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.