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Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines.

Publication ,  Journal Article
ElMallah, MK; Pagliardini, S; Turner, SM; Cerreta, AJ; Falk, DJ; Byrne, BJ; Greer, JJ; Fuller, DD
Published in: Am J Respir Cell Mol Biol
September 2015

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.

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Published In

Am J Respir Cell Mol Biol

DOI

EISSN

1535-4989

Publication Date

September 2015

Volume

53

Issue

3

Start / End Page

326 / 335

Location

United States

Related Subject Headings

  • Respiratory System Agents
  • Respiratory System
  • Respiration
  • Phrenic Nerve
  • Motor Activity
  • Mice, Knockout
  • Mice, 129 Strain
  • Isoxazoles
  • Glycogen Storage Disease Type II
  • Drug Evaluation, Preclinical
 

Citation

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ElMallah, M. K., Pagliardini, S., Turner, S. M., Cerreta, A. J., Falk, D. J., Byrne, B. J., … Fuller, D. D. (2015). Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines. Am J Respir Cell Mol Biol, 53(3), 326–335. https://doi.org/10.1165/rcmb.2014-0374OC
ElMallah, Mai K., Silvia Pagliardini, Sara M. Turner, Anthony J. Cerreta, Darin J. Falk, Barry J. Byrne, John J. Greer, and David D. Fuller. “Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines.Am J Respir Cell Mol Biol 53, no. 3 (September 2015): 326–35. https://doi.org/10.1165/rcmb.2014-0374OC.
ElMallah MK, Pagliardini S, Turner SM, Cerreta AJ, Falk DJ, Byrne BJ, et al. Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines. Am J Respir Cell Mol Biol. 2015 Sep;53(3):326–35.
ElMallah, Mai K., et al. “Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines.Am J Respir Cell Mol Biol, vol. 53, no. 3, Sept. 2015, pp. 326–35. Pubmed, doi:10.1165/rcmb.2014-0374OC.
ElMallah MK, Pagliardini S, Turner SM, Cerreta AJ, Falk DJ, Byrne BJ, Greer JJ, Fuller DD. Stimulation of Respiratory Motor Output and Ventilation in a Murine Model of Pompe Disease by Ampakines. Am J Respir Cell Mol Biol. 2015 Sep;53(3):326–335.

Published In

Am J Respir Cell Mol Biol

DOI

EISSN

1535-4989

Publication Date

September 2015

Volume

53

Issue

3

Start / End Page

326 / 335

Location

United States

Related Subject Headings

  • Respiratory System Agents
  • Respiratory System
  • Respiration
  • Phrenic Nerve
  • Motor Activity
  • Mice, Knockout
  • Mice, 129 Strain
  • Isoxazoles
  • Glycogen Storage Disease Type II
  • Drug Evaluation, Preclinical