per ml and 30 Al of motor nerve injury continue to pose a serious medical, antiserum per ml in RPMI were incubated together at 37rC for economic, and societal problem. 3 hr, incubated at 40C for 30 min, and centrifuged at 15,000 The nerve distal to a site of injury contributes to sponta- x g for 30 min, and the supernatant fraction was stored at neous regeneration (1, 2). After transection, axons can cross -200C. a gap of several millimeters and enter the distal nerve stump, Surgical Procedures. Animal care and use procedures set indicating the presence of soluble neurotrophic substances. forth by the National Institutes of Health were followed. Supporting cells in the nerve distal to a lesion indeed produce Male Sprague-Dawley rats, 12-14 wk old, were housed in soluble factors, which attract and stimulate neurite growth plastic cages on a 12-hr light/dark cycle and randomly (3-5). Freezing the distal nerve greatly reduces the popula- assigned to treatment groups. Rats were fed four pellets per tion of Schwann, fibroblast, endothelial, and other cell types day of Prolab RMH 3000 Rat Chow prior to surgery, and, and impairs regeneration (6, 7). Motor (8) but not sensory (9) afterwards, were fed ad lib. Free access to water was axons regenerate at normal rates in Ola mice, indicating that provided. Rats were anesthetized with an initial i.p. dose of different factors may regulate regeneration in each neural 90 mg ofketamine per kg and 5 mg ofxylazine per kg and were system. A deeper understanding of the mechanisms behind placed on a 370C water blanket. Depth of anesthesia was motor axon regeneration in vertebrates is likely to emerge if monitored, and maintenance doses of ketamine (45 mg/kg) the identity of diffusible substances that support motor axon were administered at --30-min intervals, as needed. regeneration were known. Motor Axon Regeneration Assay. Sciatic nerves were The polypeptide known as insulin-like growth factor II crushed as described by De Koning et al. (26). The proce- (IGF-II) (10, 11) is one candidate diffusible substance. Brain dures for implantation of miniosmotic pumps containing and spinal cord comprise the most abundant tissue sources various test substances and measurement of motor axon for IGF-II mRNAs in adult rats (12-14). IGF-II is found in regeneration distances are described in the legend to Fig. 1. cerebrospinal fluid (15), and receptors for IGFs are distrib- The stimulus consisted of square wave pulses (10 mA, 25 ls, uted widely in neural tissues (16-18). IGF-II gene expression seven pulses per s) from a Grass S44 stimulator and Grass in muscle is correlated closely with the development and constant-current unit. Evoked potentials detected by the regeneration of neuromuscular synapses (19), and IGF-II recording electrodes were amplified 500,000 with a Grass P5 supports neurite growth in cultured neuroblastoma (20), 11K preamplifier. The amplified signal was split to a Tek- sensory, sympathetic (21), and motor (22) cells. Reviews are tronix 7854 oscilloscope for signal averaging and to a Compu- available providing additional detail on the actions ofIGFs in pro system 8/16 computer for storage and analysis. neural tissues (23-25). Two hundred fifty-six successive responses to nerve stim- Two independent, but closely interrelated, hypotheses ulation were averaged for analysis ofevoked potentials. Each were evaluated in this study: (i) locally administered IGF-II averaged action potential contained 1024 data points with a The publication costs ofthis article were defrayed in part by page charge Abbreviation: IGF-II, insulin-like growth factor II (rat multiplication payment. This article must therefore be hereby marked "advertisement" stimulating activity). in accordance with 18 U.S.C. §1734 solely to indicate this fact. ITo whom reprint requests should be addressed at t. 11716 Downloaded by guest on October 1, 2021 Neurobiology: Near et al. Proc. Natl. Acad. Sci. USA 89 (1992) 11717 sampling rate of 30 gs per point. The band pass was 3 Hz to electrophysiological procedure was devised to measure mo- 10 kHz (-3 decibels). tor axon regeneration distances (Fig. 1). The evoked com- Neurofilament Immunohsochstry. Nerve segments pound action potential in anonlesioned sciatic nerve is shown containing the front of regeneration (marked by suture) were in Fig. 2A. Several precautions ensured that these potentials frozen for 20 s in a mixture (80% propane/201% ethane) that were conducted actively to the recording site and were was cooled in liquid nitrogen. Longitudinal sections (10 !Lm) recorded from motor axons. A plastic shield was used to were fixed for 10 min in 4%o formalin/0.1 M sodium acetate, electrically isolate the nerve from muscle. Nerve crush or pH 6, and then for 10 min in 4% formalin/0.1 M sodium application of a local anesthetic (lidocaine) just proximal to borate, pH 11. Following exposure to 10 mg of collagenase the recording electrode abolished the evoked potentials. per ml (1540 units/mg; Sigma, type XI) in Hanks' salts at pH Because the transected dorsal roots were reflected away, it 7.4 for 30 min, the sections were incubated in 0.1% glacial was unlikely that sensory fibers were recruited inadvertently acetic acid in ethanol at -209C for 10 min and then in 3% by the stimulus. In addition, when intact dorsal root fibers horse serum in phosphate-buffered saline for 30 min. Mouse were stimulated, ascending evoked spinal cord potentials monoclonal anti-neurofilament antibody (SM132 from Stern- were detected in spinal cord segments cranial to the dorsal burger Monoclonals) was diluted 1:5000 in phosphate- root attachment zone (28). However, following transection of buffered saline and incubated with the sections overnight. dorsal roots, such potentials were not detected. Therefore, SMI32 binds to nonphosphorylated epitopes on heavy (220 the evoked potentials recorded in the sciatic nerve distal to kDa) neurofilament subunits. Using the procedure of Hsu et a crush site were actively conducted potentials in regener- al. (27), the sections were incubated subsequently with ating motor axons. biotinylated anti-mouse IgG antibodies and a complex of Two days after sciatic nerve crush, the ventral roots were avidin-biotinylated horseradish peroxidase, following recom- stimulated electrically, and motor axons had regenerated 4 mended procedures (Vectastain Elite ABC kit, Vector Lab- mm distal to the crush site. In all experiments, several passes oratories). 3,3'-Diaminobenzidine tetrahydrochloride was of the recording electrode were made to confirm the position used as substrate. of the most distal regenerating axons. The regeneration front was labeled with a suture through the epineurium. The recorded evoked potentials at sites 2 mm proximal to the RESULTS regeneration front, at the front, and 1 mm distal to the front Correspondence Between Electrophysiologic and Immuno- are shown in Fig. 2 B, C, and D, respectively. Evoked histochemical Detection of Sciatic Nerve Regeneration. An potentials were detected proximal, but not distal, to the A Osrmotic u;rp B zzzz. Stmnnuius electrc-. Crush site suture CSut corsal rcot .V, s r-- Sciatic nerve I,';M$ site suture I.I tr IYT .-4 11 w i FIG.
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