Daily low dose ampakine treatment causes a sustained increase in diaphragm activation following chronic cervical spinal cord injury

Abstract

Cervical spinal cord injuries (SCIs) result in significant and long-lasting respiratory compromise, leading to morbidity and mortality in the SCI patient population. There is a critical need to develop therapies to counter this respiratory insufficiency. Ampakines are positive allosteric modulators of AMPA receptors that have been shown to alleviate respiratory depression following neuromuscular disorders or opioid use. We have recently shown that low dose (5mg/kg) ampakines can stimulate diaphragm muscle activation and increase overall ventilation at acute and sub-acute timepoints post C2 spinal hemisection injury in rats. Our next step in the translation pathway is to transition to a repeated daily ampakine exposure paradigm after a chronic SCI, as part of a rehabilitation approach. Previous studies in hippocampal slices have shown that repeated dosing with ampakines can support long term potentiation mechanisms and upregulate neuroplasticity related genes. In the present study, we hypothesized that daily treatment with ampakines in chronically injured rats will cause a sustained increase in diaphragm motor output following a high cervical SCI. Over the period of 8-12 weeks after C2 spinal hemisection injury, rats received daily intra-peritoneal injections of ampakine CX717 (5 mg/kg, n=8; 4M, 4F) or CX1739 (5 mg/kg, n=8; 4M, 4F) or vehicle (2-hydroxypropyl-beta-cyclodextrin; HPCD; n=8; 4M, 4F). Ventilation was measured using whole body plethysmography and diaphragm electromyogram (EMG) was assessed using in-dwelling muscle electrodes. Recordings were conducted at 8-, 10- and 12-weeks post injury. The acute response to intravenous ampakine administration was also assessed at the chronically injured timepoint of 8 weeks. Both CX717 and CX1739 were effective at stimulating ipsilateral diaphragm muscle activity (51 ± 12% and 32 ± 5% increase, respectively; p=0.002) and tidal volume (19 ± 7% and 25 ± 7% respectively; p=0.002) as compared to the HPCD group (EMG: 4 ± 3%, tidal volume: -3 ± 5%) at 8 weeks post C2 hemisection. The effect of CX717 treatment was sustained up to 15 minutes where as CX1739 returned close to baseline by 15 minutes. With daily ampakine treatment, we observed a progressive increase (treatment effect: p=0.009) in ipsilateral diaphragm EMG output during eupneic breathing at the 10- and 12-week time points in both the CX717 (13 ± 5%, 18 ± 7% respectively) and CX1739 (9 ± 4%, 17 ± 7% respectively) treated groups as compared to the EMG output at the onset of the daily ampakine therapy. No change in EMG output was observed in the daily HPCD group (-2 ± 3%, -0.5 ± 5% respectively). There was no impact of daily ampakine treatment on respiratory rate, which may indicate that the drug is acting on spinal motoneurons (vs. a medullary mechanism). Our data indicates that daily treatment with ampakines is a promising therapy to stimulate long-lasting neuroplastic changes in respiratory circuits to promote functional recovery following SCI. 1R01HL139708-01A1 (DDF), 1 R01 HL153140-01 (DDF), Craig Neilsen Foundation Fellowship (SR) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.