Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

Abstract

The excitatory neurotransmission of the central nervous system (CNS) mainly involves glutamate and its receptors, especially N-methyl-D-Aspartate receptors (NMDARs). These receptors have been extensively described on neurons and, more recently, also on other cell types. Nowadays, the study of their differential expression and function is taking a growing place in preclinical and clinical research. The diversity of NMDAR subtypes and their signaling pathways give rise to pleiotropic functions such as brain development, neuronal plasticity, maturation along with excitotoxicity, blood-brain barrier integrity, and inflammation. NMDARs have thus emerged as key targets for the treatment of neurological disorders. By their large extracellular regions and complex intracellular structures, NMDARs are modulated by a variety of endogenous and pharmacological compounds. Here, we will present an overview of NMDAR functions on neurons and other important cell types involved in the pathophysiology of neurodegenerative, neurovascular, mental, autoimmune, and neurodevelopmental diseases. We will then discuss past and future development of NMDAR targeting drugs, including innovative and promising new approaches.

Keywords: NMDA receptors; blood-brain barrier; central nervous system; excitotoxicity; inflammation; neurological diseases; therapeutic strategies.

Figure 1

Pharmacological compounds targeting the NMDARs and their associated mechanisms. CAPON: Carboxy-terminal PDZ ligand of nNOS; PSD-95: postsynaptic density 95 kD protein; PTEN: phosphatase and tensin homolog.

Figure 2

Potential mechanisms of action of innovative therapeutic drugs targeting either neuronal or endothelial NMDARs.