In recent years, we have discovered that certain drugs (methylxanthines, phosphodiesterase inhibitors and selective A1 adenosine receptor antagonists) will induce plasticity in the respiratory pathways which results in recovery of the diaphragm after cervical spinal cord injury. Furthermore, we discovered that after rats are exposed to 3 days of multiple systemic drug administrations (3 injections/day);the drug-induced recovery persists long after the animals are weaned from the drug. In an effort to test our basic science work at the clinical level, we conducted 3 clinical studies using the methylxanthine, theophylline. The results of these theophylline studies were mixed. Some patients showed promising results whereas others did not following the required systemic administration of the drug (either by mouth or intravenous administration). The lack of complete success at the clinical level could not be attributed to any single factor. However, it was very clear that the majority of the patients could not tolerate the theophylline doses necessary to induce recovery without experiencing significant side effects (nausea, nervousness, vomiting, etc.) which forced them to discontinue drug therapy. To directly address the problem of side effects following systemic theophylline therapy in cervical SCI patients, we recently developed a novel approach which combines nanotechnology and proven neurobiological principals to "selectively target" only the respiratory motor (phrenic) and pre- motor (rVRG) neurons responsible for diaphragmatic function to induce recovery. We have shown that by using this method we can induce recovery of the diaphragm in spinal cord injured rats using 1/160th the dose of theophylline necessary to induce recovery following systemic drug administration. This approach to inducing motor recovery after SCI has never been taken by any other laboratory in the world. The purpose of this application is to optimize this technique so that it may be developed for clinical use. There will be three specific aims to address the following hypotheses: 1) that following a non-systemic administration (injection into the paralyzed hemidiaphragm) of one of three different drug-delivering conjugate nanodevices, optimal recovery will be induced. 2) that the "site(s) of action" of the conjugate nanodevice in inducing recovery will be determined by using different retrograde transporters to selectively target different respiratory neurons. 3) that following the single administration of either a slow-drug release, a fast-drug release, or a combination (cocktail) of both conjugate nanodevices, long-lasting functional recovery will be achieved in the hemidiaphragm paralyzed by spinal hemisection.

Public Health Relevance

The ability to induce diaphragmatic recovery in SCI rats with conjugate nanodevices using only a small fraction of the theophylline previously necessary to induce recovery, has major translational implications for the use of this drug (and others like it) in treating SCI patients with respiratory muscle weakness. The obvious advantage is the low dose of the drug should reduce (or completely eliminate) the adverse side effects normally associated with administering theophylline systemically (i.e., orally or intravenously). The purpose of this application is to optimize our newly developed technique so that it may be further developed for clinical use as soon as possible.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Nitkin, Ralph M
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Wayne State University
Anatomy/Cell Biology
Schools of Medicine
United States
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Buttry, Janelle L; Goshgarian, Harry G (2014) Injection of WGA-Alexa 488 into the ipsilateral hemidiaphragm of acutely and chronically C2 hemisected rats reveals activity-dependent synaptic plasticity in the respiratory motor pathways. Exp Neurol 261:440-50
Goshgarian, Harry G; Buttry, Janelle L (2014) The pattern and extent of retrograde transsynaptic transport of WGA-Alexa 488 in the phrenic motor system is dependent upon the site of application. J Neurosci Methods 222:156-64
Huang, Y; Goshgarian, H G (2009) Identification of the neural pathway underlying spontaneous crossed phrenic activity in neonatal rats. Neuroscience 163:1109-18
Kajana, Satkunendrarajah; Goshgarian, Harry G (2009) Systemic administration of rolipram increases medullary and spinal cAMP and activates a latent respiratory motor pathway after high cervical spinal cord injury. J Spinal Cord Med 32:175-82
Huang, Yonglu; Goshgarian, Harry G (2009) Postnatal conversion of cross phrenic activity from an active to latent state. Exp Neurol 219:66-73
Zimmer, M Beth; Nantwi, Kwaku; Goshgarian, Harry G (2008) Effect of spinal cord injury on the neural regulation of respiratory function. Exp Neurol 209:399-406
Zimmer, M Beth; Goshgarian, Harry G (2007) Spinal cord injury in neonates alters respiratory motor output via supraspinal mechanisms. Exp Neurol 206:137-45
Zimmer, M Beth; Nantwi, Kwaku; Goshgarian, Harry G (2007) Effect of spinal cord injury on the respiratory system: basic research and current clinical treatment options. J Spinal Cord Med 30:319-30
Zimmer, M Beth; Goshgarian, Harry G (2006) Spinal activation of serotonin 1A receptors enhances latent respiratory activity after spinal cord injury. J Spinal Cord Med 29:147-55
Minor, Kenneth H; Akison, Lisa K; Goshgarian, Harry G et al. (2006) Spinal cord injury-induced plasticity in the mouse--the crossed phrenic phenomenon. Exp Neurol 200:486-95

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