The long term objective of this research is to understand the mechanisms underlying the unmasking of latent motor pathways which restore function to muscle paralyzed by spinal cord injury. The present proposal will perform pharmacological manipulations of the respiratory system to demonstrate that the output of the respiratory centers can be enhanced by drugs in order to restore function to a hemidiaphragm paralyzed by ipsilateral cervical spinal cord hemisection. The functional restitution is mediated by methylxanthine-induced activation of a latent motor respiratory pathway. The immediate goals are twofold. First, the principal investigator will focus on the specific pharmacological mechanisms of the methylxanthines on activating the latent motor pathways, and second, he will determine if methylxanthines can be used to achieve long term functional restitution of the diaphragm after cervical spinal cord injury.
Three specific aims will address the following hypotheses: 1. that activation of the latent crossed phrenic pathway by methylxanthines is mediated by central neuronal adenosine receptor antagonism, 2. that of the four cloned receptor subtypes, antagonism of the A1 receptor primarily mediates hemidiaphragmatic functional recovery in rats subjected to a C2 spinal cord hemisection, and 3. that oral administration of theophylline in C2 spinal hemisected rats will not only induce, but also will chronically maintain function in the previously paralyzed ipsilateral hemidiaphragm.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Neurology B Subcommittee 2 (NEUB)
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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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Hüttemann, Maik; Nantwi, Kwaku D; Lee, Icksoo et al. (2010) Theophylline treatment improves mitochondrial function after upper cervical spinal cord hemisection. Exp Neurol 223:523-8
Nantwi, Kwaku D (2009) Recovery of respiratory activity after C2 hemisection (C2HS): involvement of adenosinergic mechanisms. Respir Physiol Neurobiol 169:102-14
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
Petrov, Theodor; Kreipke, Christian; Alilain, Warren et al. (2007) Differential expression of adenosine A1 and A2A receptors after upper cervical (C2) spinal cord hemisection in adult rats. J Spinal Cord Med 30:331-7
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
Saharan, Rubabe S; Nantwi, Kwaku D (2006) Changes in the biochemical profiles of mid-cervically located adenosine A1 receptors after repeated theophylline administration in adult rats. J Spinal Cord Med 29:520-6
James, Elysia; Nantwi, Kwaku D (2006) Involvement of peripheral adenosine A2 receptors in adenosine A1 receptor-mediated recovery of respiratory motor function after upper cervical spinal cord hemisection. J Spinal Cord Med 29:57-66
Bae, Han; Nantwi, Kwaku D; Goshgarian, Harry (2005) Effects of carotid body excision on recovery of respiratory function in C2 hemisected adult rats. Exp Neurol 195:140-7
Bae, Han; Nantwi, Kwaku D; Goshgarian, Harry G (2005) Recovery of respiratory function following C2 hemi and carotid body denervation in adult rats: influence of peripheral adenosine receptors. Exp Neurol 191:94-103
Nantwi, Kwaku D; Goshgarian, Harry G (2005) Adenosinergic mechanisms underlying recovery of diaphragm motor function following upper cervical spinal cord injury: potential therapeutic implications. Neurol Res 27:195-205

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