title: Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines.
abstract: Pompe disease results from a mutation in the acid α-glucosidase gene leading to lysosomal glycogen accumulation. Respiratory insufficiency is common, and the current U.S. Food and Drug Administration-approved treatment, enzyme replacement, has limited effectiveness. Ampakines are drugs that enhance α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor responses and can increase respiratory motor drive. Recent work indicates that respiratory motor drive can be blunted in Pompe disease, and thus pharmacologic stimulation of breathing may be beneficial. Using a murine Pompe model with the most severe clinical genotype (the Gaa(-/-) mouse), our primary objective was to test the hypothesis that ampakines can stimulate respiratory motor output and increase ventilation. Our second objective was to confirm that neuropathology was present in Pompe mouse medullary respiratory control neurons. The impact of ampakine CX717 on breathing was determined via phrenic and hypoglossal nerve recordings in anesthetized mice and whole-body plethysmography in unanesthetized mice. The medulla was examined using standard histological methods coupled with immunochemical markers of respiratory control neurons. Ampakine CX717 robustly increased phrenic and hypoglossal inspiratory bursting and reduced respiratory cycle variability in anesthetized Pompe mice, and it increased inspiratory tidal volume in unanesthetized Pompe mice. CX717 did not significantly alter these variables in wild-type mice. Medullary respiratory neurons showed extensive histopathology in Pompe mice. Ampakines stimulate respiratory neuromotor output and ventilation in Pompe mice, and therefore they have potential as an adjunctive therapy in Pompe disease.
authors.affiliation: Divisions of 1 Pulmonary Medicine.
authors.forename: Mai K
authors.initials: MK
authors.lastname: ElMallah
authors.affiliation: 2 Department of Physiology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pagliardini
authors.affiliation: 3 Department of Physical Therapy, College of Public Health and Health Professions.|4 McKnight Brain Institute, and.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Turner
authors.affiliation: 3 Department of Physical Therapy, College of Public Health and Health Professions.|4 McKnight Brain Institute, and.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Cerreta
authors.affiliation: 5 Cellular and Molecular Therapy, and.|6 Pediatric Cardiology, Department of Pediatrics, College of Medicine.|7 Powell Gene Therapy Center, University of Florida, Gainesville, Florida; and.
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Falk
authors.affiliation: 5 Cellular and Molecular Therapy, and.|6 Pediatric Cardiology, Department of Pediatrics, College of Medicine.|7 Powell Gene Therapy Center, University of Florida, Gainesville, Florida; and.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
authors.affiliation: 2 Department of Physiology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: John J
authors.initials: JJ
authors.lastname: Greer
authors.affiliation: 3 Department of Physical Therapy, College of Public Health and Health Professions.|4 McKnight Brain Institute, and.
authors.forename: David D
authors.initials: DD
authors.lastname: Fuller
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000503:physiopathology; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010791:Phrenic Nerve / Q000187:drug effects / Q000503:physiopathology; D012119:Respiration / Q000187:drug effects*; D019141:Respiratory System Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C542518:CX717; D007555:Isoxazoles; D019141:Respiratory System Agents
keywords: Pompe disease; ampakines; medulla; neuropathology; respiratory insufficiency