Ampakines enhance weak endogenous respiratory drive and alleviate apnea in perinatal rats

• Published in: American journal of respiratory and critical care medicine 2015-03, Vol.191 (6), p.704-710
• Main Authors: Ren, Jun, Ding, Xiuqing, Greer, John J
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - pharmacology; Animals; Animals, Newborn; Apnea - drug therapy; Brain Stem - drug effects; Caffeine - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; Fetus - drug effects; In Vitro Techniques; Plethysmography; Rats; Respiration - drug effects; Respiratory Distress Syndrome, Newborn - drug therapy; Spinal Cord - drug effects
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201410-1898OC

Apnea of prematurity, which is prevalent among infants born at less than 34 weeks gestation, is treated with caffeine, theophylline, or aminophylline. However, not all newborns respond adequately to, or tolerate, methylxanthine administration, and thus alternative pharmacological therapies are required. Rodent models are used to test the hypothesis that the ampakine CX1739, a positive allosteric modulator of amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors, strengthens perinatal respiratory drive and reduces apneas. We also provide a systematic study of the effects of caffeine for comparison. Respiratory neural activity was recorded from brainstem-spinal cord in vitro perinatal rat preparations, and [Formula: see text]e was recorded in newborn rat pups using whole-body plethysmography under normoxic and hypoxic conditions. Using in vitro brainstem-spinal cord preparations, we found that CX1739 (10-100 μM) dose-dependently increases the frequency of respiratory activity generated by fetal and newborn rat preparations under normoxic and hypoxic conditions. Plethysmographic recordings in vivo from Postnatal Day 0 rats demonstrated that CX1739 (10 mg/kg) increases the frequency and regularity of ventilation, reduces apneas, and protects against hypoxia-induced respiratory depression. The net effect of ampakine enhancement of respiratory drive in perinatal rodents is a marked increase in ventilation and the regularity of respiratory patterns in perinatal rat preparations. Importantly, from the perspective of clinical applications, CX1739 readily crosses the blood-brain barrier, is metabolically stable, and has passed through phase I and II clinical trials in adults.