title: Nanoconjugate-bound adenosine A1receptor antagonist enhances recovery of breathing following acute cervical spinal cord injury.
abstract: Respiratory complications in patients with spinal cord injury (SCI) are common and can have a negative impact on the quality of patients' lives. Previously, we found that intradiaphragmatic administration of the nanoconjugate-bound A1adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) induced recovery of diaphragm function following SCI in rats. When administered immediately following the injury, recovery was observed as early as 3days following SCI and it persisted until the end of the study, 28days after the drug delivery. The recovery was observed using diaphragmatic electromyography (EMG) as well as phrenic nerve recordings; both of which were conducted under anesthetized conditions. Confounding effects of anesthetic may make data interpretation complex in terms of the impact on overall ventilatory function and clinical relevance. The objective of the present study was to test the hypothesis that intradiaphragmatic administration of nanoconjugate-bound DPCPX, enhances recovery of ventilation following SCI in the unanesthetized rat. To that end, Sprague-Dawley rats underwent C2 spinal cord hemisection (C2Hx) on day 0 and received either: (i) 0.15μg/kg of nanoconjugate-bound DPCPX or (ii) vehicle control (50μl distilled water). To assess ventilation, unrestrained whole body plethysmography (WBP) was performed on day 0 (immediately before the surgery) and 3, 7, 14, 21 and 28days following the SCI. Frequency, tidal volume, and minute ventilation data were analyzed in two minute bins while the animal was calm and awake. We found that a single administration of the nanoconjugate-bound A1adenosine receptor antagonist facilitated recovery of tidal volume and minute ventilation following SCI. Furthermore, the treatment attenuated SCI-associated increases in respiratory frequency. Taken together, this study suggests that the previously observed DPCPX nanoconjugate-induced recovery in diaphragmatic and phrenic motor outputs may translate to a clinically meaningful improvement in ventilatory function in patients with SCI.
authors.affiliation: Wayne State University, School of Medicine, Department of Anatomy and Cell Biology, 540 E. Canfield St, Detroit, MI 48201, United States; Wayne State University, School of Medicine, Cardiovascular Research Institute, 540 E. Canfield St, Detroit, MI 48201, United States. Electronic address: zminic@med.wayne.edu.
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Minic
authors.affiliation: Wayne State University, School of Medicine, Department of Anatomy and Cell Biology, 540 E. Canfield St, Detroit, MI 48201, United States.
authors.forename: Sharowyn
authors.initials: S
authors.lastname: Wilson
authors.affiliation: Wayne State University, Department of Chemical Engineering and Materials Science, 5050 Anthony Wayne Drive, Detroit, MI 48202, United States.
authors.forename: Fangchao
authors.initials: F
authors.lastname: Liu
authors.affiliation: Wayne State University, School of Medicine, Department of Anatomy and Cell Biology, 540 E. Canfield St, Detroit, MI 48201, United States; Wayne State University, School of Medicine, Cardiovascular Research Institute, 540 E. Canfield St, Detroit, MI 48201, United States; John D. Dingell VA Medical center, Department of Medicine, 4646 John R, Detroit, MI, 48201, United States.
authors.forename: Abdulghani
authors.initials: A
authors.lastname: Sankari
authors.affiliation: Wayne State University, Department of Chemical Engineering and Materials Science, 5050 Anthony Wayne Drive, Detroit, MI 48202, United States.
authors.forename: Guangzhao
authors.initials: G
authors.lastname: Mao
authors.affiliation: Wayne State University, School of Medicine, Department of Anatomy and Cell Biology, 540 E. Canfield St, Detroit, MI 48201, United States.
authors.forename: Harry
authors.initials: H
authors.lastname: Goshgarian
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D066193:Cervical Cord / Q000187:drug effects; D008297:Male; D058726:Nanoconjugates / Q000008:administration & dosage*; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058726:Nanoconjugates; D043682:Receptor, Adenosine A1
keywords: Breathing; Nanotechnology; Spinal cord injury; Targeted drug delivery; Ventilatory function