Ampakines Alleviate Respiratory Depression in Rats

Ren, Jun; Poon, Betty Y.; Tang, Yun; Funk, Gregory D.; Greer, John J.

doi:10.1164/rccm.200606-778oc

Cited by 96 publications

(83 citation statements)

References 32 publications

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“…In addition, brainstem histology confirmed extensive motoneuron pathology in Gaa 2/2 mice, and showed, for the first time, histopathology in medullary respiratory control neurons. The dramatic impact of CX717 on efferent respiratory motor output in Gaa 2/2 mice supports the hypothesis that respiratory neuropathology has a functional impact in Pompe disease (4), as ampakines stimulate breathing most effectively when respiratory neuromotor activity is blunted (13,20).…”

Section: Discussionsupporting

confidence: 63%

“…These drugs successfully stimulated breathing after opiate-induced respiratory depression in clinical trials (13,14). Importantly, preclinical studies show that ampakines most effectively stimulate breathing when the neural input to respiratory muscles is blunted (13,(15)(16)(17).…”

mentioning

confidence: 99%

“…This is a fundamental consideration, as delineation of the neuronal mechanisms contributing to respiratory failure in Pompe disease is a prerequisite for optimizing therapeutic strategies. Mechanistically, ampakines can act on both respiratory premotor circuits and motoneurons (13,20), and, accordingly, we believed it was important to determine if pathology was present in premotor respiratory control neurons, and to compare and contrast the histological appearance of these cells with respiratory motoneurons.…”

mentioning

confidence: 99%

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

ElMallah

Pagliardini

Turner

et al. 2015

Am J Respir Cell Mol Biol

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Pompe disease results from a mutation in the acid a-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 a-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 2/2 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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Section: Discussionsupporting

confidence: 63%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

ElMallah

Pagliardini

Turner

et al. 2015

Am J Respir Cell Mol Biol

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“…Two different modulators of AMPA receptors, called ampakines [54], have been shown to attenuate opioid-induced respiratory depression in animal models, without affecting opioid-induced analgesia. Ren et al [55] found that the ampakine CX546 counteracts the opioid-induced depression of ventilatory drive in both brainstem slices and en-bloc preparations. Similar results were observed in newborn rats, again with no reduction in opioid-induced analgesia.…”

Section: Opioidsmentioning

confidence: 99%

Sources of Inspiration: A Neurophysiologic Framework for Understanding Anesthetic Effects on Ventilatory Control

Czick

Waldman

Gross

2013

Curr Anesthesiol Rep

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Almost every medication that is presently available to provide sedation, analgesia, or general anesthesia significantly depresses one or more ventilatory control mechanisms. This places patients at risk of developing hypoventilation and hypoxemia during moderate or deep sedation as well as general anesthesia. As the neurophysiologic processes underlying normal ventilatory drive are discovered, new insights into the influence of anesthetics on ventilation have been recognized. More importantly, research into ways to circumvent these effects is underway. For example, drugs such as serotonin agonists and ampakines have been shown to counteract opioidinduced ventilatory depression without reversing the analgesic effect. On the other hand, efforts to identify agents that reverse the respiratory depression associated with propofol and the inhalation anesthetics have been less promising. Until reliable means for reversing drug-induced ventilatory depression are developed, prompt recognition of ventilatory insufficiency and initiation of resuscitative measures remain the keys to patient safety.

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“…The effectiveness of ampakine for treating respiratory control disorders may be different in newborn and older mice. In particular, studies in brain stem-spinal cord preparations in newborn rats showed that ampakine increased breathing frequency when given within 3 days after birth (69). The duration of this effect has not been investigated.…”

Section: Invited Reviewmentioning

confidence: 99%