Ampakines increase diaphragm activation following mid-cervical contusion injury in rats

Abstract

Ampakines are positive allosteric modulators of AMPA receptors. We hypothesized that low-dose ampakine treatment increases diaphragm electromyogram (EMG) activity after mid-cervical contusion injury in rats. Adult male and female Sprague Dawley rats were implanted with in-dwelling bilateral diaphragm EMG electrodes. Rats received a 150 kDyn C4 unilateral contusion (C4Ct). At 4- and 14-days following C4Ct, rats were given an intravenous bolus of ampakine CX717 (5 mg/kg, n = 10) or vehicle (2-hydroxypropyl-beta-cyclodextrin; HPCD; n = 10). Diaphragm EMG was recorded while breathing was assessed using whole-body plethysmography. At 4-days, ampakine administration caused an immediate and sustained increase in bilateral peak inspiratory diaphragm EMG bursting and ventilation. The vehicle had no impact on EMG bursting. CX717 treated rats were able to increase EMG activity during a respiratory challenge to a greater extent vs. vehicle treated. Rats showed a considerable degree of spontaneous recovery of EMG bursting by 14 days, and the impact of CX717 delivery was blunted as compared to 4-days. Direct recordings from the phrenic nerve at 21–24 days following C4Ct confirmed that ampakines stimulated bilateral phrenic neural output in injured rats. We conclude that low-dose intravenous treatment with a low-impact ampakine can enhance diaphragm activation shortly following mid-cervical contusion injury, when deficits in diaphragm activation are prominent.