Ampakines enhance phrenic nerve output in a ZFN rat model of Pompe Disease

Abstract

Pompe disease (PD) is caused by mutations in the gene encoding acid-α-glucosidase (GAA), an enzyme that degrades lysosomal glycogen. The resultant glycogen accumulation is associated with neurodegeneration, cardiac deficits, and impaired phrenic motoneuron and diaphragm activation. Cardiorespiratory failure is the leading cause of death in early-onset PD patients. We previously reported that a drug which acts as a positive allosteric modulator of AMPA receptors, ampakine CX717, could stimulate phrenic motor output and increase minute ventilation in a mouse model of Pompe disease (Gaa-/-). We recently created a new rat model of PD that better recapitulates the clinical phenotype of early onset PD, called the Zinc Finger Nuclease (ZFN) KO model. Phrenic nerve recordings were performed on urethane anesthetized ZFN KO rats of both sexes, and age-matched wild type (WT) controls during a baseline normoxic period, followed by a brief exposure to hypoxia (PaO2 ~ 30mmHg) and a maximal respiratory challenge with combined hypoxia-hypercapnia. Recordings were done before and after treatment with ampakine CX717 (15mg/kg) or its vehicle control (2-Hydroxypropyl)-β-cyclodextrin. Our goal was to build upon the prior data from the Gaa-/-mouse, by using the ZFN KO model to test the hypothesis that in addition to stimulating basal or “eupneic” phrenic output, ampakine CX717 could also increase the ability to respond to acute respiratory challenge. We also aimed to determine if the extent of phrenic motor deficits were different between male and female ZFN KO rats. The data confirm that both male and female ZFN KO rats exhibit cardiac irregularities and phrenic motor deficits when compared to WT controls. However, a sex difference was apparent as male ZFN KO rats exhibit greater phrenic motor deficits and blunted responses to gas challenges compared to female ZFN KO rats. Ampakine treatment enhanced phrenic output and improved the ability to respond to respiratory challenge in both sexes of the ZNF rat model of PD. We conclude that 1) sex differences are present in the phrenic motor phenotype of ZFN KO rats, 2) the ability of low dose CX717to stimulate phrenic motor output in PD is reproducible across two species, and 3) low dose CX717 can enhance the ability to respond to respiratory challenge in PD rats These data suggest that ampakines may serve as a viable adjunctive therapy for respiratory insufficiency in PD patients.