Treatment with a positive allosteric AMPA receptor modulator ("ampakine") can improve respiratory muscle activation and bladder function after sub-acute (days) to chronic (weeks to months) spinal cord injury (SCI). Prior studies of SCI and excitotoxicity provide evidence that ampakines may also promote neuroprotection. We hypothesized that initiating daily low-dose treatment with the low-impact ampakine CX1739 acutely after SCI would be neuroprotective and promote recovery. Adult rats received unilateral 150 kydne C4 contusion; CX1739 (5 mg/kg, n = 12) or vehicle (hydroxypropyl beta-cyclodextrin, HPCD; n = 11) given 15 min post-SCI and daily for 14 days. Breathing was evaluated using whole-body plethysmography, and locomotion was evaluated using an open field test. Cervical spinal cords were stained with NeuN to identify neuronal soma, MCA-6H63 to identify degenerating axons, and Iba-1 to identify microglia and macrophages. No differences between the HPCD and ampakine groups were noted in neuronal counts, number of MCA-6H63 positive axons, or Iba-1 staining. Respiratory rate and tidal volume were similar between groups. Ampakine treatment, however, was associated with reduced open-field motor scores and increased relative risk of post-SCI complications. We conclude that ampakine CX1739 (5 mg/kg) given daily over 0-14 days post-SCI provides no discernible benefit, and acute ampakine treatment is contraindicated, in contrast to delayed dosing paradigms. Ampakine treatment should be reserved for the subacute and chronic SCI conditions, beyond the acute period of glutamate-related neurotoxicity. These results will be particularly important in determining the optimal timing of ampakine administration as CX1739 progresses in clinical trials.
Keywords: AMPA; ampakine; excitotoxicity; glutamate; neuroprotection; spinal cord injury.