Pharmacological modulation of respiratory control: Ampakines as a therapeutic strategy

• Published in: Pharmacology & therapeutics (Oxford) 2025-01, Vol.265, p.108744, Article 108744
• Main Authors: Rana, Sabhya, Fusco, Anna F., Witkin, Jeffrey M., Radin, Daniel P., Cerne, Rok, Lippa, Arnold, Fuller, David D.
• Format: Article
• Language: English
• Subjects: Ampakines; Animals; Humans; Phrenic motor neurons; Receptors, AMPA; Respiration - drug effects; Respiration Disorders - drug therapy; Respiration Disorders - physiopathology; Respiratory insufficiency; Respiratory Muscles - drug effects; Respiratory physiology; Spinal Cord Injuries - drug therapy; Spinal Cord Injuries - physiopathology; Synaptic Transmission - drug effects
• ISSN: 0163-7258; 1879-016X; 1879-016X
• DOI: 10.1016/j.pharmthera.2024.108744

Ampakines are a class of compounds that are positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and enhance glutamatergic neurotransmission. Glutamatergic synaptic transmission and AMPA receptor activation are fundamentally important to the genesis and propagation of the neural impulses driving breathing, including respiratory motoneuron depolarization. Ampakines therefore have the potential to modulate the neural control of breathing. In this paper, we describe the influence of ampakines on respiratory motor output in health and disease. We dissect the molecular mechanisms underlying ampakine action, delineate the diverse targets of ampakines along the respiratory neuraxis, survey the spectrum of respiratory disorders in which ampakines have been tested, and culminate with an examination of how ampakines modulate respiratory function after spinal cord injury. Collectively, the studies reviewed here indicate that ampakines may be a useful adjunctive strategy to pair with conventional respiratory rehabilitation approaches in conditions with impaired neural activation of the respiratory muscles.