Impact of ampakine CX1739 on histological neuronal counts after acute cervical spinal cord injury (SCI)

Excitotoxicity, which is defined as toxicity resulting from excess excitatory signaling, contributes to the secondary SCI cascade. In turn, this may cause neuronal loss beyond what results from the primary injury. Previous studies have reported that administering ampakines, which are positive allosteric modulators of AMPA type glutamate receptors, can mitigate the neuronal loss that occurs during excitotoxicity induced by administration of AMPA agonist or excitotoxic drugs (PMID: 11869032). Other work suggests that ampakines may be neuroprotective when initiated 7 days after SCI (PMID: 36764296). We hypothesized that a low dose of a “low impact” ampakine (CX1739) would mitigate neuronal loss in the mid-cervical spinal cord when initiated shortly after SCI. Adult (age 11 ± 1 weeks) Sprague Dawley (SD) rats received a right unilateral C4 contusion (impact force = 150 kdyne). A control group (n=5) consisted of spinal intact rats who received the same anesthetic and analgesic regimen. CX1739 (5mg/kg; n=7) or vehicle, hydroxypropyl beta cyclodextrin (HPCD; n=7) was administered 15-min post injury and then daily for 14 days. The cervical spinal cord was harvested, sectioned (20 um), and incubated with an antibody for neuronal nuclear protein (NeuN) to identify neurons. Tissues were imaged using the PhenoImager HT (Akoya Biosciences®) microscope NeuN-positive cells were counted in the vicinity of the lesion (C4-C6) using the Cellpose cellular segmentation algorithm (PMID: 33318659). Compared to spinal-intact tissue, the SCI caused the expected reduction in neuronal counts with the greatest reduction centered at the lesion epicenter. There was no evidence that CX1739 treatment had a neuroprotective impact. Neuronal counts across the lesion (C4-C6) were similar in the CX1739 and HPCD treated groups (p=0.59). Both groups were dramatically reduced relative to the spinal intact group (p<0.0001). We conclude that administering a low dose of ampakine CX717 beginning shortly after mid-cervical contusion injury has no detectable benefit on neuronal survival. 5R01HL138708-04 (DF), 5R01HL153140-03 (DF), 5T32HD043730-19 (AFF), Frank M Davis MD Chairman Emeritus Grant (AFF), 1K99NS133388-01A (SR) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.