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.