AMPA receptors play an important role in the biological consequences of spinal cord injury: Implications for AMPA receptor modulators for therapeutic benefit

Abstract

Spinal cord injury (SCI) afflicts millions of individuals globally. There are few therapies available to patients. Ascending and descending excitatory glutamatergic neural circuits in the central nervous system are disrupted by SCI, making α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) a potential therapeutic drug target. Emerging research in preclinical models highlights the involvement of AMPARs in vital processes following SCI including breathing, pain, inflammation, bladder control, and motor function. However, there are no clinical trial data reported in this patient population to date. No work on the role of AMPA receptors in sexual dysfunction after SCI has been disclosed. Compounds with selective antagonist and potentiating effects on AMPA receptors have benefit in animal models of SCI, with antagonists generally showing protective effects early after injury and potentiators (ampakines) producing improved breathing and bladder function. The role of AMPARs in pathophysiology and recovery after SCI depends upon the time post injury, and the timing of AMPAR augmentation or antagonism. The roles of inflammation, synaptic plasticity, sensitization, neurotrophic factors, and neuroprotection are considered in this context. The data summarized and discussed in this paper document proof of principle and strongly encourage additional studies on AMPARs as novel gateways to therapeutic benefit for patients suffering from SCI. The availability of both AMPAR antagonists such as perampanel and AMPAR allosteric modulators (i.e., ampakines) such as CX1739, that have been safely administered to humans, provides an expedited means of clinical inquiry for possible therapeutic advances.

Keywords: AMPA receptor antagonists; AMPA receptors; Ampakines; CX1739; Spinal cord injury.

Figure 1.

Structures of some of the AMPAR antagonists (left column), potentiators or ampakines (middle column), and agonists (right column) discussed in this paper.

Figure 2.

Scientific literature on spinal cord injury over time from https://pubmed.ncbi.nlm.nih.gov/ on 08 December 2023. Data show total number of publications and the number of publications in the peak year in parentheses.

Figure 3.

Impairment of diaphragm electromyographic (EMG) activity in intact rats and in rats following C2 spinal hemisection (C2Hx) injury. Representative EMG traces (black) and corresponding processed traces (red; rectified, smoothed, filtered) from the diaphragm ipsilateral to C2Hx (or left side in spinal-intact animal) in intact (A) or C2Hx rats (B). Data are shown pre-injury, and 4- and 14-days post-injury (or corresponding time point in spinal-intact animals) during eupneic breathing. The diaphragm EMG recordings from the chronic indwelling electrodes were stable over the course of the study in all animals. (C) Mean ipsilateral and contralateral diaphragm EMG activity (peak amplitude) and respiratory rate. Ipsilateral EMG activity is reduced by ∼50–60% post-C2Hx, with minimal impact on contralateral EMG activity. Data are represented as mean with corresponding confidence interval, and individual data (spinal intact, gray dots, n = 7; C2Hx, black dots, n = 10). Data are from Rana et al. [95] with permission from the publisher.

Figure 4.

Impact of ampakines on peak diaphragm electromyograpic (EMG) amplitude after 4 days (top panels) or 14 days (bottom panels) after C2 spinal hemisection [C2Hx] injury. Peak ipsilateral (left columns) and contralateral (right columns) EMG (EMG_peak) responses to intravenous delivery of CX717, CX1739, or vehicle (2-hydroxypropyl-beta-cyclodextrin [HPCD]) are shown. Data are expressed as mean (diamond) ± standard error, with individual data points: CX717 (blue, n = 9), CX1739 (red, n = 8), and HPCD (black, n = 8) groups. Data are from Rana et al. [95] with permission from the publisher.

Figure 5.. Impact of ampakine treatment on cystometric bladder function.

A) Example trace of bladder cystometry in intact animals (left column) and in SCI rats five days following spinal cord injury (right column) following HPCD or ampakine CX1739 infusion (5 mg/kg, 10 mg/kg, 15 mg/kg). (B-E) Summary of the impact of ampakine treatment on cystometric outcomes in intact (n=8) and SCI (n=7) rats. Ampakine treatment significantly reduced the intercontraction interval, voided volume, and threshold pressure in injured rats. HPCD did not alter cystometry parameters compared to baseline. Ampakine treatment caused a decrease in threshold and peak pressure but did not affect intercontraction interval or voided volume in intact rats. B) Intercontraction interval (s); C) Peak pressure (cmH₂O); D) Voided volume (μl); E) Threshold pressure (cmH₂O). Data are presented as line plots with the mean for all individual data points. Group means are represented with a diamond and error bars depict ± SE. Data are from Rana et al. [109] with permission from the publisher.