Pairing ampakine with brief hypoxia evokes phrenic neuroplasticity via a spinal NMDA receptor mediated mechanism

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ID: 321429
2026
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Abstract
Brief hypoxic episodes drive neuroplasticity in animal models and humans. Pretreatment with an allosteric AMPA receptor (R) modulator (“ampakine”) enables a single hypoxic exposure to induce sustained increases in phrenic motor activity (“phrenic motor facilitation” or pMF). Phrenic nerve activity was recorded in anesthetized rats to determine if the ampakine-hypoxia (A-H) combination is unique in its ability to evoke pMF and to determine its underlying mechanisms. Pairing ampakine CX717 with brief moderate or severe hypercapnia failed to produce pMF. Pairing doxapram, a respiratory stimulant, with hypoxia did not produce pMF. We then sequentially tested the hypotheses that A-H induced pMF requires spinal serotonin, adenosine or NMDA receptor activation. Cervical intrathecal delivery of serotonin (methysergide) or adenosine 2A receptor (MSX-3) antagonists prior to A-H failed to prevent pMF. In contrast, the NMDA-R blocker MK-801 prevented pMF when administered before but not after A-H. Lastly, as a step in the translational pathway, we tested the safety and efficacy of acute A-H exposure in unanesthetized rats with indwelling diaphragm electromyogram (EMG) wires after cervical spinal cord injury (SCI). A-H was well tolerated, and at 3 months post-SCI, increased diaphragm EMG output. We conclude that the mechanism driving sustained increases in phrenic motor output after A-H is independent of spinal adenosine or serotonin receptor activation, but requires spinal NMDA-R activation for the induction, but not maintenance of A-H pMF. Ampakine pretreatment may be useful to increase the efficacy of hypoxia-based rehabilitation paradigms after SCI, particularly since clinical trials report a substantial number of “low-responders”.
Reference Key
openalex_W7169584435 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Prajwal P. Thakre, Sabhya Rana, Raphael R. Perim, Gordon S. Mitchell, David D. Fuller
Journal Food & function
Year 2026
DOI
10.1152/function.019.2026
URL
https://doi.org/10.1152/function.019.2026
Keywords Keywords not found

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