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Terence M Myckatyn

Publications and source records attributed to Terence M Myckatyn.

At least 19 recordsLinked to original sources
PubMed2006

Muscle-derived but not centrally derived transgene GDNF is neuroprotective in G93A-SOD1 mouse model of ALS.

Glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MNs), and is considered a potential agent for the treatment of amyotrophic lateral sclerosis (ALS) and other MN diseases. The effectiveness of GDNF may depend significantly upon its route of delivery to MNs. In this study we tested the neuroprotective effects of target-derived and centrally derived GDNF in the G93A-SOD1 mouse model of ALS using a transgenic approach. We found that overexpression of GDNF in the skeletal muscle (Myo-GDNF mice) significantly delayed the onset of disease and increased the life span of G93A-SOD1 mice by 17 days. The duration of disease also increased by 8.5 days, indicating that GDNF slowed down the progression of disease. Locomotor performance in Myo-GDNF/G93A-SOD1 mice was also significantly improved. The behavioral improvement correlated well with anatomical and histological data. We demonstrated that muscle-derived GDNF resulted in increased survival of spinal MNs, and twice as many MNs survived in end-stage double transgenic mice compared to end-stage G93A-SOD1 mice. Muscle-derived GDNF also had profound effects on muscle innervation and axonal degeneration. Significantly higher numbers of completely or partially innervated NMJs and large caliber myelinated axons were found in double transgenic mice. In contrast, we demonstrated that overexpression of GDNF in astrocytes in the CNS (GFAP-GDNF mice) failed to demonstrate any neuroprotective effects in G93A-SOD1 mice both on behavioral and histological levels. These data indicate that retrograde transport and signaling of GDNF is more physiological and effective for ALS treatment than anterogradely transported GDNF.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Astrocyte-derived transgene GDNF promotes complete and long-term survival of adult facial motoneurons following avulsion and differentially regulates the expression of transcription factors of AP-1 and ATF/CREB families.

Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for motoneurons (MNs). We have previously demonstrated that overexpression of GDNF in astrocytes of GFAP-GDNF mice promotes long-term survival of neonatal MNs after facial nerve axotomy. In the present study, we investigated whether astrocyte-derived GDNF could also have a neuroprotective effect on adult MNs following facial nerve avulsion. We also examined avulsion- and GDNF-induced changes in the expression pattern of several members of the AP-1 and ATF/CREB families of transcription factors, which are involved in the fate determination of neurons following injury. We demonstrated that GDNF promotes complete rescue of avulsed MNs for at least 4 months post-injury. Transgene GDNF significantly upregulates c-Jun expression in naive MNs, further upregulates injury-induced c-Jun expression in facial MNs, and results in its activation in most surviving MNs. No significant changes were found in c-Fos expression. We found that GDNF has an opposing effect on ATF2 and ATF3 expression. It dramatically downregulates increased levels of ATF3 in response to injury, whereas the expression of ATF2, which is normally reduced after injury, is completely preserved in GFAP-GDNF mice. Our data suggest that maintenance of high levels of ATF2 in injured MNs could be crucial in modulating c-Jun function, and c-Jun/ATF2 signaling could be involved in GDNF-mediated survival of mature MNs.

Activating Transcription Factors↗
PubMed2006

Repair of motor nerve gaps with sensory nerve inhibits regeneration in rats.

OBJECTIVE: Sensory nerve grafts are often used to reconstruct injured motor nerves, but the consequences of such motor/sensory mismatches are not well studied. Sensory nerves have more diverse fiber distributions than motor nerves and may possess phenotypically distinct Schwann cells. Putative differences in Schwann cell characteristics and pathway architecture may negatively affect the regeneration of motor neurons down sensory pathways. We hypothesized that sensory grafts impair motor target reinnervation, thereby contributing to suboptimal outcomes. This study investigated the effect of motor versus sensory grafts on nerve regeneration and functional recovery. STUDY DESIGN: The authors conducted a prospective, randomized, controlled animal study. METHODS: Fifty-six Lewis rats were randomized to seven groups of eight animals each. Five-millimeter tibial nerve defects were reconstructed with motor or sensory nerve grafts comprised of single, double, triple, or quadruple cables. Tibial nerve autografts served as positive controls. Three weeks after reconstruction, nerves were harvested for histologic examination and quantitative histomorphometric analysis. Wet muscle masses provided an index of functional recovery. RESULTS: Nerve regeneration was significantly greater across motor versus sensory nerve grafts independent of graft cross-sectional area or cable number. Motor grafts demonstrated increased nerve density, percent nerve, and total fiber number (P < .05). Normalized wet muscle masses trended toward improved recovery in motor versus sensory groups. CONCLUSIONS: Reconstruction of tibial nerve defects with nerve grafts of motor versus sensory origin enhanced nerve regeneration independent of cable number in a rodent model. Preferential nerve regeneration through motor nerve grafts may also promote functional recovery with potential implications for clinical nerve reconstruction.

Analysis of Variance↗
PubMed2006

Influence of aging on regeneration in end-to-side neurorrhaphy.

Aging profoundly affects the structural and functional characteristics of the peripheral nervous system. Although several experiments have investigated the effect of aging on nerve regeneration after crush and transection nerve injuries, little is known about the influence of age on end-to-side nerve repairs. It was hypothesized that decreased terminal and collateral sprouting in older animals would be associated with less robust regeneration through end-to-side nerve repairs. In this study, 27 Lewis rats underwent end-to-side repair at ages 2 weeks, 3 months, or 1 year. Histomorphometric assessments at 12 weeks demonstrated increased fiber width, percent neural tissue, and neural density in animals undergoing nerve reconstruction at the age of 2 weeks (P < 0.05). A trend toward further decline in regeneration was noted at ages 1 year versus 3 months. After end-to-side nerve repair, younger animals exhibit a more robust regenerative response, consistent with prior experience in other nerve injury models.

Aging↗
PubMed2005

Choosing the correct functional assay: a comprehensive assessment of functional tests in the rat.

While there are several ways to quantify peripheral nerve regeneration; the true measure of successful outcome is functional recovery. Functional tests are relatively easily conducted in human subjects; however it is more difficult in a laboratory animal. The laboratory rat is an excellent animal model of peripheral nerve injury and has been used extensively in the field of peripheral nerve research. Due to the intense interest in the rat as an experimental model, functional assays have been reported. In an effort to provide a resource to which investigators can refer when considering the most appropriate functional assay for a given experiment, the authors have compiled and tabulated the available functional tests applicable to various models of rat nerve injury.

Animals↗
PubMed2005

Results of reinnervation of the biceps and brachialis muscles with a double fascicular transfer for elbow flexion.

PURPOSE: To report the results of a surgical technique of nerve transfer to reinnervate the brachialis muscle and the biceps muscle to restore elbow flexion after brachial plexus injury. METHODS: Retrospective review was performed on 6 patients who had direct nerve transfer of a single expendable motor fascicle from both the ulnar and median nerves directly to the biceps and brachialis branches of the musculocutaneous nerve. Assessment included degree of recovery of elbow flexion and ulnar and median nerve function including pinch and grip strengths. RESULTS: Clinical evidence of reinnervation was noted at a mean of 5.5 months (SD, 1 mo; range, 3.5-7 mo) after surgery and the mean follow-up period was 20.5 months (SD, 11.2 mo, range, 13-43 mo). Mean recovery of elbow flexion was Medical Research Council grade 4+. Postoperative pinch and grip strengths were unchanged or better in all patients. No motor or sensory deficits related to the ulnar or median nerves were noted and all patients maintained good hand function. No patients required additional procedures to further improve elbow flexion strength. CONCLUSIONS: Transfer of expendable motor fascicles from the ulnar and median nerves successfully can reinnervate the biceps and brachialis muscles for strong elbow flexion. The reinnervation of the brachialis muscle, the primary elbow flexor, as well as the biceps muscle provides an additional biomechanical advantage that accounts for the excellent elbow flexion strength obtained using this technique. Direct coaptation of the nerve fascicles was performed without the need for nerve grafts and there was no functional or sensory donor morbidity.

Adolescent↗
PubMed2004

Anti-CD40 ligand monoclonal antibody induces a permissive state, but not tolerance, for murine peripheral nerve allografts.

Anti-CD40 ligand monoclonal antibody prevents the interaction between CD40 and its T-cell-based ligand, thereby resulting in selective inhibition of T cell costimulation without pan-T-cell suppression. This antibody has found application in several animal models of solid organ transplantation. This study investigated use of anti-CD40 ligand antibody to promote acceptance of nerve allografts. In Experiment 1, 40 BALB/cj mice with tibial nerve transplants were administered anti-CD40 ligand antibody, a control antibody, or no treatment. In Experiment 2, 40 BALB/cj mice underwent the same regimen as in Experiment 1, but were later challenged with a second nerve allograft 3 weeks after discontinuation of treatment. Animals treated with anti-CD40 ligand antibody in Experiment 1 exhibited improved functional recovery and greater mean fiber count, fiber density, and percent nerve fiber than animals treated with control antibody or no antibody (P < 0.05). These permissive effects on nerve regeneration were associated with immune unresponsiveness on Elispot assay. The benefit of anti-CD40 ligand therapy did not persist after withdrawal of treatment (Experiment 2). Active blockade of the CD40 costimulatory pathway with murine anti-CD40 ligand antibody therefore induces a permissive state conducive to nerve regeneration across allografts but does not establish long-term tolerance.

Animals↗
PubMed2004

Stem cell transplantation and other novel techniques for promoting recovery from spinal cord injury.

A number of potential approaches aim to optimize functional recovery after spinal cord injury. They include minimizing the progression of secondary injury, manipulating the neuroinhibitory environment of the spinal cord, replacing lost tissue with transplanted cells or peripheral nerve grafts, remyelinating denuded axons, and maximizing the intrinsic regenerative potential of endogenous progenitor cells. We review the application of stem cell transplantation to the spinal cord, emphasizing the use of embryonic stem cells for remyelinating damaged axons. We speculate that harnessing the potential of endogenously born stem cells already present in the spinal cord represents an important therapeutic target. We also discuss the potential application of peripheral nervous system reconstruction to recovery from spinal cord injury. The principles of peripheral nerve regeneration and concepts of nerve grafting are reviewed. Particular attention is given to peripheral nerve allotransplantation for repairing extensively injured tissue when autologous donor nerve material is scarce. The potential role of nerve transfers for reconstructing the injured spinal cord, particularly the cauda equina and lumbosacral plexus, are also described.

Animals↗
PubMed2004

A novel model for the study of peripheral-nerve regeneration following common nerve injury paradigms.

Recent advances in molecular neurobiology include the development of transgenic mice that express genes encoding fluorescent proteins under neuron-specific promoters (XFP mice). These mice have been used in the field of developmental neurobiology, but use has expanded to include the study of peripheral-nerve axonal regeneration subsequent to crush or unrepaired transection injuries. This report presents a transgenic mouse, which differs from previously reported and commercially available mice, in that enhanced yellow fluorescent protein expression (EYFP) is driven by the human thy1 promoter (hThy1). Motor and sensory peripheral nerves in these mice appear a bright yellow-green under fluorescent microscopy. This study tracks nerve regeneration in live animals using a serial imaging system. It also introduces a novel model for examining the clinically relevant nerve-injury paradigms of tibial nerve transection repaired with primary neurorrhaphy or graft, and end-to-side neurorrhaphy. Live-animal serial nerve imaging is compared with wet-mount fluorescent microscopy and histomorphometry in the same nerve specimens. The use of transgenic mice that strongly express EYFP in their peripheral neurons, coupled with serial nerve imaging, provide an important methodology for studying the heterogeneous nature of axonal elongation following peripheral-nerve injuries.

Animals↗
PubMed2004

Effects of external beam radiation in the rat tibial nerve after crush, transection and repair, or nerve isograft paradigms.

INTRODUCTION: In head and neck surgery, radiation therapy is often administered to an injured nerve. Previous studies have examined the effects of either preoperative or postoperative radiation on nerve regeneration in rodents. In these studies, histomorphometric analysis was performed up to 8 month postoperatively. Given the exceptional neuroregenerative capacity of rodents, significant differences in nerve regeneration may go undetected if nerves are evaluated at such distant postoperative time points. This study is designed with a more appropriate model and investigates the effects of radiation after three common nerve injury paradigms. METHODS: Sixty-four Lewis rates were randomized to 8 groups corresponding to uninjured, tibial nerve crush, transection and repair, or reconstruction with isografts. Half of the animals in each of these paradigms (n = 8 per group) were treated with 10 Gy of external beam radiation to the site of nerve injury at 7 days postoperatively. On postoperative day 28, functional recovery and histomorphometric assessment was performed. RESULTS: For a given paradigm of nerve injury, no significant differences in nerve fiber number, neural density, neural debris, or fiber width were noted between the control and radiated groups, and radiation did not affect functional recovery. CONCLUSION: Radiation had no discernible effect on nerve regeneration or functional recovery in the rodent nerve injury models studied. All assessments were made at time points suitable for detecting differences in nerve regeneration between groups. These findings suggest that administration of radiation to fields containing injured peripheral nerve is unlikely to adversely affect functional outcomes.

Animals↗
PubMed2004

Anti-CD40 ligand antibody permits regeneration through peripheral nerve allografts in a nonhuman primate model.

Systemic immunosuppression is typically required to prevent allograft rejection. Antibody-based therapies that induce immune unresponsiveness represent an appealing alternative to nonspecific immunosuppression, which is often associated with significant morbidity. In mice, successful prevention of nerve allograft rejection has been demonstrated through interference with the CD40/CD40 ligand interaction. This study investigated the effectiveness of anti-CD40 ligand monoclonal antibody as single-agent therapy in preventing rejection and supporting nerve regeneration across long nerve allografts in nonhuman primates. Twelve outbred cynomolgus macaques were arranged into six genetically mismatched pairs, with each animal receiving a 5-cm ulnar nerve allograft in the right arm and a 5-cm autograft in the left arm. Mixed lymphocyte reaction assays were used to assess resulting immune unresponsiveness. Treated animals (n = 10) received anti-CD40 ligand monoclonal antibody 10 mg/kg one time, locally applied, and 20 mg/kg systemically on postoperative days 0, 1, 3, 10, 18, and 28, and then monthly. Untreated animals (n = 2) served as the untreated controls. At 4 or 6 months after transplantation, nerves were harvested for histological analysis. Four treated animals underwent an additional challenge after cessation of anti-CD40 ligand monoclonal antibody therapy and nerve graft harvests. Autogenous and allogeneic skin and nerve inlay grafting was performed to assess the permanence of immune unresponsiveness induced by anti-CD40 ligand monoclonal antibody. Animals that received anti-CD40 ligand monoclonal antibody demonstrated robust regeneration across nerve allografts, similar to that seen in the autograft control in the contralateral arm. The histomorphometric analysis of allografts in the untreated animals demonstrated significantly worse measurements compared with their matched autograft controls. Animals that received anti-CD40 ligand monoclonal antibody with concomitant skin allografts had virtually no evidence of nerve regeneration through allografts. Allogeneic skin and nerve allografts applied 2 to 12 months after withdrawal of anti-CD40 ligand monoclonal antibody therapy were consistently rejected. This study demonstrates that anti-CD40 ligand monoclonal antibody prevents rejection and allows regeneration of peripheral nerve allografts in nonhuman primates. The effect of anti-CD40 ligand monoclonal antibody appears to be transient, however, with restoration of immunocompetence shortly after withdrawal of therapy.

Animals↗
PubMed2004

A review of research endeavors to optimize peripheral nerve reconstruction.

This manuscript reviews studies relating to peripheral nerve allografts, neuroregenerative agents and end-to-side neurorrhaphy. With respect to peripheral nerve allografts, animal studies with the agents cyclosporin A, FK506 and rapamycin are reviewed and related to recent clinical experience. FK506 distinguishes itself as an agent capable of reversing acute rejection of a peripheral nerve allograft and an agent with some neuroregenerative properties. In addition to systemic immunosuppression, experience with agents purported to initiate a state of donor specific tolerance are discussed. Specifically, experimental studies with administration of ultraviolet B treated donor splenocytes, antibodies to cellular adhesion molecules and antibodies to components of the costimulatory pathway of immunosuppression are reviewed. The neuroregenerative properties of FK506 and related compounds are examined in animal models. Finally, the experimental finding that reinnervation following end-to-side neurorrhaphy is mostly sensory and related to the degree of axonal damage at the level of an epineurotomy or perineurotomy is discussed.

Animals↗
PubMed2003

Use of mixed lymphocyte reaction to identify subimmunosuppressive FK-506 levels in mice.

The immunosuppressive agent FK-506 has a well-described neuroregenerative effect that is mediated by a mechanism independent of calcineurin inhibition. FK-506 levels that fall below the threshold for immunosuppression could therefore potentially enhance nerve regeneration while minimizing toxicity. The purpose of this study was to characterize the dose-dependent effects of FK506 on T-cell proliferation, and establish a subimmunosuppressive dosing regimen for FK-506 in mice. Forty BALB/cJ mice were randomized to four groups corresponding to 0, 0.25, 0.5, or 1.0 mg/kg/day doses of FK-506. Ten days postoperatively, animals were sacrificed, and mixed lymphocyte reaction assays were performed to quantify the immune response to nerve allografts. Mice receiving 0.25 and 0.5 mg/kg/day of FK-506 exhibited a robust T-cell proliferation response, with stimulation indices approaching those of untreated animals. Mice treated with 1.0 mg/kg/day of FK-506 demonstrated significantly decreased T-cell proliferation. These results establish 0.5 mg/kg/day as an upper limit for subimmunosuppressive FK-506 administration.

Animals↗
PubMed2003

The surgical management of facial nerve injury.

Treatment of facial nerve injuries depends upon a detailed understanding of its anatomic course, accurate clinical examination, and timely and appropriate diagnostic studies. Reconstruction depends upon the extent of injury, the availability of the proximal stump. and the time since injury and duration of muscle denervation. Although no alternative is perfect, these techniques, in combination with static and ancillary procedures. can protect the eye, prevent drooling, restore the smile, and improve facial symmetry. New techniques (including single-stage free tissue transfers and bioengineered nerve grafts), further research on the characteristics of the facial musculature, and methods of preserving the neuromuscular junction will undoubtedly manifest themselves as further refinements of established surgical techniques.

Acute Disease↗
PubMed2003

Functional recovery and histomorphometric assessment following tibial nerve injury in the mouse.

Longitudinal studies have established that functional recovery following sciatic nerve injury can be evaluated in the mouse. Injury to the tibial nerve offers several advantages to sciatic nerve injury, including improved lower extremity sensation and end-organ reinnervation. Functional recovery following tibial nerve crush injury was studied in 55 C3H mice randomized into five groups harvested for histomorphometric evaluation from either normal nerves or 2, 3, 4, or 6 weeks postoperatively. Walking tracks were obtained preoperatively, and at regular intervals postoperatively, and foot print lengths measured. Significant normalization of print length occurred 14 days postoperatively, and complete recovery was noted 28 days postoperatively. Significant histomorphologic evidence of neuroregeneration was detected between 2 and 4 weeks postoperatively. Injury to the tibial nerve is a viable alternative to the sciatic nerve for studying neural regeneration in mice, and the print length factor can be used to monitor functional recovery in this model.

Animals↗
PubMed2002

The effects of rapamycin in murine peripheral nerve isografts and allografts.

The FKBP-12-binding ligand FK506 has been successfully used to stimulate nerve regeneration and prevent the rejection of peripheral nerve allografts. The immunosuppressant rapamycin, another FKBP-12-binding ligand, stimulates axonal regeneration in vitro, but its influence on nerve regeneration in peripheral nerve isografts or allografts has not been studied. Sixty female inbred BALB/cJ mice were randomized into six tibial nerve transplant groups, including three isograft and three allograft (C57BL/6J) groups. Grafts were left untreated (groups I and II), treated with FK506 (groups III and IV), or treated with rapamycin (groups V and VI). Nerve regeneration was quantified in terms of histomorphometry and functional recovery, and immunosuppression was confirmed with mixed lymphocyte reactivity assays. Animals treated with FK506 and rapamycin were immunosuppressed and demonstrated significantly less immune cell proliferation relative to untreated recipient animals. Although every animal demonstrated some functional recovery during the study, animals receiving an untreated peripheral nerve allograft were slowest to recover. Isografts treated with FK506 but not rapamycin demonstrated significantly increased nerve regeneration. Nerve allografts in animals treated with FK506, and to a lesser extent rapamycin, however, both demonstrated significantly more nerve regeneration and increased nerve fiber widths relative to untreated controls. The authors suggest that rapamycin can facilitate regeneration through peripheral nerve allografts, but it is not a neuroregenerative agent in this in vivo model. Nerve regeneration in FK506-treated peripheral nerve isografts and allografts was superior to that found in rapamycin-treated animals. Rapamycin may have a role in the treatment of peripheral nerve allografts when used in combination with other medications, or in the setting of renal failure that often precludes the use of calcineurin inhibitors such as FK506.

Animals↗
PubMed2002

Axonal regeneration after cold preservation of nerve allografts and immunosuppression with tacrolimus in mice.

OBJECT: The purpose of this study was to combine the immunosuppressive and neuroregenerative effects of tacrolimus (FK506) with cold preservation of peripheral nerve allografts to maximize axonal regeneration across short peripheral nerve gaps. METHODS: Ninety-six male C3H mice were randomized to six groups, which were composed of animals with isografts (Group 1, positive control), allografts (Group 2, negative control), allografts treated with subtherapeutic doses of FK506 without and with cold preservation (Groups 3 and 4), and allografts treated with therapeutic doses of FK506 without and with cold preservation (Groups 5 and 6). Results were determined using walking-track data and histomorphometric measurements. Three weeks postoperatively, animals treated with therapeutic doses of FK506 after receiving cold-preserved allografts demonstrated accelerated functional recovery relative to all other groups. In addition, histomorphometric parameters in these animals (1,257 +/- 847 total axons, 6.7 +/- 3.3% nerve tissue, 11.8 +/- 6.5% neural debris, 8,844 +/- 4,325 fibers/mm2 nerve density, and 2.53 +/- 0.25 microm fiber width) were the same as or better than in all other groups. The parameters of percent nerve tissue (p < 0.016), nerve density (p < 0.038), and percent neural debris (p < 0.01) were statistically significantly better than those in all other groups, including Group 1 (isograft, positive control). CONCLUSIONS: The combination of FK506 treatment with cold preservation of nerve allografts resulted in functional and histomorphometric recovery superior to that with either modality alone.

Animals↗