The long term objective of this proposed research is to elucidate the mechanisms that underlie the unmasking and subsequent pharmacologic activation of latent respiratory motor pathways to restore function to respiratory muscles paralyzed by spinal cord injury. The present application proposes multiple pharmacologic manipulations of the respiratory system to demonstrate that the respiratory output can be enhanced further to improve respiratory function after spinal cord injury (SCI). We will address clinically-relevant issues attendant to the use of theophylline in spinal cord injured patients. First, we will focus in on selective peripherally-mediated mechanisms that can minimize respiratory muscle fatigue that may be attendant to prolonged methylxanthine (theophylline) use. We will also focus in on putative mechanisms that may underlie the clinical observation that some spinal cord injured patients are nonresponsive to theophylline therapy. There are three specific aims to test the following hypotheses: (1) that following pharmacological activation of peripheral chemoreceptors in the carotid bodies, theophylline-induced respiratory muscle recovery can be modulated to more closely approximate normal firing frequencies. (2) that the GABA B receptor agonist, baclofen, used frequently in SCI patients as an antispasticity and muscle relaxant medication, does not modify theophylline's ability to restore function to paralyzed respiratory muscle following upper cervical spinal cord hemisection. (3) that the systemic administration of 4-aminopyridine (4AP), a potassium channel blocker, will enhance conduction in partially demyelinated latent respiratory axons and thus improve theophylline's action of restoring function to paralyzed respiratory muscle after cervical spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD035766-07
Application #
6622062
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Nitkin, Ralph M
Project Start
1997-09-15
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
7
Fiscal Year
2003
Total Cost
$232,535
Indirect Cost
Name
Wayne State University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
H├╝ttemann, 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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